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APPLICATION NUMBER:

209500Orig1s000

MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 209500 Multi-disciplinary Review and Evaluation Caplyta ()

NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 209500 Priority or Standard Standard Submit Date(s) September 27, 2018 Received Date(s) September 27, 2018 PDUFA Goal Date December 27, 2019 Division/Office Division of / Office of Drug Evaluation-I Review Completion Date December 20, 2019 Established/Proper Name Lumateperone (Proposed) Trade Name Caplyta Pharmacologic Class Atypical Code name ITI-007 Applicant Intra-Cellular Therapies, Inc. Dosage form 42 mg Capsules Applicant proposed Dosing 42 mg by mouth once daily Regimen Applicant Proposed /Adults Indication(s)/Population(s) Applicant Proposed 58214004 | Schizophrenia (disorder) SNOMED CT Indication Disease Term for each Proposed Indication

Recommendation on Approval Regulatory Action Recommended Schizophrenia/Adults Indication(s)/Population(s) (if applicable) Recommended SNOMED 58214004 | Schizophrenia (disorder) CT Indication Disease Term for each Indication (if applicable) Recommended Dosing 42 mg by mouth once daily Regimen

1 Version date: October 12, 2018

Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Table of Contents Table of Tables ...... 5 Table of Figures ...... 10 Reviewers of Multi-Disciplinary Review and Evaluation ...... 12 Glossary ...... 16 1 Executive Summary ...... 18 Product Introduction ...... 18 Nomenclature...... 18 Conclusions on the Substantial Evidence of Effectiveness ...... 18 Benefit-Risk Assessment ...... 20 Patient Experience Data ...... 30 2 Therapeutic Context ...... 31 Analysis of Condition ...... 31 Analysis of Current Treatment Options ...... 32 3 Regulatory Background ...... 33 U.S. Regulatory Actions and Marketing History ...... 33 Summary of Presubmission/Submission Regulatory Activity ...... 33 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ...... 36 Office of Scientific Investigations ...... 36 Product Quality ...... 37 Clinical Microbiology ...... 37 Devices and Companion Diagnostic Issues ...... 37 5 Nonclinical Pharmacology/Toxicology...... 38 Executive Summary ...... 38 Referenced NDAs, BLAs, DMFs ...... 44 Pharmacology ...... 45 ADME/PK ...... 54 Toxicology ...... 70 General Toxicology ...... 70 Genetic Toxicology ...... 101 Carcinogenicity ...... 103 Reproductive and Developmental Toxicology ...... 104 Other Toxicology Studies ...... 120

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

6 Clinical Pharmacology ...... 123 Executive Summary ...... 123 Summary of Clinical Pharmacology Assessment ...... 125 6.2.1 Pharmacology and Clinical ...... 125 6.2.2 General Dosing and Therapeutic Individualization ...... 126 Comprehensive Clinical Pharmacology Review ...... 128 6.3.1 General Pharmacology and Pharmacokinetic Characteristics ...... 128 6.3.2 Clinical Pharmacology Questions ...... 129 7 Sources of Clinical Data and Review Strategy ...... 142 Table of Clinical Studies ...... 142 Review Strategy ...... 145 Description of Efficacy and Safety Assessments ...... 145 8 Statistical and Clinical Evaluation ...... 150 Review of Relevant Individual Trials Used to Support Efficacy ...... 150 Study ITI-007-005 (Study 005; ClinicalTrials.gov Identifier NCT01499563) ...... 150 Study ITI-007-005 Results ...... 158 Study ITI-007-301 (Study 301; ClinicalTrials.gov Identifier NCT02282761) ...... 170 Study ITI-007-301 Results ...... 178 Study ITI-007-302 (Study 302: ClinicalTrials.gov Identifier NCT02469155) ...... 189 Study ITI-007-302 Results ...... 198 Assessment of Efficacy across Trials ...... 209 Integrated Assessment of Effectiveness ...... 215 Review of Safety ...... 216 Safety Review Approach ...... 216 Review of the Safety Database ...... 216 Adequacy of Applicant’s Clinical Safety Assessments ...... 217 Safety Results ...... 218 Analysis of Submission-Specific Safety Issues ...... 237 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 239 Safety Analyses by Demographic Subgroups ...... 240 Specific Safety Studies/Clinical Trials ...... 240 Additional Safety Explorations ...... 256 Expectations on Safety in the Postmarket Setting ...... 257 Integrated Assessment of Safety ...... 257 Statistical Issues ...... 258 Conclusions and Recommendations ...... 258 3 Version date: October 12, 2018

Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

9 Advisory Committee Meeting and Other External Consultations ...... 260 10 Pediatrics ...... 261 11 Labeling Recommendations ...... 262 12 Risk Evaluation and Mitigation Strategies ...... 264 13 Postmarketing Requirements and Commitments ...... 265 14 Appendices ...... 268 References ...... 268 Financial Disclosure ...... 271 Nonclinical Pharmacology/Toxicology...... 273 OCP Appendices (Technical documents supporting OCP recommendations) ...... 275 Statistical Appendices ...... 287 MedDRA Terms Included in Custom MedDRA Queries Used for Analysis of Data on Treatment-Emergent Adverse Events ...... 292 Internal FDA Pathology Consult for Lumateperone: Brain and Spinal Cord Glass Slide Review of the 9-month Dog and 2-Year Rat Studies ...... 306

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Table of Tables

Table 1. In Vitro Binding Affinity (Ki) of Lumateperone at 5-HT2A and D2 Receptors ...... 45 Table 2. In Vitro Binding Affinity (Ki) of Lumateperone at SERT and D1, D4, α1B Receptors ...... 46 Table 3. In Vitro Binding Affinity (Ki) of Pharmacologically Active Metabolites at SERT and 5- HT2A, D1, D2, D4, and α1B Receptors ...... 47 Table 4. In Vitro Functional Activity of Lumateperone at Human D2 Receptors ...... 48 Table 5. Exposure to IC201337 and IC201338 in Plasma Following Administration of Lumateperone to Rats in Study No. 11220 ...... 61 Table 6. Exposure to IC201337 and IC201338 in Plasma Following Administration of Lumateperone to Dogs in Study No. 11221 ...... 61 Table 7. Exposure to IC201337 and IC201338 in Plasma Following Administration of IC200131 to Dogs in Study No. 11602 ...... 62 Table 8. TK of Lumateperone and Metabolites in Rats Following 26-Weeks Oral Administration ...... 69 Table 9. TK of Lumateperone and Metabolites in Dogs Following 39-weeks Oral Administration ...... 70 Table 10. Study Design, 6 Month Rat Toxicology Study ...... 72 Table 11. Incidence of Neuronal Pigmentation in the Brain and Spinal Cord Following Administration of Lumateperone to Rats for 6-Months...... 77 Table 12. Incidence and Severity of Lesions in the Eye Following Administration of Lumateperone to Rats for 6-Months...... 78 Table 13. Incidence and Severity of Lesions in the Heart Following Administration of Lumateperone to Rats for 6-Months...... 78 Table 14. Incidence and Severity of Lesions in the Sciatic Nerve Following Administration of Lumateperone to Rats for 6-Months...... 78 Table 15. Study Design, Rat Carcinogenicity Study...... 80 Table 16. Incidence of Adverse Clinical Signs Following Administration of Lumateperone in the Rat Carcinogenicity Study ...... 80 Table 17. Incidence and Severity of Lesions in the Eye Following Administration of (b) (4) Lumateperone to Rats in the Carcinogenicity Study ...... 85 Table 18. Incidence and Severity of Lesions in the Heart Following Administration of Lumateperone to Rats in the Carcinogenicity Study...... 86 Table 19. Incidence of Neuronal Pigmentation in the Brain and Spinal Cord Following (b) (4) Administration of Lumateperone to Rats in the Carcinogenicity Study ...... 87 Table 20. Incidence and Severity of Selected Lesions in the Peripheral Nervous System Following (b) (4) Administration of Lumateperone to Rats in the Carcinogenicity Study ...... 87 Table 21. Incidence and Severity of Lesions in the Brain Following Administration of Lumateperone to Dogs for 3-Months...... 91 Table 22. Incidence and Severity of Lesions in the Spinal Cord Following Administration of Lumateperone to Dogs for 3-Months...... 91 5 Version date: October 12, 2018

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Table 23. Incidence and Severity of Lesions in the Brain Following Administration of Lumateperone to Dogs for 9-Months...... 96 Table 24. Incidence and Severity of Lesions in the Spinal Cord Following Administration of Lumateperone to Dogs for9-Months...... 98 Table 25. Incidence of Intracellular Pigment Accumulation in the Brain and Spinal Cord Following Administration of Lumateperone to Mice for 3-Months...... 99 Table 26. Incidence of Intracellular Pigment Accumulation in the Brain and Spinal Cord Following Administration of Lumateperone to Mice in the Carcinogenicity Study...... 101 Table 27. Incidence and Severity of Sciatic Nerve Axonal Degeneration Following Administration of Lumateperone to Mice in the Carcinogenicity Study...... 101 Table 28: Drug-related Clinical Observations during the Pre-mating Treatment Period in the Rat Fertility Study ...... 108 Table 29: Drug-related Abnormal Female Estrous Cycles in the Rat Fertility Study ...... 108 Table 30: Drug-related Decreases in Sperm Parameters in the Rat Fertility Study ...... 108 Table 31: Drug-related Decreases in Mating and Fertility Indices in the Rat Fertility Study ..... 109 Table 32: Mating Performance to Untreated Naive Females in the Rat Fertility Study ...... 109 Table 33: Drug-related Gross Pathology Findings in the Rat Fertility Study ...... 109 Table 34: Drug-related Histopathology Findings in the Rat Fertility Study ...... 109 Table 35: Drug-related Decreases in Fetal Weight in the Rat Embryo-fetal Developmental Study ...... 112 Table 36: Drug-related Clinical Signs in the Rat Embryo-fetal Developmental Toxicity Study with the Metabolite IC200131 ...... 116 Table 37: Drug-related Decreases in Fetal Weights in the Rat Embryo-fetal Developmental Toxicity Study with the Metabolite IC200131 ...... 116 Table 38: Drug-related Fetal Visceral and Skeletal Malformations in the Rat Embryo-fetal Developmental Toxicity Study with the Metabolite IC200131...... 117 Table 39: Drug-related Decreases in F1 Pup Viability in the Rat Pre- and Post-natal Developmental Toxicity Study ...... 120 Table 40: Decreases in F1 Pup Body Weight Relative to Vehicle Control in the Rat Pre- and Post- natal Developmental Toxicity Study ...... 120 Table 41. Lysosomal Trapping Potential of Lumateperone and Metabolites ...... 121 Table 42: Binding Affinities of ITI-007 and Its Major Metabolites ...... 131 Table 43: Relative Abundance of Metabolite to ITI-007 Following Administration of 42 mg ITI- 007 for 5 Days ...... 131 Table 44: Statistical Comparisons of Plasma PK Parameters for Lumateperone, IC200161, IC201308 and IC200131: Hepatic Impairment versus Normal Function (%Geomean Ratio [90% CI]) ...... 132 Table 45 : Statistical Comparisons of Plasma PK Parameters for Lumateperone, IC200161, IC201308 and IC200131: Renal Impairment versus Normal Function (%Geomean Ratio [90% CI]) ...... 133 Table 46: Statistical Analysis of Plasma Pharmacokinetic Parameters of ITI-007 (IC200056) and Major Metabolites: Rifampin/ITI-007 vs ITI-007 (% geomean ratio [90%CI]) ...... 135

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Table 47: Statistical Analysis of Plasma PK Parameters of IC200056 and Major Metabolites: /ITI-007 vs ITI-007 (% geomean ratio [90%CI]) ...... 136 Table 48: Statistical Analysis of Plasma PK Parameters of IC200056 and Major Metabolites: /Lumateperone vs Lumateperone (% geomean ratio [90%CI]) ...... 136 Table 49: Summary Statistics of the Plasma PK Parameters of IC200056 and Metabolite IC200131, IC200161 and IC200565: Fed vs Fasted (%Geomean Ratio, [90%CI]) ...... 137 Table 50: Statistical Analysis of Plasma PK Parameters of Midazolam and 1-Hydroxymidazolam: ITI-007/Midazolam vs Midazolam (% geomean ratio [90%CI]) ...... 137 Table 51: Listing of Clinical Trials to Support Efficacy and Safety ...... 143 Table 52: Study 005: Schedule of Assessments ...... 154 Table 53: Study 005: Disposition of Randomized Patients ...... 159 Table 54: Study 005: Major Protocol Deviations ...... 160 Table 55: Study 005: Demographic Characteristics, Intent-to-Treat Population ...... 161 Table 56: Study 005: Baseline Clinical Characteristics, ITT Population ...... 163 Table 57: Study 005: , Benztropine, and Use, ITT Population ...... 165 Table 58: Study 005: Primary Efficacy Results ...... 165 Table 59: Study 005: Exploratory Subgroup Analysis by Sex ...... 168 Table 60: Study 005: Exploratory Subgroup Analysis by Race ...... 169 Table 61: Study 301: Schedule of Assessments ...... 174 Table 62: Study 301: Disposition of Randomized Patients ...... 179 Table 63: Study 301: Major Protocol Deviations, Intent-to-Treat Population ...... 180 Table 64: Study 301: Demographic Characteristics, Safety Population ...... 182 Table 65: Study 301: Baseline Clinical Characteristics, ITT Population ...... 183 Table 66: Study 301: Primary Efficacy Results ...... 185 Table 67: Study 301: Exploratory Subgroup Analysis by Sex ...... 188 Table 68: Study 301: Exploratory Subgroup Analysis by Race ...... 188 Table 69: Study 302: Schedule of Assessments ...... 194 Table 70: Study 302: Disposition of Randomized Patients ...... 199 Table 71: Study 302: Major Protocol Deviations, Intent-to-Treat Population ...... 200 Table 72: Study 302: Demographic Characteristics, Safety Population ...... 202 Table 73: Study 302: Baseline Clinical Characteristics, ITT Population ...... 204 Table 74: Study 302: Primary Efficacy Results ...... 205 Table 75: Difference in Least Squares Means for Primary Efficacy Endpoints (Placebo-subtracted Change in PANSS Total Score) for the Three Controlled Studies ...... 210 Table 76: Study 005: Questions from PANSS Showing Improvement from Baseline, Lumateperone 84-mg Treatment Group (N=81) ...... 213 Table 77: Study 005: Questions from PANSS Showing Worsening from Baseline, Lumateperone 84-mg Treatment Group (N=81) ...... 214 Table 78: Safety Population, All Randomized, Double-blind, Placebo-controlled Trials (Studies 005, 301, and 302) ...... 217 Table 79: Listing of treatment-emergent SAEs in Study 303 (all patients receiving lumateperone 42 mg) ...... 219

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Table 80: Study 005: Discontinuations of Study Drug Due to Treatment-Emergent Adverse Event or Lack of Efficacy ...... 223 Table 81: Study 301: Discontinuations of Study Drug Due to Treatment-Emergent Adverse Event or Lack of Efficacy ...... 224 Table 82: Study 302: Discontinuations of Study Drug Associated with Treatment-Emergent Adverse Event or Lack of Efficacy ...... 224 Table 83: Laboratory Finding Treatment-Emergent Adverse Events Occurring in ≥2 Subjects Receiving Lumateperone in Studies 005, 301, and 302 ...... 226 Table 84: Study 005: Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients Treated with Lumateperone and More Frequently than in Patients Treated with Placebo, Safety Population ...... 227 Table 85: Study 301: Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients Treated with Lumateperone and More Frequently than in Patients Treated with Placebo, Safety Population ...... 228 Table 86: Study 302: Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients Treated with Lumateperone and More Frequently than in Patients Treated with Placebo, Safety Population ...... 229 Table 87: Studies 005, 301, and 302: Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients Treated with Lumateperone 42 mg and More Frequently than in Patients Treated with Placebo, Safety Population ...... 230 Table 88: Study 005: Total , Mean Change from Baseline to End of Treatment ..... 231 Table 89: Study 005: Glucose, Mean Change from Baseline to End of Treatment ...... 231 Table 90: Study 005: Prolactin, Mean Change from Baseline to End of Treatment ...... 232 Table 91: Study 005: Triglycerides, Mean Change from Baseline to End of Treatment ...... 232 Table 92: Study 005: Body Weight, Mean Change from Baseline to End of Treatment ...... 233 Table 93: Study 301: Hemoglobin A1c. Mean Change from Baseline to End of Treatment ...... 233 Table 94: Study 302: Hemoglobin A1c. Mean Change from Baseline to End of Treatment ...... 234 Table 95: Study 302: Prolactin, Mean Change from Baseline to End of Treatment ...... 234 Table 96: Study 302: Triglycerides, Mean Change from Baseline to End of Treatment ...... 234 Table 97: Subjects with Markedly Abnormal Post-Baseline Vital Sign Values, Studies 005, 301, and 302 ...... 236 Table 98: Subjects with Treatment-Emergent Extrapyramidal Symptoms (Studies 005, 301, 302) ...... 237 Table 99: Study 303: Schedule of Assessments ...... 240 Table 100: Study 303: Change in Lab Values Following Long-Term Exposure to Lumateperone ...... 242 Table 101. Incidence and Severity of Histopathology Findings Following Administration of Lumateperone to Rats for up to 6-Months ...... 273 Table 102. Incidence and Severity of Histopathology Findings Following Administration of Lumateperone to Dogs for 9-Months...... 275 Table 103: Mass Balance Study in Humans, Dogs and Rats Using 14C-Labeled Lumateperone . 276 Table 104. Population demographics all together and stratified by study...... 285

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Table 105. Final model (Model 3499) parameter estimates and precisions (root mean square errors percent, RSE%), together with parameter medians and confidence intervals (95%) obtained from bootstrap analysis...... 286 Table 106: Discontinuation Reasons Study 005 ...... 287 Table 107: Discontinuation Reasons Study 301 ...... 287 Table 108: Discontinuation Reasons Study 302 ...... 288

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Table of Figures

Figure 1. Inhibition of Serotonin-induced [3H] Phosphate (IP) Accumulation by Lumateperone in HEK Cells Expressing Human 5-HT2A Receptors ...... 48 Figure 2. Heat Map Representation Showing Phosphorylation-Site Responses ...... 50 Figure 3. Dopamine Levels in the of Rats Following Administration of Lumateperone 51 Figure 4. Dopamine Levels in the mPFC of Rats Following Administration of Lumateperone ..... 52 Figure 5. Putative Lumateperone Metabolic Scheme ...... 67 Figure 6. Putative Mechanism for Metabolite Formation ...... 68 Figure 7. Putative Mechanism for Metabolic Activation of ...... 68 Figure 8. Relationships of Dose-Benefit (Left) and Dose-Risk (Right) ...... 130 Figure 9. Mean (+/-) SD Dose Normalized Lumateperone Concentrations by Age (<50y, ≥50y) from Studies ITI-007-002, ITI-007-006 and ITI-007-009...... 134 Figure 10. Mean (+/-) SD Dose Normalized Lumateperone Concentrations by Race (Caucasian, Black) from Studies ITI-007-002, ITI-007-006 and ITI-007-009...... 134 Figure 11. Mean (+/-) SD Dose Normalized Lumateperone Concentrations by Sex (Male, Female) from Studies ITI-007-002, ITI-007-006 and ITI-007-009...... 135 Figure 12: Representative Chromatograms For IC201337(A) And IC201338(B) ...... 140 Figure 13: Study 005: Design Schematic ...... 151 Figure 14. Primary Efficacy Endpoint (Change from Baseline in PANSS Total Score to Day 28) [Study 005, ITT set] ...... 166 Figure 15. Percent of Patients with Specified Magnitude of PANSS Total Score Improvement at the End of Week 4 [Study 005, ITT set] ...... 167 Figure 16: Study 301: Design Schematic ...... 171 Figure 17. Primary Efficacy Endpoint (Change from Baseline in PANSS Total Score to Day 28) [Study 301, ITT set] ...... 185 Figure 18. Percent of Patients with Specified Magnitude of PANSS Total Score Improvement at the End of Week 4 [Study 301, ITT set] ...... 186 Figure 19: Study 302: Design Schematic ...... 191 Figure 20. Primary Efficacy Endpoint (Change from Baseline in PANSS Total Score to Day 42) [Study 302, ITT set] ...... 206 Figure 21. Percent of Patients with Specified Magnitude of PANSS Total Score Change at the End of Week 6 [Study 302, ITT set] ...... 207 Figure 22. PANSS Total Score LS Mean Change from Baseline (42 mg Lumateperone vs. Placebo) by Study [ITT set] ...... 212 Figure 23: Study 303: Serum Glucose Results ...... 244 Figure 24: Study 303: Serum Insulin Results ...... 245 Figure 25: Study 303: Serum Hemoglobin A1c Results ...... 246 Figure 26: Study 303: Serum High-Density Lipoproteins ...... 247 Figure 27: Study 303: Serum Low-Density Lipoproteins ...... 248 Figure 28: Study 303: Serum Total Cholesterol ...... 249 Figure 29: Study 303: Serum Triglycerides ...... 250 10 Version date: October 12, 2018

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Figure 30: Study 303: Serum Creatine Phosphokinase ...... 251 Figure 31: Study 303: Serum Alanine Aminotransferase ...... 252 Figure 32: Study 303: Serum Aspartate Aminotransaminase ...... 253 Figure 33: Study 303: Serum Gamma-Glutamyl Transferase ...... 254 Figure 34: Study 303: Serum Lactate Dehydrogenase ...... 255 Figure 35: Pathways to Formation of Lumateperone Major Unconjugated Metabolites ...... 277 Figure 36: Relative Exposure of Unconjugated Metabolites to Lumateperone at Steady State 278 Figure 37: Formation of Aniline Metabolites ...... 278 Figure 38: Plasma Concentration Time Profile of M337 and M338 on Day 280 Following Daily Oral Administration of Lumateperone (1.75 or 3.5 mg/kg/day) in Dogs ...... 279 Figure 39: Dog Plasma Radiochromatogram ...... 280 Figure 40: Human Plasma Radiochromatogram ...... 281 Figure 41: Representative Chromatograms For IC201337(A) And IC201338(B) ...... 283 Figure 42. Integrated PK model for parent drug (IC200056) and direct metabolites IC200131 and IC200161, including first pass effect description. Compartments numeration is indicated at their left bottom angle...... 284 Figure 43: PANSS trajectories (observed) and dropout reasons (Study 301) ...... 289 Figure 44: PANSS trajectories (observed) and dropout reasons (Study 301) ...... 290 Figure 45: PANSS trajectories (observed) and dropout reasons (Study 302) ...... 291 Figure 46: PANSS trajectories (observed) and dropout reasons (Study 302) ...... 292

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Reviewers of Multi-Disciplinary Review and Evaluation

Regulatory Project Manager Jasmeet (Mona) Kalsi Nonclinical Reviewer Darren Fegley Nonclinical Team Leader Ikram Elayan Associate Director for Pharmacology/Toxicology Paul Brown Office of Clinical Pharmacology Reviewer(s) Huixia Zhang Pharmacometrics reviewer Atul Bhattaram Office of Clinical Pharmacology Team Leader(s) Luning (Ada) Zhuang Clinical Pharmacology Division Director Mehul Mehta Clinical Reviewer David Millis Clinical Team Leader Michael Davis Statistical Reviewer Thomas Birkner Statistical Team Leader Peiling Yang Division Director (OB) Jim Hung Cross-Disciplinary Team Leader Michael Davis Division Director, Psychiatry Tiffany R Farchione Office Director (Office of Drug Evaluation-I) Ellis Unger

Additional Reviewers of Application OPQ • David Claffey • Teshara Bouie • Rajan Pragani (Drug Substance) • Mari Chelliah (Drug Product) • Zhong Li (Process and Facilities) • Ron Bloom (Environmental Assessment) • OPTIONAL: Wendy Wilson Microbiology N/A OPDP Domenic D’Alessandro/Aline Moukhtara OSI Cara Alfaro/Philip Kronstein(TL) OSE/DEPI Vicky Chan OSE/DMEPA Loretta Holmes OSE/DRISK Sangeeta Tandon/Selena Ready(TL) Other DPMH: • Peds: Lily Mulugeta (TL: Hari Sachs) – not a part of the review • Maternal: Kristie Baisden (TL: Tamara Johnson) OCP Pharmacometrics: Atul Bhattaram (popPK and ER) OPQ=Office of Pharmaceutical Quality; OPDP=Office of Prescription Drug Promotion; OSI=Office of Scientific Investigations; OSE= Office of Surveillance and Epidemiology; DEPI= Division of Epidemiology; DMEPA=Division of Error Prevention and Analysis; DRM=Division of Risk Management

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Signatures

SECTIONS AUTHORED/ DISCIPLINE REVIEWER OFFICE/DIVISION AUTHORED/ APPROVED APPROVED Select one: Darren B. Fegley, PhD, ON/DPT-N Sections: 5 _X_ Authored Nonclinical Reviewer DABT ___ Approved

Signature: See appended electronic signature

Select one: Ikram Elayan, ON/DPT-N Sections: 5 ___ Authored PhD Nonclinical Supervisor _X_ Approved

Signature: See appended electronic signature

Select one: Paul Brown, OND/IO Sections: 5 ___ Authored PhD Associate Director _X_ Approved Pharmacology/Toxicology Signature: See appended electronic signature

Select one: Huixia Zhang, Sections: 6, 14.4.1, OCP/DNP _X__ Authored Clinical Pharmacology PhD and 14.4.3 ___ Approved Reviewer Signature: See appended electronic signature

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

SECTIONS AUTHORED/ DISCIPLINE REVIEWER OFFICE/DIVISION AUTHORED/ APPROVED APPROVED Select one: Luning (Ada) Zhuang, OCP/DNP Section: 6 and 14.4 ___ Authored Clinical Pharmacology PhD Team Leader _ X __ Approved Signature: See appended electronic signature Select one: Atul Bhattaram, PhD OCP/DPM Section: 6 and 14.4.2 _X__ Authored Pharmacometrics Team ___ Approved Leader/Reviewer Signature: See appended electronic signature

Select one: Mehul Mehta, PhD OCP/DNP Section: 6 and 14.4 ___ Authored Clinical pharmacology _ X __ Approved Division Director Signature: See appended electronic signature

Select one: David H. Millis, MD, Sections: 7, 8, 9, 10, ON/DP _X__ Authored PhD 11, 12, 13 Clinical Reviewer ____ Approved

Signature: See appended electronic signature

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

SECTIONS AUTHORED/ DISCIPLINE REVIEWER OFFICE/DIVISION AUTHORED/ APPROVED APPROVED Select one: Sections: 1 (Authored); Michael Davis, ON/DP 2, 3, 4, 7, 8, 9, 10, 11, _X__ Authored Clinical Team MD, PhD 12, 13 (Approved) _X__ Approved Leader Signature: See appended electronic signature

Select one: Tiffany R ___ Authored ON/DP Sections: 1-14 Division Director Farchione, MD _X_ Approved (Clinical) Signature: See appended electronic signature

Select one: Ellis Unger, Office of Drug Evaluation-I Sections: 1-14 ___ Authored Office Director MD (ODE I) _X_ Approved Signature: See appended electronic signature

Select one: Thomas OTS/OB/DB1 Sections: 8.1, 8.3 _X_ Authored Statistical Birkner, PhD ___ Approved Reviewer Signature: See appended electronic signature

Select one: Peiling Yang, OTS/OB/DB1 Sections: 8.1, 8.3 ___ Authored Statistical Team PhD _X_ Approved Leader Signature: See appended electronic signature

Select one: Jim Hung, PhD OTS/OB/DB1 Sections: 8.1, 8.3 ___ Authored Division Director _X__ Approved (OB) Signature: See appended electronic signature

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Glossary

ADME absorption, distribution, metabolism, AE adverse event AIMS Abnormal Involuntary Movement Scale AKR aldo-keto reductase BARS Barnes Akathisia Rating Scale BLA biologics license application BMI body mass index BPRS Brief Psychiatric Rating Scale CDER Center for Drug Evaluation and Research CDSS Calgary Scale for Schizophrenia CFR Code of Federal Regulations CGI-S Clinical Global Impression–Severity COA Clinical Outcome Assessment CSR clinical study report C-SSRS Columbia Severity Rating Scale DI deionized DOPAC dihydroxyphenylacetic acid DSM Diagnostic and Statistical Manual of Mental Disorders EAC Eligibility Adjudication Committee ECG electrocardiogram EPS extrapyramidal symptoms FDA Food and Drug Administration GCP good clinical practice GD gestation day GI gastrointestinal IAP interim analysis plan ICH International Council for Harmonisation IND Investigational New Drug ISS integrated summary of safety ITT intent to treat IV intravenous LD low dose LLOQ lower limit of quantification MAR missing at random MedDRA Medical Dictionary for Regulatory Activities MMRM mixed-effect model repeated measures MRHD maximum recommended human dose NDA new drug application NPC Niemann-Pick C protein OPQ Office of Pharmaceutical Quality 16 Version date: October 12, 2018

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OSI Office of Scientific Investigation PANSS Positive and Negative Syndrome Scale PK pharmacokinetics PMC postmarketing commitment PMR postmarketing requirement PND postnatal day PRO patient-reported outcome PSP Personal and Social Performance Scale PSQI Pittsburgh Quality Index REMS risk evaluation and mitigation strategy SAE serious adverse event SAP statistical analysis plan SAS Simpson-Angus Scale TEAE treatment emergent adverse event

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1 Executive Summary

Product Introduction

Lumateperone (ITI-007, proposed trade name: Caplyta) is a new molecular entity that has been developed for the treatment of schizophrenia. Lumateperone is also being developed for the treatment of sleep disorders, depression, and other neuropsychiatric and neurological disorders. Lumateperone appears to function as a serotonin 5HT2A and postsynaptic dopamine D2 . In addition, lumateperone displays relatively high binding affinity for the (SERT).

In this new drug application (NDA), the Applicant is proposing that lumateperone be approved for the treatment of schizophrenia in adults. The proposed dosing regimen is 42 mg once daily by mouth. The application includes the results from three randomized, double-blind, placebo- controlled trials designed to evaluate the safety and efficacy of lumateperone for the treatment of schizophrenia, as well as one 12-month uncontrolled safety study.

Nomenclature

In the nonclinical and clinical study reports, study drug doses were expressed as milligrams of lumateperone tosylate, a salt of lumateperone. For the product label, drug doses will be expressed as milligrams of lumateperone free base. To maintain consistency with the doses presented in the label, drug doses will be expressed as milligrams of lumateperone free base throughout this document. To convert a quantity of the base to the equivalent quantity of the salt, the dose of the base is multiplied by 1.43 (i.e., 42 mg lumateperone free base = 60 mg lumateperone tosylate).

Conclusions on the Substantial Evidence of Effectiveness

Substantial evidence is defined in Section 505(d) of the Federal Food, Drug, and Cosmetic Act as “evidence consisting of adequate and well-controlled investigations [note plurality]…by experts qualified…to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded…that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling….”. Based on the plural form of the word “investigations,” substantial evidence of effectiveness generally requires at least two adequate and well-controlled investigations.

The Applicant provided results of two clinical studies (Studies 005 and 301) that met their primary efficacy endpoint for the 42-mg lumateperone dose. Both Studies 005 and 301 are considered to be adequate and well-controlled investigations. The primary efficacy measure (Positive and Negative Syndrome Scale) is accepted for use in demonstrating the efficacy of for the treatment of schizophrenia. Of note, the results from a third adequate and well-

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controlled trial described in this review (Study 302) did not provide evidence that lumateperone was superior to placebo for the treatment of schizophrenia. Although the results from Study 302 raised questions about the magnitude and reliability of the lumateperone treatment effect, these findings did not change the overall conclusion of effectiveness for the 42-mg dose as demonstrated by Studies 005 and 301.

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Benefit-Risk Assessment

Benefit-Risk Summary and Assessment

Lumateperone is an atypical antipsychotic that has been developed for the treatment of schizophrenia in adults. The drug is intended to reduce the symptoms of schizophrenia, which include , delusions, and disorganized thinking and behavior. We recommend that lumateperone be approved for the treatment of schizophrenia in adults.

Schizophrenia is a serious condition, associated with significant disability and a shortened life expectancy. The current standard of care for schizophrenia includes treatment of exacerbations of psychotic symptoms with antipsychotic drugs, with treatment continued indefinitely to reduce the risk of relapses. Nonadherence to is common in individuals with schizophrenia and can lead to acute exacerbations of psychotic symptoms, psychiatric hospitalization, and other adverse outcomes. With the exception of (which is indicated for treatment-resistant schizophrenia), currently marketed antipsychotics appear to differ mostly in their safety profiles. Overall, the needs of the schizophrenia patient population are only partially met by currently available drugs. Most patients do not achieve full remission of schizophrenia symptoms, and current drugs are generally ineffective for negative symptoms and cognitive deficits of schizophrenia.

Lumateperone 42 mg was demonstrated to be superior to placebo on the primary efficacy endpoint in two 4-week studies (Studies 005 and 301). Both of these studies are considered to be adequate and well-controlled investigations. Although the mean placebo-subtracted treatment effects were modest, ranging from -4 to -6 on the Positive and Negative Syndrome Scale (PANSS) total score (range of baseline mean scores: 85 to 90), response distribution histograms illustrate that a greater percentage of patients receiving lumateperone 42 mg experienced large improvements on the PANSS (i.e., >30-point decrease) than those receiving placebo. Thus, the benefit is expected to be clinically meaningful for a substantial proportion of patients who receive the treatment. Of note, although the Applicant assessed 14-mg, 28-mg, 42-mg, and 84-mg doses in placebo-controlled efficacy studies, only the 42-mg dose was found to be efficacious. Although there are many antipsychotics approved for the treatment of schizophrenia, patients often require trials of numerous antipsychotics over the course of the illness before an optimal treatment is identified. Thus, having an additional antipsychotic in the treatment armamentarium provides some value to patients.

The safety database included 1724 patients exposed to lumateperone, 811 of whom were exposed in the three placebo-controlled Studies 005, 301, and 302. The safety database included 329 patients exposed to lumateperone 42 mg for ≥6 months and 108 patients for 12 months, which were adequate durations of exposure to facilitate premarketing characterization of safety. The most common adverse reactions to lumateperone were /sedation, , dry mouth, dizziness, and creatine phosphokinase increased. Based on review of metabolic changes (e.g., hyperglycemia, dyslipidemia, weight gain) across the studies, lumateperone is expected to have a qualitatively lower (but non- 20 Version date: October 12, 2018

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negligible) risk of metabolic changes compared to many other atypical antipsychotics. The most concerning potential safety concern for lumateperone, discussed at length in this review, was based on findings from nonclinical studies in dogs and rats that were attributed to exposure to aniline metabolites. Humans receiving lumateperone for up to 12 months did not exhibit adverse events suggestive of those observed in dogs and rats. Furthermore, the lack of quantifiable aniline metabolites in humans receiving 42 mg lumateperone, in conjunction with a plausible metabolic rationale of why anilines would accumulate in dogs and rats but not humans, provides additional support that the nonclinical safety findings are not relevant to humans. The safety concerns of lumateperone can be managed in the postmarket setting by labeling known and anticipated risks, postmarketing pharmacovigilance, and the conduct of postmarketing studies.

In conclusion, considering the balance of benefits and risks that were observed in the development program, we recommend that lumateperone 42 mg be approved for the treatment of schizophrenia in adults. The totality of evidence on benefit (including consideration of the negative results from Study 302 and the lack of efficacy for doses other than 42 mg) suggests that lumateperone 42 mg is superior to placebo, but that it is unlikely to have any meaningful efficacy advantages over other drugs in its class. Additionally, the safety findings from human studies suggest that lumateperone is unlikely to have meaningful safety disadvantages over other drugs in its class. The nonclinical safety findings, if assessed as relevant to human exposure to lumateperone, would have been sufficient to shift the benefit/risk balance against approval; however, multiple lines of evidence suggest that the nonclinical findings are not relevant to humans.

Dimension Evidence and Uncertainties Conclusions and Reasons • Schizophrenia is a serious mental illness characterized by chronic or Schizophrenia is a serious condition, associated recurrent (e.g., delusions, hallucinations, and thought with significant disability and a shortened life disorganization). expectancy. Evidence informing the • Schizophrenia is also frequently associated with negative symptoms understanding of the condition of (e.g., social withdrawal, avolition, blunted affect) and cognitive schizophrenia is from the published literature Analysis of deficits (e.g., attention, executive function, working memory, and and psychiatric textbooks, as well as clinical Condition social cognition). experience with this population. • The pathogenesis of schizophrenia is not well-understood, but it likely involves an interaction between genetic and environmental risk factors. • Individuals with schizophrenia experience significant impairments in social and occupational functioning and, on average, have a life

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Dimension Evidence and Uncertainties Conclusions and Reasons expectancy around 15 years less than individuals without schizophrenia. • Approximately 50% of individuals with schizophrenia experience a relapse/exacerbation in psychotic symptoms within one year after their last episode; most relapses occur in the context of medication nonadherence. • The worldwide prevalence of schizophrenia is approximately 0.5 to 1%, and schizophrenia is one of the leading causes of years lost due to disability worldwide. • Antipsychotics are the first-line medication therapy for schizophrenia; Antipsychotics reduce the severity of positive current practice guidelines recommend that antipsychotics should be symptoms of schizophrenia and the risk of initiated as soon as possible in an acute schizophrenia exacerbation psychosis exacerbations. Nonadherence to and continued indefinitely to reduce the risk of relapse. antipsychotics is common in individuals with • Currently available antipsychotics are believed to be most effective schizophrenia and can lead to acute psychosis for reducing positive symptoms of schizophrenia (e.g., delusions, exacerbations, psychiatric hospitalization, and hallucinations, disorganized thinking and behavior). Negative other adverse outcomes. With the exception of symptoms and cognitive deficits of schizophrenia generally show little clozapine, currently available antipsychotics Current to no improvement from antipsychotic treatment. appear to differ mostly with respect to their Treatment • Antipsychotics are broadly categorized as first-generation/typical safety profiles. Options antipsychotics (e.g., , , , etc.) and second-generation/atypical antipsychotics (e.g., clozapine, Overall, this patient population’s needs are , , , and ). In general, being only partially met by currently available first-generation antipsychotics have a higher risk of extrapyramidal therapies. Most patients do not achieve full side effects than second-generation antipsychotics. remission of schizophrenia symptoms, and • Except for clozapine (which has significant evidence supporting its current are generally ineffective efficacy in patients who have not responded to other antipsychotics), for negative symptoms and cognitive deficits of antipsychotics differ mostly with respect to their safety profiles. schizophrenia. Additional treatment options However, individual patients often require trials of numerous agents that target unmet clinical needs are needed.

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Dimension Evidence and Uncertainties Conclusions and Reasons before an optimal treatment is identified. • Adverse reactions from antipsychotics vary between drugs and may Clinically, patients often require trials of include weight gain, adverse metabolic changes, extrapyramidal side numerous antipsychotics over the course of effects, increased prolactin, sedation, and QT prolongation. the illness before an optimal treatment is • In addition to antipsychotic medications, patients with schizophrenia identified. Having additional antipsychotic are frequently treated with adjunctive medications to target treatments in the armamentarium is valuable depression, , obsessions and compulsions, and side effects of to clinicians and patients. antipsychotics (e.g., dystonia, , , and akathisia). • When integrated with pharmacotherapy, psychosocial interventions have been shown to improve the course of schizophrenia. These interventions include cognitive behavioral therapy, assertive community treatment, supported employment, and social skills therapy. • The efficacy of lumateperone for the treatment of schizophrenia was The submitted evidence meets the evidentiary evaluated in three short-term randomized controlled trials: Study 005 standard for substantial evidence of (N=335; treatment arms: lumateperone 42 mg, lumateperone 84 mg, effectiveness. Specifically, lumateperone risperidone 4 mg, placebo); Study 301 (N=450; treatment arms: 42 mg was found to be superior to placebo on lumateperone 42 mg, lumateperone 28 mg, placebo); and Study 302 the primary efficacy endpoint in two 4-week (N=696; treatment arms: lumateperone 42 mg, lumateperone 14 mg, studies (Studies 005 and 301). Both of these risperidone 4 mg, placebo). studies are considered to be adequate and Benefit • The primary efficacy endpoint for Studies 005, 301, and 302 was the well-controlled investigations. Although the change from baseline to end of treatment (Day 28 for Studies 005 and mean placebo-subtracted treatment effects 301; Day 42 for Study 302) on the Positive and Negative Syndrome were modest, ranging from -4 to -6 on the Scale (PANSS) total score. The PANSS is a clinician-rated measure that PANSS total score across the studies (mean includes items assessing the severity of positive symptoms, negative baseline scores: 85 to 90), response symptoms, and general psychiatric symptoms associated with distribution histograms illustrate that a greater schizophrenia. The PANSS has been used to demonstrate the efficacy percentage of patients receiving lumateperone

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Dimension Evidence and Uncertainties Conclusions and Reasons of numerous antipsychotics approved by the FDA for the treatment of 42 mg than placebo experienced large schizophrenia. The change from baseline to end of treatment on the improvements on the PANSS (i.e., >30 points). Clinical Global Impression – Severity (CGI-S) measure was a secondary Thus, the benefit of lumateperone is expected endpoint in Study 005 and a key secondary endpoint in Studies 301 to be clinically meaningful for a substantial and 302. proportion of patients who receive the • Lumateperone 42 mg was found to be superior to placebo on the treatment. Because only one of the studied primary efficacy endpoint in Studies 005 and 301. The baseline mean doses of lumateperone was found to be PANSS total scores ranged from 85 to 90 across the treatment groups efficacious in clinical trials, the 42-mg dose will in both studies. The least-squares (LS) mean placebo-subtracted be the only recommended dose in product differences (95% confidence interval, p-value) were -5.8 (-10.5, -1.1, labeling. Although many antipsychotics are p=0.045) for Study 005 and -4.2 (-7.8, -0.6, p=0.014) for Study 301. In approved for the treatment of schizophrenia, Study 302, lumateperone 42 mg was not found to be superior to patients often require trials of numerous placebo on the primary efficacy endpoint (p=0.789). In addition, the antipsychotics over the course of their illness 84-mg, 28-mg, and 14-mg doses of lumateperone were not found to before an optimal treatment is identified. be superior to placebo in the three studies. On the key secondary Thus, having an additional antipsychotic option endpoint (CGI-S) in Study 301, lumateperone 42 mg was found to be in the treatment armamentarium is valuable. superior to placebo. • It is not entirely clear why lumateperone 42 mg was not superior to placebo in Study 302, which had the largest sample size and the longest treatment duration. The active comparator, risperidone 4 mg, separated from placebo based on the primary efficacy model (LS mean placebo-subtracted difference (95% CI) = -5.4 (-8.9, -1.9), nominal p=0.003), suggesting the study had assay sensitivity, i.e., the ability to detect a treatment effect. In comparison, lumateperone 42 mg had an LS mean placebo-subtracted difference (95%) CI) of 0.5 (- 2.9, 3.8). Based on post-hoc sensitivity analyses, the Applicant considers Study 302 to be a failed, rather than a negative, study (i.e., a study lacking assay sensitivity). Specifically, the Applicant proposed

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Dimension Evidence and Uncertainties Conclusions and Reasons that their primary efficacy analysis model was not suited for the higher discontinuation rate in the risperidone arm (37%, as compared to 21% for placebo and 25% for lumateperone 42 mg), and risperidone would not have been nominally superior to placebo with more appropriate assumptions in the model. • It is also not clear why the 84-mg dose of lumateperone was not found to be superior to placebo in Study 005, considering that most antipsychotics exhibit dose-dependent increases of efficacy up to a plateau, beyond which further dose increases do not confer additional efficacy. An FDA exploratory analysis of PANSS item-level data suggested that patients receiving lumateperone 84 mg might have experienced worsening in certain behaviors assessed by the PANSS that may have counterbalanced improvements on other items; however, this is speculative and there is not a definitive explanation for the lack of efficacy of the 84-mg dose. • There were no obvious differences in the efficacy of lumateperone 42 mg according to demographic subgroups (age, sex, race), although the studies did not have enough subjects within subpopulations to be conclusive. • Studies 005, 301, and 302 were all conducted in adult inpatients who were experiencing acute exacerbations of schizophrenia. In real-world clinical use, patients with schizophrenia are frequently initiated on antipsychotic drugs in the hospital setting to treat the acute psychotic symptoms that led to the admission. For an antipsychotic drug that is effective acutely, continuation is generally recommended following hospital discharge to reduce the risk of relapse. Although the efficacy of maintenance lumateperone treatment for reducing the risk of relapse was not assessed in the development program, there is no

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Dimension Evidence and Uncertainties Conclusions and Reasons reason to expect that it would not function similar to other antipsychotics in this context of use and reduce the likelihood of relapse.

• The safety database includes 1949 subjects who received at least one The safety profile of lumateperone is dose of lumateperone; this total includes 1724 patients with adequately characterized for the anticipated schizophrenia, 24 subjects with hepatic impairment, 24 subjects with patient population and expected long-term renal impairment, 19 subjects with , 5 geriatric subjects with use. Overall, the safety profile appears to be , and 153 healthy volunteers. A total of 811 patients with generally consistent with other atypical schizophrenia were exposed to lumateperone in the three placebo- antipsychotics (i.e., most common adverse controlled Studies 005, 301, and 302. reaction: somnolence/sedation). • At the time of submission of the 120-Day Safety Update, 329 patients Lumateperone is expected to have a had at least 6 months of exposure and 108 had at least 1 year of qualitatively lower (but non-negligible) risk of exposure to lumateperone at the 42-mg dose proposed for marketing. metabolic changes as compared to many other The extent of exposure in the safety database fulfills the minimum drugs in this class. Risk and Risk exposure recommended by guidance on the extent of population Management exposure to assess clinical safety for drugs intended for long-term The most concerning potential safety concern treatment of non-life-threatening conditions. for lumateperone, discussed at length in this • The overall understanding of the lumateperone safety profile is review, are based on findings from nonclinical informed, in part, by pre- and postmarketing safety findings for other studies in dogs and rats that were attributed to atypical antipsychotics. exposure to aniline metabolites in these • The most common adverse reactions to lumateperone 42 mg (LUM) in species. Humans receiving lumateperone for 4- to 6-week placebo-controlled trials were somnolence/sedation up to 1 year did not exhibit safety findings (24% LUM vs. 10% placebo (PBO)), nausea (9% LUM vs. 5% PBO), dry concerning such as those seen in mouth (6% LUM vs. 2% PBO), dizziness (5% LUM vs. 3% PBO), hepatic dogs and rats. Furthermore, the lack of enzymes increased (2% LUM vs. 1% PBO), creatine phosphokinase detectable aniline metabolites in humans increased (4% LUM vs. 1% PBO), fatigue (3% LUM vs. 1% PBO), and receiving 42 mg lumateperone, in conjunction vomiting (3% LUM vs. 2% PBO). with a plausible metabolic rationale of why

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Dimension Evidence and Uncertainties Conclusions and Reasons • Three deaths occurred to subjects in the lumateperone development anilines would be accumulated in dogs and rats program, only one of which occurred in a subject receiving but not humans, provides additional support lumateperone. This case was assessed as unlikely related to that the nonclinical safety findings are not lumateperone treatment because it occurred two weeks after the last relevant to humans. dose of study drug. Only two treatment-emergent serious adverse events occurred in subjects receiving lumateperone in the 4- to 6- The known risks of lumateperone use can be week placebo-controlled studies: one case of convulsive episode in a managed by product labeling, and ongoing patient receiving lumateperone 28 mg who had pre-existing risk postmarketing pharmacovigilance will be factors, and one case of agitation secondary to psychosis in a patient important to monitor safety signals that were receiving lumateperone 42 mg. In the long-term open-label study, 20 not observed in the development program. patients experienced treatment-emergent serious adverse events, the most common being worsening of schizophrenia symptoms. The The product label should include warnings and incidence of treatment discontinuation secondary to adverse events precautions for significant safety concerns was low in the 4- to 6-week placebo-controlled studies: 1.0% in anticipated based on the drug class and subjects receiving lumateperone 42 mg vs. 0.7% in subjects receiving findings from the development program; these placebo. include the potential for increased mortality in • Lumateperone did not appear to have a significant short-term risk for elderly patients with dementia-related causing metabolic changes (e.g., hyperglycemia, type 2 , psychosis; cerebrovascular adverse reactions in dyslipidemia, and changes in weight) based on analyses of 4- to 6- elderly patients with dementia-related week placebo-controlled studies. In the long-term uncontrolled study, psychosis; neuroleptic malignant syndrome; there were some patients who experienced increases in glucose, tardive dyskinesia; metabolic changes; insulin, LDL cholesterol, and weight, but overall there were no clear leukopenia, neutropenia, and agranulocytosis; trends suggesting significant concern with lumateperone. orthostatic hypotension and syncope; falls; • Concomitant use of lumateperone with moderate or strong CYP3A4 seizures; cognitive and motor impairment; inhibitors increases exposure to lumateperone. Additionally, body temperature dysregulation; and concomitant use of lumateperone with UGT inhibitors may increase dysphagia. Because it is unknown whether exposure to lumateperone and/or its metabolites. By increasing infants exposed to lumateperone (if present) in exposure to lumateperone or its metabolites, these drug-drug breast milk will exhibit comparable

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Dimension Evidence and Uncertainties Conclusions and Reasons interactions could increase the risk of adverse reactions. lumateperone metabolism and elimination • In nonclinical studies, lumateperone caused intracytoplasmic pathways as adults, the label will specify that accumulation of pigmented material at exposures relevant to human breastfeeding is not recommended during exposure. Specifically, in dogs, accumulation of pigmented material in treatment with lumateperone. the brain and spinal cord was associated with neuronal degeneration and necrosis, followed by axonal degeneration and histiocytic The Applicant will have postmarketing inflammation after oral administration of lumateperone for up to 9- requirements to conduct studies to evaluate months. Following administration of lumateperone for up to 2 years remaining safety uncertainties. These include in rats, accumulation of pigmented material was associated with conducting a lactation study to assess the adverse CNS effects (histiocytic inflammation in the brain and axonal presence of lumateperone in human milk and degeneration in the spinal cord), peripheral nervous system (satellite conducting a drug-drug interaction study to glial clusters in the dorsal root ganglia and histiocytic inflammation evaluate the impact of UGT inhibitors on the and axonal degeneration in peripheral nerves), eye (retinal pharmacokinetics of lumateperone and its degeneration and hypertrophy/hyperplasia of the retinal pigmented metabolites. Following completion of these epithelium), and heart (cardiomyopathy). Colocalization of pigmented studies, the new safety information should be material in the tissues with inflammation and degenerative changes incorporated in labeling. support the role of the pigmented materials in causing the lesions. Although the specific identities of the constituents of the pigmented material were not established, the material is thought to be composed of polymers or protein adducts formed from aniline metabolites of lumateperone that accumulate in the lysosome. • There are known differences in between human and non-human species (i.e., humans may be expected to rapidly glucuronidate and eliminate lumateperone and its metabolites prior to aniline accumulation, in contrast to nonclinical species with less prominent glucuronidation activity). It is uncertain whether infants exposed to lumateperone (if present) in breast milk will exhibit comparable lumateperone metabolism and elimination pathways as

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Dimension Evidence and Uncertainties Conclusions and Reasons adults. • The Applicant submitted bioanalytical data of plasma from humans exposed to lumateperone. At the to-be-marketed dose of 42 mg, plasma levels of the aniline metabolites implicated in the nonclinical toxicities were below the lower limit of quantification in humans. Finally, there was no evidence for the development of relevant adverse events in humans exposed to lumateperone for up to one year of treatment.

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Patient Experience Data

Patient Experience Data Relevant to this Application (check all that apply) X The patient experience data that were submitted as part of the Section of review where application include: discussed, if applicable X Clinical outcome assessment (COA) data, such as □ Patient-reported outcome (PRO) □ Observer reported outcome (ObsRO) X Clinician reported outcome (ClinRO) 8.1 □ Performance outcome (PerfO) □ Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel, etc.) □ Patient-focused drug development or other stakeholder meeting summary reports □ Observational survey studies designed to capture patient experience data Natural history studies □ □ Patient preference studies (e.g., submitted studies or scientific publications) □ Other: (Please specify): □ Patient experience data that were not submitted in the application, but were considered in this review: □ Input informed from participation in meetings with patient stakeholders □ Patient-focused drug development or other stakeholder meeting summary reports □ Observational survey studies designed to capture patient experience data □ Other: (Please specify): □ Patient experience data was not submitted as part of this application.

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2 Therapeutic Context

Analysis of Condition

Schizophrenia is a serious mental illness, characterized by a constellation of symptoms that may include delusions, hallucinations, disorganized speech, disorganized behavior, diminished emotional expression, and avolition (American Psychiatric Association 2013). Accurate diagnosis requires ruling out other potential causes of psychosis, such as other chronic psychiatric illnesses (i.e., , ), substance use, and other medical conditions.

Specific clinical features of schizophrenia are categorized as positive symptoms (e.g., hallucinations, delusions, disorganized thinking and behavior), negative symptoms (e.g., decreased expressiveness, , avolition), cognitive impairment (e.g., decreased processing speed, attention, memory, reasoning, and social cognition), and other mood and anxiety symptoms. The most widely used outcome measure used to support approval of drugs for the treatment of schizophrenia is the Positive and Negative Syndrome Scale (PANSS, discussed in detail in Section 8), which includes items assessing a broad range of clinical features.

The pathogenesis of schizophrenia is not well-understood, possibly due to the heterogeneity of the syndrome, but it likely involves an interaction between genetic (e.g., multiple genes with additive small effects, copy number variants) and environmental risk factors (e.g., obstetrical complications, maternal infections, cannabis use, and traumatic life events) (Tandon, Keshavan et al. 2008). Hypothetical neurochemical models of schizophrenia include excessive mesolimbic activity, hypoactivity of N-methyl-D-aspartate (NMDA) glutamate receptors, and dysfunctional gamma-amino-butyric acid (GABA)-mediated modulation of pyramidal neurons (Kantrowitz and Javitt 2010).

The onset of schizophrenia is typically in early adulthood, and the course of illness is heterogeneous, with many patients experiencing acute symptom exacerbations and remissions within a chronic and disabling illness. On average, the age of onset occurs 5 to 7 years later in females than males, and when the course of schizophrenia is compared between men and women, women tend to have better premorbid functioning and less prominent negative symptoms and cognitive impairment (Tandon, Nasrallah et al. 2009).

Schizophrenia is associated with significant impairments in social and occupational functioning and is the 11th leading cause of years lost due to disability worldwide (World Health Organization 2016). Patients with schizophrenia have a significantly higher mortality rate than the general population, with proportionally higher rates of suicide (particularly in younger patients) and cardiovascular disease, as well as other causes (Auquier, Lançon et al. 2006). The years of potential life lost in individuals with schizophrenia has been estimated to be 14.5 years

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(Hjorthøj, Stürup et al. 2017). Overall, schizophrenia is a serious condition, associated with significant disability and a shortened life expectancy.

Analysis of Current Treatment Options

Antipsychotics constitute the first-line medication treatment for schizophrenia. Psychiatric practice guidelines recommend that antipsychotics should be initiated as soon as possible in patients with an acute schizophrenia exacerbation and continued through the stable/maintenance phase of the illness to reduce the risk of relapse (Herz, Liberman et al. 1997, Kreyenbuhl, Buchanan et al. 2010). Antipsychotics are broadly classified as first- generation/typical antipsychotics and second-generation/atypical antipsychotics. Typical antipsychotics include those approved before clozapine (before 1989); representative medications of this class are chlorpromazine, fluphenazine, and haloperidol. Atypical antipsychotics include clozapine and others approved after 1989; drugs representative of this class include risperidone, olanzapine, quetiapine, and aripiprazole.

Antipsychotics appear to be most effective at reducing the positive symptoms of schizophrenia, and are not thought to have clinically meaningful effects on negative symptoms or cognitive impairment associated with schizophrenia (Davis, Horan et al. 2014). The mechanism by which antipsychotics improve psychotic symptoms is not completely understood but may involve antagonism of dopamine D2 receptors and/or serotonin 5-HT2A receptors. In general, typical antipsychotics have a higher risk for causing extrapyramidal side effects (EPS), such as dystonia, parkinsonism, and tardive dyskinesia, and many atypical antipsychotics, including risperidone, are associated with significant weight gain and other metabolic effects.

Over 20 antipsychotics are approved for the treatment of schizophrenia in the United States. Except for clozapine, which has significant evidence supporting its efficacy in patients who have not responded to other antipsychotics, antipsychotics differ mostly with respect to their safety profiles. However, individual patients often require trials of numerous antipsychotics before an optimal treatment is identified, and there are some patients for whom an effective treatment cannot be identified despite multiple trials. Thus, having additional treatment options in the armamentarium is valuable.

In addition to antipsychotic medications, patients with schizophrenia are frequently treated with adjunctive medications to target depression, anxiety, obsessions and compulsions, and adverse reactions of antipsychotics (e.g., dystonia, parkinsonism, tardive dyskinesia, and akathisia). These adjunctive medications may include drugs (e.g., benztropine, ), beta-blockers (e.g., propranolol), benzodiazepines, and .

Beyond pharmacotherapy, several psychosocial treatments have substantial evidence bases and are recommended for use alongside antipsychotic therapy. Psychosocial treatments may reduce relapse risk, improve coping skills, improve social and vocational functioning, and help individuals with schizophrenia function more independently. Recommended psychosocial

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interventions include cognitive behavioral therapy, assertive community treatment, supported employment, and social skills therapy.

3 Regulatory Background

U.S. Regulatory Actions and Marketing History

Lumateperone is not currently marketed in the United States for any indication.

Summary of Presubmission/Submission Regulatory Activity

The Applicant submitted Investigational New Drug (IND) application 079690 on October 15, 2007. The IND-opening study was an open-label receptor occupancy study; no hold issues were identified and the study was allowed to proceed on November 15, 2007.

In June 2014, FDA met with the Applicant to discuss the phase 3 clinical trials for schizophrenia, the plans for clinical pharmacology and drug-drug interaction studies, and the nonclinical development plan. FDA requested that the Applicant conduct a trial of at least 6 weeks’ duration to assess efficacy and stressed the importance of including different doses in the phase 3 trials to characterize the full dose-response. FDA suggested that the Applicant integrate dose-response and receptor-occupancy analyses to help select a broader range of doses for the phase 3 studies. FDA raised concerns with respect to the histopathology findings showing neuronal degeneration, neuronal necrosis, and pigmentation in the brain and spinal cord in the 3-month dog toxicity study. The Applicant agreed to characterize the red pigmentation and to determine whether the accumulation of the drug and/or its metabolites were responsible.

On September 13, 2016, the Applicant submitted a new phase 3 protocol to evaluate the safety of lumateperone administration for up to one year (Study ITI-007-303). In review of this protocol, the Division noted continued concern with toxicities observed in rats and dogs after three months of dosing. The Applicant made the case that the observed toxicities were not relevant to humans. However, the Division was not convinced and notified the Applicant that the IND would be placed on partial clinical hold unless the protocol was modified to limit lumateperone exposure to 6 weeks. The Applicant amended the clinical protocol accordingly and the Division did not place the IND on partial clinical hold.

On January 13, 2017, the Division provided Written Response Only comments to the Applicant in response to a Type C Guidance meeting request. The Applicant questioned whether they could submit an NDA based on substantial evidence of efficacy from Studies 005 and 301. The Division responded that unanswered questions about the safety of lumateperone in humans would be an impediment to approval of the drug for treatment of a , such as schizophrenia.

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On May 23, 2017 and August 2, 2017, the Applicant submitted nonclinical information to make the case that the metabolic pathways differ between dogs and humans and that the neurotoxicity observed in dogs is correlated with the formation of aniline metabolites (IC201337 and IC201338) that do not appear to be formed in humans. In response, on August 18, 2017, the Division agreed that Study 303 could proceed with exposure for up to a year, under the conditions that: 1) blood samples collected at each visit would be assessed for circulating levels of aniline metabolites; and 2) bioanalysis would be performed frequently to ensure that aniline metabolites remained undetectable throughout the study. The Division noted that if aniline metabolites remained undetectable for up to three months, bioanalysis could be performed less frequently going forward. The Division also asked the Applicant to evaluate the rat brains at the end of the two-year carcinogenicity study for possible neurotoxicity.

In September 2017, the Applicant submitted requests for both Fast Track and Breakthrough Therapy Designations, based on the premise that lumateperone is better-tolerated than approved drugs for the treatment of schizophrenia. The Division denied the Breakthrough Therapy request because of the lingering safety concerns with respect to toxicity observed in the nonclinical studies, and because the Applicant’s human safety data were limited to six weeks in duration. However, because lumateperone appeared to be well-tolerated in 6-week human trials and because animal data suggested that the concerning toxicities may not be relevant to humans, the Fast Track request was granted.

On March 7, 2018, a pre-NDA meeting was held. In the meeting minutes, the Division provided nonclinical comments reiterating that the Applicant needed to perform a careful evaluation of rat brains for possible neurotoxicity in the carcinogenicity study. If any drug-related neurotoxicity findings were observed, they were asked to determine whether these findings were related to the lysosomal accumulation of the drug observed in rats and dogs in different organs including the brain, or whether they were caused by other mechanisms. In addition, the Applicant was asked to assess the relevance of the lysosomal accumulation of drug-related material observed in different organs in animals as compared to humans. FDA requested submission of the final study reports for the 2-year rat and mouse carcinogenicity studies, signed by the pathologist, with the initial NDA submission. The Division also expressed concern about the inconsistent efficacy results across the trials and how they might be conveyed in labeling. The Applicant was encouraged to submit any additional analyses that may help to explain the findings.

The application was granted a rolling review based on the program’s Fast Track designation. The nonclinical study reports for the carcinogenicity studies were submitted on April 19, 2018 and April 26, 2018. The Applicant submitted the final portion of the NDA on September 27, 2019. The NDA was filed on December 10, 2018.

Although the Applicant designed their development program to assess the known safety concerns associated with atypical antipsychotics, as noted above, nonclinical studies in the

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program suggested some unique safety issues, including concerns that arose late in the development program based on the findings of the two-year nonclinical carcinogenicity study. In order to incorporate outside expertise into our assessment of whether the benefits of lumateperone outweigh its risks, an Advisory Committee Meeting was scheduled for July 31, 2019.

A late-cycle meeting was held with the Applicant on July 18, 2019. At this meeting, we discussed several elements of the available nonclinical data that made it difficult for us to reach a final conclusion on the long-term safety of lumateperone for humans. The Applicant indicated that they would be able to complete additional nonclinical studies and additional analyses of existing nonclinical samples in order to clarify the mechanisms of toxicities observed in the animal studies and establish that these toxicities were unlikely to occur in humans. We reached an agreement that the data the Applicant pledged to provide would allow the Division to reach a conclusion on the safety of lumateperone without the assistance of an Advisory Committee. The Division cancelled the Advisory Committee Meeting. The Applicant filed a Major Amendment to the NDA application, documenting a plan for additional nonclinical studies and data analyses. The PDUFA goal date for the application was extended from September 27, 2019 to December 27, 2019.

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4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety

Office of Scientific Investigations

The Office of Scientific Investigations (OSI) conducted inspections of four clinical sites participating in Study 005 and Study 301 as well as the site of the Applicant, Intra-Cellular Therapies. The selection of clinical sites for inspection was based on the relatively large numbers of subjects enrolled at the sites and their contribution to the results on the primary efficacy endpoint.

Summary findings from the OSI inspections are as follows:

1. Although there were inspectional observations noted at the clinical investigator sites and the Applicant’s site, they are unlikely to have a significant impact on the overall study results. The studies appear to have been conducted adequately, and the data generated by the sites and submitted by the Applicant appear acceptable in support of the application.

2. Inspectional observations at the clinical sites included lack of documentation of assessment of potential adverse events during several study activities. The most significant under- reported adverse event was one subject experiencing orthostatic hypotension and syncope, with only orthostatic hypotension being reported to the Applicant.

3. For Study 301, Site #106 was not able to provide full information on the total dose and times of administration of as-needed doses of lorazepam for 28 of 31 enrolled subjects. This made it difficult to establish an accurate count of the number of protocol deviations related to use of lorazepam as a concomitant medication. The administration of lorazepam close to the time of a PANSS assessment could potentially have had an effect on the scoring of the primary efficacy endpoint.

4. For Study 005, the Applicant disclosed that some sites did not have a large enough supply of investigational product to administer the study drug according to the arm to which each patient had been randomized. Fifteen patients were “forced randomized” and received a different investigational product than assigned per the randomization schedule.

5. During the inspection, the Applicant stated that the database for Study 005 was unlocked approximately one month following database lock and unblinding of the study to correct some data discrepancies and then relocked one week later. The Applicate reported to OSI that the discrepancies prompting the database unlock included waist circumference recorded in inches rather than centimeters, an incorrect dose date, an incorrect birth year for a patient, and a suicide attempt year incorrectly recorded as 2007 instead of 2010.

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Clinical reviewer comment: Items #1 and #2 were explored through sensitivity analyses by the Division of Biometrics (see Sections 8.1.2 and 8.1.4). The sensitivity analyses showed no effect of either item on the efficacy results for the studies involved. Regarding Item #3, it is not anticipated that these corrections to the database would have an effect on the efficacy or safety analyses for Study 005.

Product Quality

The application was reviewed by the Office of Pharmaceutical Quality (OPQ); please refer to the Quality Assessment document for full details of their review. In summary, no issues related to product quality were identified in the course of OPQ’s review that could affect clinical data or approvability of the drug. The proposed commercial formulation was the same as that used in Phase 2 and Phase 3 studies.

Please refer to Section 1.2 for a discussion of dose nomenclature related to presenting milligrams of lumateperone free base vs. lumateperone tosylate.

Clinical Microbiology

Not applicable; there were no new clinical microbiology data submitted with this application.

Devices and Companion Diagnostic Issues

Not applicable; there are no device issues or companion diagnostic issues relevant to this application.

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5 Nonclinical Pharmacology/Toxicology

Executive Summary

The submitted application by Intra-cellular Therapies, is a 505(b)1 NDA for lumateperone (lumateperone tosylate) proposed for the treatment of schizophrenia. The maximum recommended human dose (MRHD) is 42 mg of lumateperone (free base), which is equivalent to 60 mg lumateperone tosylate salt. The doses in the nonclinical study reports were expressed as mg of lumateperone tosylate. To maintain consistency with the clinical doses in the label, these doses have been converted to correspond to the free base throughout this review.

The efficacy of atypical antipsychotic drugs in schizophrenia is thought to be mediated through a combination of antagonist or partial activity at central dopamine D2 receptors and antagonist activity at the serotonin 5-HT2A receptors (Lieberman, Bymaster et al. 2008). Consistent with other atypical antipsychotic drugs, lumateperone binds with relatively high affinity to 5-HT2A (0.52-10 nM) and moderate affinity to D2 receptors (19.2-49 nM), where it appears to act as an antagonist based on in vitro functional assays. In vivo, lumateperone appears to act as an antagonist at central 5-HT2A receptors and postsynaptic D2 receptors.

In addition, lumateperone binds with moderate to high affinity to dopamine D1 (Ki = 20 – 78 nM) and D4 (Ki = 40 – 104 nM) and α1B adrenergic (Ki = 36.9 nM) receptors; targets that are also thought to play a role in mediating the efficacy of antipsychotic drugs. The overall binding profile for lumateperone is consistent with other marketed atypical antipsychotic agents with the possible exception of binding to the serotonin transporter (SERT) with a relatively high affinity (Ki = 16 – 33 nM); although the functional consequence of this binding was not assessed. Most other antipsychotic agents do not bind to SERT, and the Applicant believes this will confer an advantage to lumateperone for the treatment of schizophrenia (Helfer, Samara et al. 2016, Li, Snyder et al. 2016).

Lumateperone is extensively metabolized in humans and multiple pharmacologically active metabolites have been identified, which are present in humans at similar or greater levels than lumateperone and may contribute to its overall pharmacological and/or toxicological profile. In particular, IC200131 and IC200161 have binding affinities comparable to lumateperone and are present in systemic circulation at levels equal to, or 4 times greater than, lumateperone, respectively.

Toxicity Issues of Concern

The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively. Its carcinogenic potential was studied following oral administration for up to 21 months in rats and mice, providing additional information on its toxicology. The potential contributions of lumateperone and its metabolites

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to the toxicity profile are currently unknown; therefore, safety margins are expressed as mg/m2 body surface area. It is important to note, however, that safety margins based on mg/m2 body surface area were relatively consistent with those based on total AUC exposure when these values were available.

Oral administration of lumateperone caused systemic intracytoplasmic accumulation of pigmented material in dogs, rats, and mice, with little to no exposure margin relative to the 42- mg MRHD on both a mg/m2 and AUC plasma exposure basis. The distribution and severity of pigment accumulation tended to increase with increasing doses and increasing treatment duration. Of particular concern is the accumulation of pigmented material in tissues with low regenerative capacity. Apparently irreversible pigment accumulation was observed in the brain and spinal cord in all three species, and in cardiomyocytes and the retina of rats, although, recovery was assessed over a relatively short period of time (1 to 2 months). Accumulation of pigmented material was co-located in degenerating cells in rats and dogs; therefore, a causal role of intracellular pigment accumulation in cell degeneration and necrosis is likely.

In rats, accumulation of pigmented material was observable on gross necropsy and often located within parenchymal cells and infiltrating macrophages and other mononuclear inflammatory cells in multiple organs and occasionally in the extracellular space (e.g., fibrous connective tissue replacing myocardiocytes in the heart and free within alveoli of the lung). Accumulation of pigmented material was associated with adverse effects in the (e.g., histiocytic inflammation in the brain and axonal degeneration in the spinal cord), peripheral nervous system (e.g., satellite glial clusters in the dorsal root ganglia consistent with prior neuronal injury and loss, histiocytic inflammation and axonal degeneration in peripheral nerves), eye (e.g., retinal degeneration), and heart (e.g., cardiomyopathy).

Retinal degeneration and progressive cardiomyopathy can be common background lesions in such studies in rats (Yamashita, Hoenerhoff et al. 2016). Based on the weight of evidence, however, the dose-related increase in the incidence and severity of these findings indicates they are not incidental background lesions, but instead caused by lumateperone administration and are related to intracellular accumulation of pigmented material in these tissues. It should be noted that the significant accumulation of pigmented macrophages and accumulation of extracellular pigmented material within alveoli of the lung also contributed to the progression of cardiopulmonary disease (see more detail in the review). Similarly, axonal degeneration in the sciatic nerve and spinal cord can occur in aging rats (Cotard-Bartley, Secchi et al. 1981, Kaufmann, Bolon et al. 2012); however, the dose-related increase in incidence and severity compared to control rats suggests this degeneration is lumateperone-related. The intracellular accumulation of pigmented material in neurons of the spinal cord could be associated with a disruption of neuronal homeostasis that results in axonal degeneration in the white matter tracts but not neuronal necrosis or degeneration. In addition, there is evidence of an inflammatory response and axonal degeneration in the dorsal root ganglion nerves and spinal nerve roots associated with neuronal accumulation of pigmented material.

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In the rat 6-month chronic toxicology study, adverse effects occurred at doses of lumateperone that are ~ 5 times the MRHD of 42 mg on a mg/m2 basis. The dose of lumateperone that corresponds to the NOAEL was 2.4 times the MRHD of 42 mg on a mg/m2 basis. In the rat carcinogenicity study, adverse effects occurred at doses with little margin of safety relative to MRHD of 42 mg on a mg/m2 bases (1.6 to 2.4 times in male and female rats, respectively). The dose of lumateperone that corresponds to the NOAEL in the rat carcinogenicity study was below the MRHD of 42 mg on a mg/m2 basis.

In the dog, accumulation of pigmented material was often observed within parenchymal cells and infiltrating macrophages and other mononuclear inflammatory cells in multiple organs. In the central nervous system, neuronal degeneration and necrosis were first noted in the brain and spinal cord following approximately 10.5 weeks of administration, while axonal degeneration was noted following administration for up to 9 months. Axonal degeneration was pervasive (cerebrum, midbrain, and medulla oblongata, cerebellum, and all three sections of the spinal cord) and evidence of an adverse inflammatory reaction (perivascular cuffing, microglial activation) was noted in the midbrain and cerebrum (to a lesser extent in the medulla oblongata, cerebellum, and spinal cord) of dogs following lumateperone administration for up to 9 months. Adverse effects in the central nervous system of dogs occurred at doses of lumateperone that are 4 times the MRHD of 42 mg on a mg/m2 basis. The dose of lumateperone that corresponds to the NOAEL was 2 times the MRHD of 42 mg on a mg/m2 basis.

In mice, accumulation of pigmented material was often observed within parenchymal cells and infiltrating macrophages and other mononuclear inflammatory cells in multiple organs, including neurons in the brain and spinal cord. Intracellular accumulation of pigmented material was not clearly associated with degenerative changes in any affected organs following lumateperone administration for up to 3 months. Similarly, in the carcinogenicity study intracellular accumulation of pigmented material was not clearly associated with degenerative changes; however, a dose-related increase in lesions in the peripheral nervous system (sciatic nerve axonal degeneration) was reported with little to no margin of safety relative to humans at the MRHD of 42 mg on a mg/m2 basis (≤ 2-times). Although a NOAEL for lesions in the sciatic nerve was achieved, there was no margin relative to the MRHD of 42 mg on a mg/m2 basis.

The identity of the constituents that make up the intracellular pigmented material observed in the toxicology studies was not fully characterized by the Applicant; however, it does not appear to be a common endogenous intracytoplasmic pigment (e.g., hemosiderin, calcium, lipofuscin) and, based on electron microscopy, it appears to be localized within the lysosomes of cells. Based on in vitro assays, it is likely that the intracellular pigmented material is composed of polymers and/or protein adducts formed from aniline metabolites of lumateperone, IC201337 and IC201338. It is well-established that aniline-containing compounds can undergo significant chemical changes (oxidation, dehydrogenation, polymerization) when exposed to oxidants in an acidic environment (Shennawy, Gee et al. 1984, Tang, Wang et al. 2011, Sapurina and Shishov 2012, Abu-Thabit 2016). These chemical changes often result in color changes and formation of

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pigmented material, a property that has been exploited to stain lysosomal proteins for histology (e.g., aniline blue) (Shennawy, Gee et al. 1984). Consistent with this, both the aniline metabolites, IC201337 and IC201338, are capable of forming pink and/or red polymers when oxidized in an acidic environment. Importantly, neither lumateperone nor any of the non- aniline metabolites formed pink or red material under these conditions.

The aniline metabolites are cationic amphiphilic amines (CADs), possessing a weakly basic functional amine group and a hydrophobic aromatic ring structure. At physiological pH, CADs are not ionized and, owing to their hydrophobic domain, readily diffuse across lipid bilayers. Upon entering a cellular organelle with an acidic pH, such as lysosomes, they are protonated (ionized), which significantly limits their membrane permeability and results in intralysosomal accumulation (Daniel 2003, Anderson and Borlak 2006, Nonoyama and Fukuda 2008, Goldman, Funk et al. 2009). Therefore, it is likely that the aniline metabolites will accumulate in lysosomes, which are chemically reactive acidic oxidative environments, and undergo chemical reactions, including polymerization, with subsequent trapping resulting in lysosomal dysfunction (Saftig and Klumperman 2009, Dielschneider, Henson et al. 2017). The physiological significance and clinical relevance of the accumulation of the pigmented material is not completely understood; however, if the pigmented material is caused by the formation of polymers and/or protein adducts from the aniline metabolites, they are likely to cause lysosomal dysfunction, leading to cellular dysfunction. This conclusion is supported by the observation that accumulation of pigmented material was consistently co-located in cells with degenerative changes and/or signs of inflammation. Therefore, based on the weight of evidence, it is likely that aniline metabolites are responsible for the accumulation of pigmented material and play a significant role in causing the toxicities observed in the nonclinical studies.

In addition to the aniline metabolites, lumateperone and most of the circulating unconjugated metabolites, are also CADs. Accumulation of drugs in lysosomes, which play a role in degradation and processing of foreign materials, may be a benign indicator of physiological clearance; however, CADs are known to interact directly with membrane proteins such as sphingomyelinase, Niemann-Pick C1 (NPC1), NPC2, acid ceramidase, and various phospholipases, or to bind directly to membrane phospholipids resulting in disruption of lysosomal homeostasis and the eventual loss of cell viability (Anderson and Borlak 2006, Nonoyama and Fukuda 2008, Kuzu, Toprak et al. 2017, Lenz, Braendli-Baiocco et al. 2018). In addition to affecting lysosomal enzymes or phospholipids through a direct interaction, it is possible that accumulating material achieves concentrations in the lysosome that exceed their solubility, resulting in precipitation and significant accumulation (Goldman, Funk et al. 2009). Over time, the accumulation of precipitated material could adversely affect lysosomal function leading to cellular dysfunction (Lenz, Braendli-Baiocco et al. 2018). Although lumateperone and the unconjugated non-aniline metabolites do not appear to be involved in formation of the pigmented material, a role in causing lysosomal disfunction cannot be ruled out. However, the toxicological potential of such accumulations (i.e., lumateperone or the non-aniline metabolites) is likely comparable to other antipsychotic agents or CADs known to accumulate in lysosomes (e.g., and aripiprazole).

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The Applicant does not consider the intracellular accumulation of pigmented material in nonclinical species adverse; however, based on our assessment above, accumulation of pigmented material is clearly associated with adverse degenerative changes and inflammatory responses. Instead, the Applicant proposes that the aniline metabolites undergo metabolic activation. In support of this the Applicant demonstrated that both IC201337 and IC201338 formed a single glutathione conjugate in microsomes from rats, dogs, and mice. The proposed metabolic activation pathway is via dehydrogenation of the 7-aminoindoline ring system. Therefore, it is possible that metabolic activation of the anilines contributes to the toxicities observed, particularly in the dog, which appears to be exposed to the highest levels of these substances. Regardless of the mechanism of action (i.e. direct toxic effect, accumulation in the lysosome, or both) the aniline metabolites appear to play a significant role in causing the toxicities observed. Therefore, it is important to clearly establish that these metabolites are not formed in humans.

The qualitative metabolism of lumateperone is similar between humans and nonclinical species; however, significant quantitative interspecies differences exist. In humans, phase I metabolism appears to occur via reduction of the ketone in the side chain to form the principle metabolite IC200131. Demethylation of the tertiary amine and amidation of the ring are also primary metabolic pathways in humans forming the phase I metabolites IC200565 and IC201309. The level of these phase I metabolites is 4- to 6-times that of lumateperone in humans based on AUC. In contrast, nonclinical species, particularly rats, appear to be less efficient at reducing the ketone in the butyrophenone side chain; however, demethylation of the tertiary amine and amidation of the piperazine ring does occur. Therefore, rats and dogs have relatively low circulating levels of IC200131, IC200565, and IC201309 compared to humans and relatively high circulating levels of IC20161 (dog and rat) and IC201308 (rat), which have not undergone ketone reduction. Because of the different metabolic profile observed in rats and dogs relative to humans and the apparent role this difference plays in the toxicological profile of lumateperone, the Applicant conducted numerous studies using alternative nonclinical species (monkey, hamster, guinea pig, minipig) in an attempt to identify a species with a similar metabolic profile to humans. The Applicant was unable to identify an alternative nonclinical species with a similar metabolic profile to humans and, therefore, the rat and dog were used.

The Applicant proposes that the piperazine ring in lumateperone is susceptible to oxidative cleavage and formation of aniline metabolites in dogs, and to a lesser extent in rats, but not in humans. This metabolic pathway would result in the formation of the aniline metabolites as well as a 2-carbon fragment lost from the piperazine ring. This hypothesis is supported by the mass balance studies in rats and dogs in addition to the presence of detectable levels of the aniline metabolites (IC201337 and IC201338) in the systemic circulation of both dogs and rats. In the mass balance studies, the 14C label was placed on one of the carbons that would be lost during oxidative cleavage of the piperazine ring. In dogs, following a single oral dose of [14C]- lumateperone, a large early eluting peak was observed in the radio-chromatograms accounting

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for ~72% of radioactivity recovered from pooled plasma samples collected 2 to 8 h post-dose. A similar peak (~17% of radioactivity) was present in the radio-chromatograms from the rat mass balance study following a single oral dose of [14C]-lumateperone. Although efforts to identify the constituents of this peak were unsuccessful, it is likely composed of highly polar compounds resulting from oxidative cleavage of the piperazine ring yielding a 2-carbon fragment containing the 14C label. The relative size of this early eluting peak indicates this is a major metabolic pathway in dogs and to a lesser extent in rats. However, there is no evidence directly supporting this concept because the anilines theoretically formed during this metabolic process are actually present at relatively low levels in plasma of both dogs and rats. Indeed, their combined AUC-based exposure is below the level of lumateperone and the other two most abundant unconjugated metabolites that have been identified in dogs and rats. The discrepancy between the levels of these anilines measured in the systemic circulation in the general toxicology studies and their theoretical formation based on results from the mass balance study could have been addressed by placing the [14C] label on a different carbon from the ones lost via piperazine ring cleavage. This would have allowed for retention of the [14C] label on the aniline metabolites and thus a more accurate assessment would have been determined with respect to the levels that are formed and their potential for accumulation in tissue relative to plasma.

Although the Applicant has conducted no studies to directly assess the reasons for the apparent discrepancy in theoretical aniline formation based on the mass balance study and the circulating levels measured in the general toxicology studies, there is evidence that indicates aniline metabolites are present at significant levels in dogs and to a lesser extent in rats. It is possible that IC201337 and IC201338 are retained in tissue or that additional metabolism clears them from systemic circulation and, therefore, plasma levels are not representative of total exposure. As noted above, significant intracellular accumulation of pigmented material was reported in multiple organs in the dog and rat repeat dose toxicology studies. Although the composition of this pigmented material was not directly characterized by the Applicant, they have provided evidence that IC201337 and IC201338 undergo polymerization and a color change consistent with the pigmented material when incubated with oxidative agents in vitro. It is also possible that additional aniline metabolites that were not fully investigated using mass spectrometry were present. For example, the Applicant notes that a third aniline metabolite (IC200131-diamine) was present in the urine in the dog mass balance study; however, no further information on the levels of this aniline were provided and no further characterization appears to have occurred.

The metabolic pathway responsible for the formation of the aniline metabolites from lumateperone has not been definitively characterized; however, it likely involves oxidation of the piperazine ring resulting in scission as was observed with and as proposed in bioactivation pathway for 2-(3-chlorobenxyloxy)-6-(piperazin-1-yl)pyrazine (Baillie, Neill et al. 1979, Kalgutkar, Dalvie et al. 2007). The presence of this pathway in the metabolism of lumateperone is supported both by the presence of detectable levels of aniline metabolites in dog and rat plasma and the presence of the early eluting peak in the radiochromatograms

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(proposed to be a two-carbon entity) from the nonclinical mass balance studies. It should be noted that this metabolic pathway should be operative in humans; therefore, it is not clear why humans wouldn’t form aniline metabolites, although rapid glucuronidation and elimination may play a role.

It should be pointed out that the aniline metabolites, IC201337 and IC201338, which appear to be responsible for the accumulation of pigmented material, were not detected in humans at levels that could be quantified; however, the potential for lumateperone or other metabolites to accumulate in lysosomes and contribute to the observed toxicities cannot be ruled out. Therefore, these animal findings need to be described in the label as the nonclinical studies could not definitively establish that they are of no clinical relevance. In conclusion, from a nonclinical perspective, the application is considered approvable pending the description of the relevant findings in animals in section 13.2 of the label.

Genotoxicity and Carcinogenicity Lumateperone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or the mouse lymphoma test in the absence of metabolic activation. Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test. Lumateperone was negative for clastogenic activity in the in vivo micronucleus assay in rats and was not genotoxic in the in vivo Comet assay in rats at doses ~16 times the MRHD of 42 mg on a mg/m2 basis. Oral administration of lumateperone did not cause any increase in tumors at doses approximately 3.2 and 1.6 times the MRHD of 42 mg/day for male and female rats, respectively, on a mg/m2 basis. Oral administration of lumateperone to male and female mice did not cause any increase in tumors at doses approximately 2 times the MRHD of 42 mg/day on a mg/m2 basis.

Reproductive and Developmental Toxicology Oral administration of lumateperone to male and female rats adversely affected male and female fertility and caused estrus cycle irregularities at doses approximately equal to the MRHD of 42 mg lumateperone on a mg/m2 basis. Oral administration of lumateperone caused testicular toxicity in rats at a dose approximately 5 times the MRHD of 42 mg lumateperone on a mg/m2 basis. Oral administration of lumateperone to rats and rabbits did not cause fetal malformations at doses approximately 14.5 and 10 times, respectively, the MRHD of 42 mg lumateperone on a mg/m2 basis. In rats, fetal variations were observed; however, these occurred in the presence of maternal toxicity and, therefore, are of limited clinical relevance. Oral administration of the metabolite IC200131 to rats caused an increase in fetal visceral malformations (cleft palate) and skeletal malformations at doses approximately 27 and 20 times, respectively, the human exposure observed following administration of lumateperone at the MRHD of 42 mg on an AUC plasma exposure basis. Exposures to IC200131 at the NOAEL for malformations was the same as those observed in humans following administration of lumateperone at the MRHD of 42 mg on an AUC plasma exposure basis.

Referenced NDAs, BLAs, DMFs

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None

Pharmacology

Numerous pharmacology studies were performed by the Applicant. Only the studies relevant to the potential mechanism of action of lumateperone and associated labeling claims proposed by the Applicant are reviewed here.

The Applicant proposes that “lumateperone is a potent serotonin subtype 2A (5-HT2A) receptor antagonist, a dopamine 2 (D2) receptor pre-synaptic partial agonist and post-synaptic antagonist, a dopamine 1 (D1) receptor-dependent modulator of glutamate, and a serotonin reuptake inhibitor” based on evidence from in vitro and in vivo studies. Therefore, the Applicant asserts that lumateperone has a pharmacologic profile that differs from other antipsychotic agents and “is a first-in-class, small molecule, new molecular entity that selectively and simultaneously modulates serotonin, dopamine, and glutamate neurotransmission.”

Reviewer Note: Based on the in vitro and in vivo assays conducted by the Applicant, there is no substantial evidence that lumateperone modulates serotonin, dopamine, or glutamate neurotransmission in ways that are unique relative to other currently marketed atypical antipsychotic drugs with the possible exception of serotonin reuptake inhibition. In addition, the in vivo data, although somewhat supportive of presynaptic partial agonist activity at D2 receptors, is not sufficient to override the in vitro functional activity data demonstrating lumateperone is an antagonist at D2 receptors. Thus, it is not clear whether lumateperone is an antagonist or partial agonist at presynaptic D2 receptors from the data available at this time.

Primary Pharmacology The in vitro receptor binding profile of lumateperone at targets thought to mediate the efficacy of atypical antipsychotic drugs (Arnt and Skarsfeldt 1998, Lieberman, Bymaster et al. 2008) was investigated using standard methods. Consistent with other atypical antipsychotic drugs, lumateperone binds with relatively high affinity (nM concentrations) to human recombinant serotonin 5-HT2A and dopamine D2 receptors. Although variability was observed across assay systems, lumateperone appears to bind with higher affinity to the human recombinant 5-HT2A receptor relative to both the long (L) and short (S) isoforms of the human recombinant D2 receptor (Table 1).

Table 1. In Vitro Binding Affinity (Ki) of Lumateperone at Serotonin 5-HT2A and Dopamine D2 Receptors Receptor 5-HT2A (h) D2S (h) D2L (h) D2 (r) Ki (nM) 0.52 to 10 nM < 100 nM* 49 nM 19.2 to 32 nM h: Human receptor; r: Rat receptor *Ki at the D2S receptor not determined. 45-56% inhibition of radioligand binding at single conc. of 100 nM Source: Nonclinical Reviewer; Study Nos. ITIDP-1004, ITINOV-001, ITINOV-002, ITI-007 ITI EURO

Lumateperone also binds with moderate to high affinity to dopamine D1 and D4 receptors and α1B adrenergic receptors (Table 2); targets that are also thought to play a role in mediating the

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efficacy of some antipsychotic drugs (Arnt and Skarsfeldt 1998, Lieberman, Bymaster et al. 2008). In addition, lumateperone binds with relatively high affinity to the serotonin transporter (SERT); however, the functional consequence of binding to SERT was not assessed by the Applicant. The overall binding profile for lumateperone is consistent with other marketed atypical antipsychotic agents, with the possible exception of binding to SERT. Most other antipsychotic agents do not bind to SERT, and the Applicant believes this will confer an advantage to lumateperone for the treatment of schizophrenia (Helfer, Samara et al. 2016, Li, Snyder et al. 2016).

Table 2. In Vitro Binding Affinity (Ki) of Lumateperone at SERT and D1, D4, α1B Receptors Receptor SERT (h) D1 (h) D4 (h) α1B (r) Ki (nM) 16 to 33 nM 20 to 78 nM 39.7 to 104 nM 36.9 nM h: Human receptor; r: Rat receptor Source: Nonclinical Reviewer; Study Nos. ITIDP-1004, ITI NOV005, ITI NOV006, ITI NOV008, ITI-007 ITI EURO

The Applicant proposes that higher affinity binding for the 5-HT2A receptor relative to D1 and D2 receptors will allow for full saturation of cortical 5-HT2A receptors and antipsychotic efficacy at doses that do not produce motor side effects thought to result from high occupancy of striatal D2 receptors. Support for this hypothesis comes from other atypical antipsychotic drugs with lower affinity for dopamine receptors relative to the 5-HT2A receptors (e.g., clozapine and quetiapine) or partial agonism at D2 receptors (e.g., aripiprazole and ).

Lumateperone is extensively metabolized to multiple pharmacologically active metabolites in humans and nonclinical species (Table 3). These metabolites are present in the systemic circulation at similar or greater levels than lumateperone (see section ADME/PK) and may contribute to the overall pharmacological activity. The desmethyl metabolite IC20161 and the reduced carbonyl metabolite IC200131 have similar binding profiles to lumateperone. IC20161 binds with moderate to high affinity to 5-HT2A, D1, D2, D4, α1B receptors and with moderate to low affinity to SERT (Table 3). IC200131 binds with moderate to high affinity to 5-HT2A, D2s receptors, and SERT (Table 3). The secondary metabolites IC200565 and IC201308 are less pharmacologically active than lumateperone. IC200565 binds with moderate affinity to the 5- HT2A receptor (Table 3). IC201308 binds with high affinity to 5-HT2A and D1 receptors (Table 3).

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Table 3. In Vitro Binding Affinity (Ki) of Pharmacologically Active Metabolites at SERT and 5-HT2A, D1, D2, D4, and α1B Receptors IC200161 IC200131 IC200565 IC201308 Target Ki (nM) Ki (nM) Ki (nM) Ki (nM) 5-HT2a (h) 1.6 61 160 11 D2 (r) 30 NT NT NT a c 3 D2S (h) NSB 57 NSB ND 4 D2L (h) NT NT NT NC c c D1 (h) 86 NSB NSB 22 1 2 c D4 (h) ND ND NSB NT c c α1B (r) 11 -66 NSB NSB NT SERT (h) 390 71 NSBc NC5 ND: Not determined; NT: Not tested; NSB: No significant binding; h: Human receptor; r: Rat receptor 1: Ki at the D4 receptor not determined. 45% inhibition of radioligand binding at single conc. of 100 nM 2: Ki at the D4 receptor not determined. 81% inhibition of radioligand binding at single conc. of 1000 nM 3: Ki at the D2S receptor not calculated. 50% inhibition of radioligand binding at highest conc. of 243 nM 4: Ki at the D2L receptor not calculated. 47% inhibition of radioligand binding at highest conc. of 243 nM 5: Ki at SERT not calculated. 44% inhibition of radioligand binding at highest conc. of 243 nM a: 100 nM; b: 243 nM; c: 1000 nM Source: Nonclinical Reviewer; Study Nos. ITIDP-1004, ITI NOV003, ITI NOV004, ITI NOV006, ITI NOV007, ITI NOV008, ITI10-7051, ITI-007 ITI EURO

Reviewer Note: Lumateperone and its metabolites lack significant binding affinity to D3, 5-HT1A, and 5-HT7 receptors; these additional targets are thought to contribute to the efficacy of other atypical antipsychotic agents.

Functional activity of lumateperone In Vitro: In in vitro cell-based assays, lumateperone acts as an antagonist at 5-HT2A and D2 receptors.

The functional activity of lumateperone was investigated in human embryonic kidney cells expressing human 5-HT2A receptors (Study No. ITI DPI005). Lumateperone significantly inhibited serotonin-induced [3H]inositol phosphate accumulation at concentrations ranging from 50 to 200 nM (Figure 1).

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Figure 1. Inhibition of Serotonin-induced [3H]Inositol Phosphate (IP) Accumulation by Lumateperone in HEK Cells Expressing Human 5-HT2A Receptors

Source: Applicant; Study No. ITI DPI005 IS895: Lumateperone tosylate; 5-HT: Serotonin

The functional activity of lumateperone was investigated in Chinese hamster ovary cells expressing either the long (D2L) or short (D2S) isoforms of the human D2 receptor (Study Nos. ITI- 007 INT D2 & ITI-007-INT-AD17-01). Lumateperone blocked the reduction in cAMP induced by the D2 agonist in cells expressing either the D2L or D2S receptor at nM concentrations; however, no agonist activity was demonstrated when administered alone at concentrations up to 3 μM (Table 4). There is substantial evidence that the D2L isoform is expressed in structures targeted by dopaminergic fibers indicating a postsynaptic localization, whereas the D2S isoform is preferentially expressed in dopaminergic cell bodies and axons indicating a presynaptic localization (Khan, Mrzljak et al. 1998, Ford 2014). Therefore, based on the in vitro functional assays conducted by the Applicant, lumateperone acts as an antagonist at both postsynaptic and presynaptic D2 receptors.

Table 4. In Vitro Functional Activity of Lumateperone at Human D2 Receptors Receptor Species Cell Type Antagonist (IC50) Agonist (EC50) Study Number D2L Human CHO 32 nM > 3 μM ITI-007 INT D2 D2S Human CHO 70 nM > 3 μM ITI-007-INT-AD17-01 Source: Nonclinical Reviewer; Study Nos. ITI-007 INT D2, ITI-007-INT-AD17-01

No other in vitro assays to assess the functional activity of lumateperone or metabolites were performed by the Applicant.

In Vivo: According to the Applicant, the in vivo studies described below provide experimental evidence for the assertion that the efficacy of lumateperone is mediated by antagonism at 5-

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HT2A, D1, and postsynaptic D2 receptors, partial agonism at presynaptic D2 receptors, and inhibition of SERT.

Reviewer Note: The data do not provide enough support for the Applicant’s proposal that lumateperone is a partial agonist at presynaptic D2 receptors to overcome the in vitro data indicating it is an antagonist at these receptors.

The functional activity of lumateperone was investigated in vivo using an in- technology platform, CNSProfile, developed by the Applicant (Study No. ITI-INT-001). According to the Applicant, CNSProfile allows for the investigation of the phosphorylation state of proteins that are downstream of a drug’s pharmacological targets. Using CNSProfile, the Applicant investigated the effects of lumateperone (1-3 mg/kg PO) on the phosphorylation state of a number of phosphoproteins and compared these effects to those observed following administration of clozapine (5 mg/kg ip), aripiprazole (10-30 mg/kg PO), quetiapine (10 mg/kg ip), olanzapine (1 mg/kg ip), risperidone (1-3 mg/kg sc), (2mg/kg sc), (100 mg/kg ip), (3 mg/kg ip), haloperidol (0.3-1 mg/kg ip), chlorpromazine (10 mg/kg ip), and (0.5 mg/kg ip) to mice.

The phosphorylation state of numerous phosphoproteins was altered by lumateperone and the other antipsychotic drugs assessed; however, there were differences between these drugs in their respective profiles. Lumateperone produced an increase in the phosphorylation state of numerous proteins thought to be downstream from receptors at which it displays in vitro binding affinity; however, these increases were consistently less significant relative to the other drugs studied (Figure 2).

Reviewer Note: The Applicant proposes that these data support their assertion that lumateperone is a “ phosphoprotein modulator;” however, these results are not distinct from those observed with other antipsychotic drugs (Figure 2). Therefore, these data do not support labeling for lumateperone that would be distinct from other atypical antipsychotic drugs.

Lumateperone did not significantly increase phosphorylation at the S40 residue (a regulatory domain) on hydroxylase (TH). Increased TH phosphorylation at the S40 residue thought to be downstream of antagonist activity at dopamine D2 receptors. Thus, the Applicant proposes that lumateperone is a partial agonist at presynaptic dopamine D2 receptors. This theory is based on the similar effects observed with aripiprazole (a partial agonist), in contrast to the robust increase in phosphorylation state observed with other antipsychotic drugs in this study (Figure 2).

Reviewer Note: The Applicant also observed that clozapine, which is an antagonist at D2 receptors, did not increase TH phosphorylation in mice. This finding is consistent with studies in the literature investigating the effects of clozapine on TH phosphorylation (Hakansson, Pozzi et al. 2004); however, it is inconsistent with the Applicant’s conclusion that lack of an effect on TH

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phosphorylation is unique to D2 partial . In contrast, Salvatore et al (Salvatore, Garcia- Espana et al. 2000) found that clozapine, similar to haloperidol, produced a significant increase in TH phosphorylation in rats, although at a significantly higher dose (30 vs. 5 mg/kg) (Salvatore, Garcia-Espana et al. 2000). Furthermore, lower doses of haloperidol (0.1 mg/kg) do not increase TH phosphorylation at the S40 residue (Hakansson, Pozzi et al. 2004). Therefore, based on the low-dose versus high-dose effects of haloperidol and clozapine, it appears that substantial blockade of presynaptic D2 receptors is required to induce TH phosphorylation at the S40 residue. In addition, published reports on the effects of partial agonists, including aripiprazole, were not provided by the Applicant or identified during review of the relevant literature. Therefore, the Applicant has not established that this effect is unique to D2 receptor partial agonists and may instead be an artifact of the dose selection due to the relatively low levels of D2 receptor occupancy. This possibility is consistent with the relatively low levels of phosphorylation induced by lumateperone at all proteins examined in this assay (Figure 2).

Figure 2. Heat Map Representation Showing Phosphorylation-Site Responses

Source: Figure 2; Study No. ITI-INT-001

To further characterize the functional consequence of the observed absence of TH phosphorylation induced by lumateperone the Applicant assessed the effects of lumateperone administration on dopamine and dihydroxyphenylacetic acid (DOPAC) levels via microdialysis in the striatum and medial prefrontal cortex (mPFC) of rats following acute oral administration (3 (b) (4) and 10 mg/kg) (study No. ITI--001). Lumateperone increased dopamine levels in the striatum (Figure 3) and to a more significant degree in the mPFC (Figure 4) of rats. A similar effect on DOPAC levels was observed (data not shown). In contrast, aripiprazole (30 mg/kg) had no effect on dopamine or DOPAC levels in either the striatum or mPFC relative to vehicle control under the conditions of this study.

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Reviewer Note: The finding that lumateperone produced differential effects in the striatum relative to the mPFC is consistent with literature reports for atypical antipsychotic drugs (Hertel 2006).

Figure 3. Dopamine Levels in the Striatum of Rats Following Administration of Lumateperone

Source: Figure 3; Study No. ITI (b) (4) -001

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Figure 4. Dopamine Levels in the mPFC of Rats Following Administration of Lumateperone

Source: Figure 1; Study No. ITI--(b) (4) 001

The Applicant assessed the effects of lumateperone on striatal dopamine metabolism (measured as the ratio of dopamine metabolites to dopamine) in mice following acute and 21- day repeat oral administration (1, 3, and 10 mg/kg) (study No. ITI-CDC-001). Lumateperone did not induce changes in dopamine metabolism in the striatum at doses up to 10 mg/kg following acute or 21 days of treatment. This finding was similar to that observed with aripiprazole (3 and 30 mg/kg) in this study, which is consistent with published literature reports (Nakia, Hirose et al. 2003, Hertel 2006). In contrast, both haloperidol (1 and 3 mg/kg) and risperidone (1 and 10 mg/kg) produced significant increases in dopamine metabolism in the mouse striatum in this study, consistent with the observed effects of these drugs on TH phosphorylation state and published literature reports (Nakia, Hirose et al. 2003, Hertel 2006).

Reviewer Note: The Applicant did not provide raw numbers on the levels of dopamine or its metabolites in this study; therefore, an assessment of the effects of lumateperone on the level of dopamine in the striatum was not possible. In addition, studies in the published literature used longer post-treatment durations (6 to 10 hr) prior to assessing effects on dopamine metabolism relative to those used in the current study (2 hr), which allows for the increase in dopamine synthesis produced to dissipate and the compensatory increase in metabolism to appear (Nakia, Hirose et al. 2003, Hertel 2006). Therefore, it is not clear from the current data whether the lack of apparent effects on metabolism is due to an actual lack of effect or an artifact of dopamine levels remaining elevated, together with increases in the levels of dopamine metabolites. Alternatively, the majority of studies examining the effects of D2 antagonists on dopamine metabolism have used haloperidol or risperidone with relatively

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limited information available for relatively weak D2 receptor antagonists (e.g., clozapine, quetiapine). Therefore, the lack of effect could also be due to a relatively modest increase in striatal dopamine levels, consistent with what was observed in the rat study and published literature reports for other atypical antipsychotics (Hertel 2006). In conclusion, the in vitro and in vivo data indicate that lumateperone is a postsynaptic D2 receptor antagonist; however, they do not provide enough evidence to establish antagonist or partial agonist activity at presynaptic D2 receptors.

Lumateperone displayed in vivo functional activity in several rodent models of antipsychotic activity including 5-HT2 receptor agonist-induced head twitch in rats and mice (study Nos. ITI DPI001 & ITI-007 INT IC200131, Inhibition of DOI-Induced Head Twitch), conditioned avoidance response (study No. ITI DPI002), and inhibition of -induced hyperlocomotion in rats (study No. ITI-007 INT IC200131, Inhibition of Amphetamine-Induced Hyperlocomotion).

Consistent with the in vitro data indicating lumateperone is a high affinity antagonist of 5-HT2A receptors, oral administration of lumateperone inhibited head twitch behavior induced by in rats (ED50 = 0.12 mg/kg) and DOI (1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane) in mice (ED50 = 0.088 mg/kg). In addition, the metabolite IC200161 inhibited quipazine-induced head twitch in mice (ED50 = 0.08 mg/kg) and the metabolite IC200131 inhibited DOI-induced head twitch in mice (ED50 = 0.31 mg/kg).

Oral administration of lumateperone inhibited the conditioned avoidance response in rats (ED50 = 1.5 mg/kg) with a maximal response noted 2 hr post dose and diminishing 3 hr post dose. This effect was similar to that observed with haloperidol (2 mg/kg); however, the effect of haloperidol displayed a longer duration of effect (up to 6 hr).

Oral administration of lumateperone inhibited the hyperlocomotion induced by amphetamine (1 mg/kg, ip) with an ED50 of 0.95 mg/kg. In addition, the metabolite IC200131 inhibited amphetamine-induced hyperlocomotion with an ED50 of 3.98 mg/kg.

Reviewer Note: The in vitro binding data, which suggest that lumateperone has significantly higher affinity for 5-HT2A and D2 receptors than its metabolites, are not consistent with the in vivo efficacy data from these studies. Therefore, based on this in vivo data, it is likely that the metabolites IC200161 and IC200131 play a role in the pharmacological profile of lumateperone at therapeutically relevant doses.

The potential for lumateperone to produce extrapyramidal side effects was investigated using the rodent and canine catalepsy models (study Nos. ITI DPI006 & ITI DPI007). Oral administration of lumateperone produced a relatively modest cataleptic effect in rats at doses ≥10 mg/kg. Oral administration of lumateperone to dogs produced a cataleptic-like behavioral profile at doses of 3 and 6 mg/kg, which lasted for up to 6 hr post dose.

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ADME/PK

Type of Study Major Findings Absorption Limited studies investigating the absorption of Intestinal Permeability lumateperone were conducted in nonclinical species and Effects on ITI-007 on Human Plasma no information on the oral of lumateperone Protein Binding and Permeability (Study in nonclinical species was provided by the Applicant. No. ITI-AS-001) In Vitro Permeability and Solubility Study Lumateperone demonstrated high bi-directional of ITI-007 According to the permeability through Caco-2 cell monolayers. The efflux Biopharmaceutics Classification System ratio close to 1 indicates lumateperone permeates Caco-2 (BCS) Guidelines Issued by the United cells primarily by passive diffusion. Together these data States Food and Drug Administration indicate lumateperone should have high intestinal (Study No. 15INTRP1R3GLPS323) absorption with low efflux potential.

Distribution No information on the of lumateperone in nonclinical species was provided by the Applicant. Studies investigating the distribution of lumateperone following IV and IM administration were conducted by the Applicant; however, they are not discussed in detail here as the clinical route of administration is oral.

Protein Binding Effects on ITI-007 on Human Plasma Lumateperone was highly bound to human plasma Protein Binding and Permeability (Study proteins (97%). Reviewer Note: Information on the No. ITI-AS-001) concentration dependence of human plasma protein binding and the specific plasma proteins bound was not provided by the Applicant.

Drug transporters In vitro Evaluation of ITI-007 and Lumateperone and the metabolite, IC200131, do not IC200131 as Inhibitors of Human appear to be substrates for the human efflux transporter OATP1B1, OATP1B3, OAT1, OAT3 and BCRP (ABCG2). Reviewer Note: IC200131 is the most OCT2 and Substrates of BCRP prominent non-glucuronidated metabolite of Transporters (Study No. XT148028) lumateperone in humans. These data are consistent with the relatively high ratio of brain to plasma exposure of lumateperone and IC200131 observed in vivo in rats (see brain distribution below).

Whole Body Distribution [14C] ITI-007: Tissue Distribution and In pigmented rats administered [14C]-lumateperone (7 Excretion Study in Rats to Support mg/kga) via oral gavage, drug-related radioactivity was Human Dosimetry (Study No. ICT/01) rapidly absorbed from the gastrointestinal tract and extensively distributed into tissues and organs. Peak concentrations of radioactivity in blood and tissues, except the meninges, were achieved within 6 hr post-dose (first collection time). The majority of tissues contained concentrations of radioactivity greater than whole blood throughout the time period investigated (up to 840 hr). The highest concentrations of radioactivity were observed 54 Version date: October 12, 2018

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Type of Study Major Findings in the gastrointestinal tract, uveal tract/retina, liver, , adrenal gland, kidney, spleen, and pancreas. The decline in radioactivity appeared relatively protracted in numerous tissues with 5 to 40% of peak concentrations of radioactivity noted up to 336 hr post- dose. Notably the uveal tract/retina contained 64% and 42% of peak concentrations of radioactivity 336 hr and 840 hr post-dose, respectively, indicating lumateperone- related material may bind to melanin. Significant concentrations of radioactivity were observed in the brain and spinal cord indicating good exposure to drug-related material. Reviewer Note: Lumateperone, IC200131, and IC200161 were tested for phototoxicity potential and found to be negative.

Brain Distribution A Study to Investigate the Bioavailability Lumateperone was rapidly distributed to the brain of rats of Two Test Items in Male SD Rats (<1 hr) following oral administration. In rats, Following Three Different Routes of lumateperone was measurable at 1 hr and 4 hr following Administration (Study No. CXR0398S) oral administration of a 7 mg/kga dose with blood to brain Determination of IC200056 and ratios ranging from 1:3.4 to 1:21 indicating relatively rapid Metabolites IC20130 and IC200131 distribution out of the blood into the brain and good brain Concentrations in Rat Plasma and Brain exposure. The pharmacologically active metabolite, after Oral Administration (Study No. IC200161, was detectable in the brain of rats 1 and 4 hr CXR0448S) following oral administration of lumateperone (7 mg/kga); however, the levels of IC200161 were ~10-fold lower than lumateperone. Levels of the pharmacologically active metabolite, IC200131, were just above the lower limit of quantitation in the brain 1 hr following oral administration of lumateperone (7 mg/kga) and below the lower limit of quantitation at 4 hr. Reviewer Note: These data indicate that the rat CNS is exposed to lumateperone and the pharmacologically active metabolites, IC200161 and IC200131; however, lumateperone appears to be the primary pharmacologically active moiety in rats.

Metabolism Significant interspecies variability in metabolism were observed in rats and dogs relative to humans; therefore, the Applicant conducted numerous studies in alternative nonclinical species (monkey, hamster, guinea pig, minipig) in an attempt to identify a species with a similar metabolic profile to humans. The Applicant was unable to identify a nonclinical species with a similar metabolic profile to humans. Therefore, this review will focus on the metabolic profile in rats and dogs, which were the species used in the nonclinical toxicology studies.

Lumateperone is extensively metabolized following oral administration to rats, dogs, and humans. Although phase I metabolism appears qualitatively similar, significant quantitative interspecies differences in metabolism were

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Type of Study Major Findings observed. The phase I metabolic scheme is depicted in Figure 5. In general, the major metabolic pathway identified in nonclinical species was demethylation of the piperazine ring to form the N-desmethyl metabolite IC200161. In humans, the major metabolic pathway appears to involve ketone reduction of the butyrophenone side chain to form the reduced carbonyl metabolite IC200131. In humans, glucuronidation at the enol/keto position of the butyrophenone side chain of lumateperone appears to be the predominant phase II metabolic pathway. In contrast, glucuronidation appears to play a less significant role in the metabolism of lumateperone in nonclinical species. Study Nos. ITI-007 INT and ICT/11 Lumateperone was rapidly metabolized by rat, dog, and human hepatocytes.

In rat hepatocytes, the major phase I metabolic pathways identified involved the formation of the N-desmethyl metabolite IC200161 (10.39%) and secondary metabolism via amidation of the piperazine ring to form IC201308 (11.92%) or ketone reduction to form IC200565 (6.47%). A tertiary metabolite, IC201309 (8.55%), formed from ketone reduction of IC201308 or amidation of IC200565, was also identified. Reviewer Note: The metabolite IC200131 was not detected in rat hepatocytes suggesting ketone reduction plays a limited role in the phase I metabolism of lumateperone in rat hepatocytes.

In dog hepatocytes, the major phase I metabolic pathways identified involved the formation of the N-desmethyl metabolite IC200161 (9.24%) and secondary metabolism via ketone reduction to form IC200565 (11.49%). In addition, the reduced carbonyl metabolite IC200131 (5.82%) was detected in dog hepatocytes; however, at lower levels than human hepatocytes. The metabolites, IC201308 and IC201309 were also detected, however, at low levels (<5%) in dog hepatocytes.

In human hepatocytes, the major phase I metabolic pathways identified involved ketone reduction to IC200131 (24.78%) and formation of the secondary N- desmethyl metabolite IC200565 (10.41%) and amidation to from the tertiary metabolite IC201309 (6.39%). All identified metabolites were detected in at least one nonclinical species investigated.

Multiple glucuronide conjugates of lumateperone and its phase I metabolites were identified in human hepatocytes, indicating glucuronidation may play a significant role in the metabolism of lumateperone in humans. Reviewer Note: No glucuronide conjugates were

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Type of Study Major Findings identified in dog hepatocytes and significantly fewer glucuronide conjugates were identified in rat hepatocytes relative to humans, indicating glucuronidation may not play a significant role in phase II metabolism of lumateperone in these species.

(Study Nos. ITI-007 INT 20160413 AKR, Consistent with the above findings, the aldo-keto ITI-007 INT Hepatocytes MPA, reductase (AKR)1C inhibitor medroxyprogesterone CSR0411S, and IC200131 CYP3A4) acetate (MPA) significantly reduced lumateperone metabolism by human hepatocytes (95% without MPA vs. 79% with MPA [50 μM]). The primary AKRs involved in the conversion of lumateperone to IC200131 appear to be the human AKR1C1 enzyme and to a lesser extent AKR1B10. AKR1C4 and AKR1C3 appear to play little to no role in the metabolism of lumateperone to IC200131. In addition, several enzymes (CYP3A4 > CYP2C8 > CYP1A2 > CYP2A6) appear to be involved in phase I metabolism of lumateperone. Interestingly, CYP3A4 appears to be capable of metabolizing IC200131 to either IC200565 or back to lumateperone.

Identification of the Major UGT Drug The phase II metabolism of lumateperone and its Metabolizing Enzymes Involved in metabolites to glucuronide conjugates was investigated Human Hepatic Metabolism In Vitro using recombinant uridine diphosphoglucuronosyl (Study No. ICT/08) transferase (UGT) enzymes. The primary UGTs involved appear to be: • Lumateperone: UGT1A1, UGT1A4, and URG2B15 • IC200131: UGT2B7, UGT2B15, and UGT2B17 • IC200161: UGT2B10 and UGT2B15 • IC200565:UGT1A3 • IC201308: UGT1A6 • IC201309: UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B17 Reviewer Note: Numerous UGTs are involved in the glucuronidation of lumateperone indicating this may be a primary metabolic pathway in humans. Consistent with this, numerous conjugated glucuronide metabolites of lumateperone and its phase I metabolites were identified in humans. In Vivo: [14C]-ITI-007: Preclinical Metabolite A single oral dose of [14C]-lumateperone (7 mg/kga) to Analysis in Rat Plasma (Study No. Sprague-Dawley resulted in peak levels of radioactivity 2 ICT/04) hr post-dose and a t1/2 of ~20 hr. Consistent with findings using rat hepatocytes, 20 individual radioactivity peaks were obtained from plasma extracts, indicating extensive metabolism of lumateperone in vivo. Lumateperone accounted for ~2% of total circulating radioactivity in rat plasma. No peaks in the radio-chromatogram accounted for >10% of total circulating radioactivity with the exception of an early eluting peak (M1), accounting for up

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Type of Study Major Findings to 17% of circulating radioactivity, and M9, accounting for up to 11% of circulating radioactivity.

Parameter Plasma tmax (hr) 2 t1/2 19.75 Cmax (μg eq/g) 0.439 AUC0-t (μg eq·hr/g) 6.491 AUC0-inf (μg eq·hr/g) 11.25 tmax = time to reach Cmax; Cmax = maximum concentration observed; t1/2 = half-life; AUC0-t = area under the curve from 0 to tlast; AUC0-inf = area under the curve from 0 to infinity; eq = equivalents [14C]-lumateperone

Reviewer Note: Although only 2 peaks accounted for >10% of total circulating radioactivity, 20 peaks were present at levels ≥ lumateperone indicating they may collectively play a role in the pharmacological or toxicological profile. Unfortunately, the Applicant did not positively identify any of the constituents that make up the radio-chromatogram peaks in the rat mass balance study. An early eluting peak in the radiochromatogram represented ~17% of total circulating radioactivity The Applicant proposes that the early eluting peak is due to oxidative cleavage of the piperazine ring and formation of a 2-carbon fragment containing the [14C] label and aniline metabolites. For a more detailed discussion of the metabolic pathway involved, see the dog mass balance study (No. ICT/07) reviewed below. The existence of this pathway is supported by the presence of the early eluting peak in the rat mass balance study as well as quantifiable levels of all intermediate metabolites and the aniline metabolites (IC201337 and IC201338) in rat plasma collected during the 6-month rat toxicology study (No. 11220). The aniline metabolites should be formed in a 1:1 stochiometric ratio with the 2-carbon fragments. Therefore, they should account for up to 17% of the circulating drug-related material based on the size of the early eluting peak in the rat mass balance study. In contrast, IC201337 and IC201338 were only detected at levels ≤ the lower limit of quantitation of 1 ng/mL in the 6- month general toxicology study while the Cmax for lumateperone in male rats was 3.32 ng/mL following a 3.5 mg/kga dose. To put this into perspective, lumateperone only accounted for ~2% of radioactivity in the mass balance study; therefore, the anilines appear to be present at levels significantly below those that would be expected based on the mass balance study. It is not clear why this difference in apparent exposure exists; however, it is possible that the anilines are retained by tissues or further metabolized and, therefore, not detectable in the 58 Version date: October 12, 2018

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Type of Study Major Findings systemic circulation at levels representative of their formation. Furthermore, it is possible that additional aniline metabolites that were not investigated using mass spectrometry were also present. For example, the Applicant notes that a third aniline metabolite (IC200131- diamine) was present in the urine in the dog mass balance study; however, no further information on the levels of this aniline were provided and no further characterization appears to have occurred. The discrepancy between the levels of these anilines in the plasma and the size of the early eluting peak that theoretically represents their formation could have been addressed by placing the [14C] label on a carbon different from the ones lost via piperazine ring cleavage. This would have allowed for retention of the [14C] label on the aniline metabolites and thus a more accurate assessment would have been determined with respect to the levels that are formed and their potential for accumulation in tissue relative to plasma.

[14C]-ITI-007: Metabolism and Excretion A single oral dose of [14C]-lumateperone (3.5 mg/kga) to Following Single Oral Administration to male beagle dogs resulted in peak levels of radioactivity 1 Male Dogs (Study No. ICT/07) hr post-dose and a t1/2 of ~115 hr. Consistent with findings using dog hepatocytes, 33 individual radioactivity peaks were obtained from plasma extracts, indicating extensive metabolism of lumateperone in vivo. Lumateperone accounted for ~3% of total circulating radioactivity in dog plasma. No radio-chromatogram peaks accounted for >10% of total circulating radioactivity with the exception of an early eluting peak (M1), which accounted for up to 72% of circulating radioactivity, and a glucuronide conjugate IC201318, which accounted for up to 15.5% of circulating radioactivity.

Parameter Plasma tmax (hr) 1 t1/2 (hr) 115.7 Cmax (μg eq/g) 0.631 AUC0-t (μg eq·hr/g) 33.68 AUC0-inf (μg eq·hr/g) 51.23 tmax = time to reach Cmax; Cmax = maximum concentration observed; t1/2 = half-life; AUC0-t = area under the curve from 0 to tlast; AUC0-inf = area under the curve from 0 to infinity; eq = equivalents [14C]-lumateperone

Reviewer Note: Although only 2 peaks accounted for > 10% of total circulating radioactivity, 30 peaks were present at levels ≥ lumateperone indicating they may collectively play a role in the pharmacological or toxicological profile. The Applicant identified 18 of the constituents that make up these peaks in this study. In 59 Version date: October 12, 2018

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Type of Study Major Findings addition, although the Applicant was not able to positively identify the constituents of the early eluting peak, they propose the peak is due to the oxidative cleavage of the piperazine ring in lumateperone and the formation of a 2- carbon fragment containing the [14C] label and aniline metabolites (e.g., IC201337 and IC201338). One proposed metabolic pathway involves the demethylation of lumateperone to form the N-desmethyl metabolite IC200161 (step 1, Figure 6), amidation to form IC201308 (step 2, Figure 6), and hydroxylation to form monohydroxy-IC201308 (step 3, Figure 6) followed by oxidative cleavage and ring opening (step 4, Figure 6) to form a 2-carbon fragment containing the [14C] label and the aniline IC201338. A similar pathway would result in the formation of the aniline metabolite, IC201337, from either intermediate metabolite IC200565 or IC201309. The existence of this pathway is supported by the presence of the early eluting peak in the dog mass balance study as well as detectable levels of all intermediate metabolites and the aniline metabolites (IC201337 and IC201338) in dog plasma collected during the 9-month dog toxicology study (No. 11221). The aniline metabolites should be formed in a 1:1 stochiometric ratio with the 2- carbon fragments. Therefore, they should account for ~70% of the circulating drug-related material based on the size of the early eluting peak in the dog mass balance study. In contrast, IC201337 and IC201338 were only detected at levels ≤ the lower limit of quantitation of 1 ng/mL in the 9-month general toxicology study while the Cmax for lumateperone in male dogs was 7.34 ng/mL following a 3.5 mg/kga dose. To put this into perspective, lumateperone only accounted for ~3% of radioactivity in the mass balance study; therefore, the anilines appear to be present at levels significantly below those that would be expected based on the mass balance study. It is not clear why this difference in apparent exposure exists; however, it is possible that the anilines are retained by tissues or further metabolized and, therefore, not detectable in the systemic circulation at levels representative of their formation. Furthermore, it is possible that additional aniline metabolites that were not investigated using mass spectrometry are also present. For example, the Applicant notes that a third aniline metabolite (IC200131-diamine) was present in the urine of dogs in the mass balance study; however, no further information on the levels of this aniline were provided and no further characterization appears to have occurred. The discrepancy between the levels of these anilines in the plasma and the size of the early eluting peak that theoretically represents their formation could have been addressed by placing the [14C] label on a carbon different

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Type of Study Major Findings from the ones lost via piperazine ring cleavage. This would have allowed for retention of the [14C] label on the aniline metabolites and thus a more accurate assessment would have been determined with respect to the levels that are formed and their potential for accumulation in tissue relative to plasma. In Vivo Formation of Anilines Quantitation of IC201337 and IC201338 Consistent with the theoretical formation of aniline Plasma Levels in TK Rats Following Daily metabolites based on oxidative cleavage of the piperazine Oral Administration of ITI-007 for 6 ring, the aniline IC201338 was formed in rats administered Months (Study No. 11220-AN170728) lumateperone for up to 6 months (Table 5, Study No. 11220). In addition, although levels of IC201337 were not present above the limit of quantitation (1 ng/mL) they were present above the limit of detection of 0.1 ng/mL in rats administered 21 and 42 mg/kg.a

Table 5. Exposure to IC201337 and IC201338 in Plasma Following Administration of Lumateperone to Rats in Study No. 11220 IC201337 IC201338 Dose Cmax AUC Cmax AUC (mg/kga) (ng/mL) (ng·hr/mL) (ng/mL) (ng·hr/mL) 0.6 3.5 BLOD -- 1 (BLOQ) 0.4 21 NC 2.1 14 (BLOQ) 0.8 42 6 2.8 35 (BLOQ) BLOD = Below Limit of Detection (0.1 ng/mL) BLOQ = Below Limit of Quantitation (1 ng/mL) NC = Not Calculated

Demonstration of Metabolism Consistent with the theoretical formation of aniline Dependent Formation of Anilines in Dogs metabolites based on oxidative cleavage of the piperazine Following 9-Month Administration of ITI- ring, the anilines IC201337 and IC201338 were formed in 007 or 3-Month Administration of beagle dogs administered lumateperone for up to 9 months IC200131 (Study No. ITI-007-AN170701) (Table 6, Study No. 11221) or the metabolite IC200131 for up to 3 months. Reviewer Note: Most of the concentrations reported for IC201337 at doses of 1.75 and 3.5 mg/kga were below the limit of quantitation (1 ng/mL) and, therefore, care should be taken when interpreting these data.

Table 6. Exposure to IC201337 and IC201338 in Plasma Following Administration of Lumateperone to Dogs in Study No. 11221 IC201337 IC201338 Dose Cmax AUC Cmax AUC (mg/kga) (ng/mL) (ng·hr/mL) (ng/mL) (ng·hr/mL) 1.75 0.8 13 BLOQ NC (BLOQ) 61 Version date: October 12, 2018

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Type of Study Major Findings 3.5 1.6 27 1 15 7 3.3 61 2.1 37 BLOQ = Below Limit of Quantitation (IC201337, 1 ng/mL; IC201338, 0.1 ng/mL) NC = Not Calculated

Table 7. Exposure to IC201337 and IC201338 in Plasma Following Administration of IC200131 to Dogs in Study No. 11602 IC201337 IC201338 Dose Cmax AUC Cmax AUC (mg/kga) (ng/mL) (ng·hr/mL) (ng/mL) (ng·hr/mL) 1.75 1.1 23 BLOQ NC 3.5 2.7 57 0.2 3 7 6.1 138 0.3 6 BLOQ = Below Limit of Quantitation (IC201337, 1 ng/mL; IC201338, 0.1 ng/mL) NC = Not Calculated Reactive Metabolites GSH Trapping of Reactive Metabolites of To assess whether the aniline metabolites, IC201337 or IC201337 and IC201338 in Rat, Dog, and IC201338 are capable of undergoing metabolic activation Human Liver Microsomes (Study No. the Applicant performed an in vitro glutathione trapping 14920) assay using rat, dog and human liver microsomes.

Both IC201337 and IC201338 formed a single glutathione conjugate in microsomes from all 3 species. The proposed metabolic activation pathway is via dehydrogenation of the 7-aminoindoline ring system and a resulting diiminoquinone intermediate, which is captured by glutathione conjugation (Figure 7).

GSH Adduct Profiling of IC201337 and To further characterize the potential for metabolic IC201338 with Recombinant CYP450s activation of the aniline metabolites, the Applicant (Study No. 14925) investigated the ability of various recombinant cytochrome P450 enzymes to generate the glutathione adduct identified in study No. 14920 (Figure 7).

The following recombinant cytochrome 450 enzymes were capable of forming the glutathione adduct from both IC201337 and IC201338: CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5.

CYP2D6 and CYP3A4 produced the greatest levels of the glutathione adduct in vitro following incubation with IC201337.

CYP2C8, CYP2D6, CYP3A4, and CYP1A1 produced the greatest levels of the glutathione adduct in vitro following incubation with IC201338.

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Type of Study Major Findings Reviewer Note: These studies indicate that metabolic activation of the aniline metabolites is possible across all species. Based on the currently available data, any species- specific toxicity attributed to the metabolic activation of the aniline metabolites should be linked to differences in formation of the anilines and not any species difference in metabolic activation. Consistent with the potential for these metabolites to be linked to toxicity, the most significant levels of the aniline metabolites are reported for the dog, which is the most sensitive species regarding the adverse effects of lumateperone (see General Toxicology section below).

Drug-Drug Interaction: An In Vitro, High Throughput, Inhibition In an in vitro assay lumateperone did produce a significant Screen to Determine the IC50 Values of inhibition of the following major drug metabolizing Ten Test Items Against Five Major cytochrome P450 enzymes at therapeutically relevant Human Cytochrome P450 Enzymes concentrations: CYP1A2, CYP2C19, CYP2C9, CYP2D6, (Study No. CXR0346S) CYP3A4.

IC200131 Pharmacokinetics in Male Based on in vitro metabolism, the lumateperone Mice in the Presence and Absence of metabolite IC200131 appears to be metabolized by (Study No. ITI-007 INT CYP3A4. Consistent with these in vitro data, oral IC200131) administration of IC200131 (10 mg/kg) to mice pretreated with the CYP3A4 inhibitor ketoconazole (50 mg/kg via oral gavage) resulted in a significant increase in exposure to IC200131 relative to mice treated with IC200131 only. Brain and plasma exposure to IC200131 increased 22- and 15-fold, respectively. Reviewer Note: Increased levels of the products of CYP3A4 metabolism of IC200131 (lumateperone, IC200565, and IC200161) were also observed in the brain and plasma of ketoconazole-treated mice, consistent with in vitro data indicating this enzyme is involved in the metabolism of these compounds as well; however, it is important to note that their levels were significantly lower than levels of IC200131.

In Vitro Evaluation of ITI-007 and Lumateperone and the metabolite IC200131 do not IC200131 as Inhibitors of Human appear to be inhibitors (IC50 > 10 μM) of the human OATP1B1, OATP1B3, OAT1, OAT3 and hepatic uptake transporters OAT1B1, OAT1B3, OAT1, OCT2 and Substrates of BCRP OAT3, or OCT2, indicating limited potential for drug-drug Transporters (Study No. XT148028) interactions at these transporters.

Excretion

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Type of Study Major Findings [14C] ITI-007: Tissue Distribution and In pigmented rats, [14C]-Lumateperone-related Excretion Study in Rats to Support radioactivity was predominantly eliminated via the fecal Human Dosimetry (Study No. ICT/01) route with 86.3% recovered in the feces within 48 hr of oral administration of 7 mg/kg.a Urine accounted for only 9.8% of 14C-lumateperone-related radioactivity. Reviewer Note: Despite a relatively protracted decline in tissue/organ concentrations observed in this study, only ~3.4% of radioactivity was recovered from the carcass 168 hr post-dose.

Concentrations of IC200056, IC200130, Following oral administration of lumateperone (3.5 and IC200131 in Rat Plasma and Bile mg/kga) to bile duct-cannulated male rats, the Samples (Study No. 6INTRP1R1) concentration of lumateperone was higher in bile than plasma at the 2-hr time point, indicating that this is not a major route of excretion for the parent. The concentration of the metabolite, IC200161, was higher in the bile than plasma at all time points, indicating this may be a significant route of excretion for this metabolite. Reviewer Note: IC200161 is an N-desmethyl metabolite and, therefore, more polar than lumateperone, which likely accounts for its excretion and elimination via bile.

[14C] ITI-007: Metabolism and Excretion Following oral administration of lumateperone (3.5 Following Single Oral Administration to mg/kga) to male beagle dogs, the primary route of Male Dogs (Study No. ICT/07) excretion in dogs appears to be fecal, with ~46% of the radioactive dose recovered in the feces by 168 hr post dose. In contrast, urine accounted for ~14% of the radioactive dose. A significant amount of radioactivity was retained in the carcass, with only ~62% of the radioactive dose recovered from feces, urine, and cage washings at 168 hr post dose. Notably, ~20% of the administered radioactive dose was still present in the liver 5 weeks post dose. Reviewer Note: The Applicant proposes the retention of radioactive material is due to the oxidative cleavage of the piperazine ring in lumateperone and the formation of a 2-carbon fragment containing the [14C] label, which is incorporated into the endogenous carbon pool. The proposed mechanism of this oxidative cleavage is discussed in more detail in the above section on metabolism and shown in Figure 6. TK data from general toxicology studies Rat: 6-Month General Toxicology Study Table 8 displays the TK parameters for lumateperone and (Study No. 11220) measured circulating metabolites in rats. • Samples collected at 0.25, 0.5, 1, 2, 4, and 24 hr following oral The metabolite IC200161 was the most significant administration on dosing day 1 component of drug-related material measured in this and during week 13 and 26. study, followed by lumateperone and metabolite • TK parameters were estimated IC201308. Consistent with the finding that ketone for lumateperone and reduction is not a major metabolic pathway in rats, the metabolites using Phoenix PK metabolites IC200131, IC200565, and IC201309 were software detected at relatively low levels in plasma.

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Type of Study Major Findings • NOAEL for overt toxicity is 10.5 mg/kg/day in both male and Dose Proportionality: In general, exposure to female rats lumateperone and circulating metabolites increased with • NOEL for CNS pigment increasing dose. The increase was dose-proportional from accumulation is 10.5 21 to 42 mg/kg and greater than dose-proportional from mg/kg/day in male rats and 3.5 3.5 to 10.5 mg/kg and 10.5 to 21 mg/kg. mg/kg/day in female rats (see toxicology tables below) Sex Differences: In general, females had higher exposure to lumateperone. The exposure difference was significant at the lower doses, consistently exceeding 2-fold; however, no sex difference was noted at the highest dose of 42 mg/kg/day. No consistent sex difference in exposure to the metabolites was observed at the 42 or 21 mg/kg doses. Females had > 2-fold higher exposures to metabolites IC200161 and IC201308 at the 3.5 mg/kg and 10.5 mg/kg doses.

Accumulation: A significant amount of accumulation occurred in male and female rats, particularly at the higher doses. Lumateperone accumulation ratios based on AUC ranged from 0.97 to 22.9 in male rats and from 1.9 to 8.48 in female rats. IC200161 accumulation ratios based on AUC ranged from 0.93 to 19.6 in male rats and from 2.15 to 10.7 in female rats.

Dog: 9-Month General Toxicology Study Table 9 displays the TK parameters for lumateperone and (Study No. 11221) measured circulating metabolites in dogs. • Samples collected at 0.25, 0.5, 1, 2, 4, and 24 hr following oral The metabolite IC200161 was the most significant administration on dosing day 1 component of drug-related material measured in this and during week 13 and 26. study followed by lumateperone and metabolite • TK parameters were IC200565. Consistent with the finding that dogs are less determined for lumateperone efficient at reducing the ketone on the butyrophenone and metabolites using Phoenix side chain, IC200131 and IC201309 are present at lower PK software levels in dogs relative to humans; however, ketone • NOAEL for degenerative reduction appears to be more prominent in dogs relative changes or signs of an to rats. inflammatory response (see toxicity tables below) is 1.75 Dose Proportionality: In general, exposure to mg/kg/day in both male and lumateperone and circulating metabolites increased with female dogs increasing dose in a greater than dose-proportional • LOEL for CNS pigment manner. accumulation is 1.75 mg/kg/day. Sex Differences: No consistent sex difference in exposure to lumateperone or metabolites was observed.

Accumulation: A significant amount of accumulation of lumateperone occurred, particularly at the 7 and 10.5 mg/kg/daya dose levels. A significant amount of accumulation of the metabolites IC200161 and IC200565 occurred at all dose levels. Lumateperone accumulation

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Type of Study Major Findings ratios based on AUC ranged from 0.34 to 3.68. IC200161 accumulation ratios based on AUC ranged from 2.54 to 17.6. IC200565 accumulation ratios based on AUC ranged from 1.57 to 11.

TK data from reproductive toxicology studies An Oral (Gavage) Embryo-Fetal Rat: Developmental Toxicity Study of ITI-007 Lumateperone: in the Sprague Dawley Rat (Study No. • Dose-dependent increases in clinical signs, 11053) consistent with known pharmacology of lumateperone, in dams at all doses • Decreases in maternal body weight gain and fetal weight at ≥ 21 mg/kg/day • Increases in fetal variation (e.g., dilated ureter, incomplete ossification, unossified bone with cartilage present) at 62 mg/kg/day • No increases in fetal malformations up to 62 mg/kg/day. • NOAEL for maternal and embryofetal toxicity is 10.5 mg/kg/day, which is ~2.4 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

An Oral Embryo-Fetal Developmental IC200131: Toxicity Study of IC200131 in the • Dose-dependent increases in clinical signs Sprague Dawley Rat (Study No. 11865) (hypoactivity, , splayed hindlimbs, ptosis, lacrimation) at all doses. • Decreases in maternal body weight and fetal weight at ≥ 60 mg/kg/day. • Increases in fetal visceral malformation (cleft palate) at 100 mg/kg/day • increases in skeletal malformations (missing and fused ribs, missing thoracic arches and centra, unaligned thoracic centra, fused 3rd and 4th sternebrae, missing lumbar arches) at 60 mg/kg/day. • NOAEL for maternal toxicity and embryo-fetal toxicity is 15 mg/kg/day. • The exposure (AUC) to IC200131 at 15 mg/kg/day was 321 ng·hr/mL on GD 17, which is ~1.2 times the anticipated exposure to IC200131 in humans at the lumateperone MRHD of 42 mg.

An Oral (Gavage) Embryo-Fetal Rabbit: Development Toxicity Study of ITI-007 in Lumateperone: the New Zealand White Rabbit (Study • No overt maternal or fetal toxicity was observed No. 11055) at doses up to 21 mg/kg/day. • NOAEL for maternal and embryo-fetal toxicity was 21 mg/kg/day, which is ~9.7 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

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Type of Study Major Findings TK data from Carcinogenicity studies 104-Week Oral Gavage Carcinogenicity Rat: Study in Rats with ITI-007 (Study No. • Study was terminated at Week 94 for male rats 8328209) and as early as Week 75 for high-dose female rats. • The NOAELs for neoplastic lesions in male and female rats were 14 mg/kg/day and 10.5/7 mg/kg/day, respectively. • These doses are ~3.2 and 1.6 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

104-Week Oral Gavage Carcinogenicity Mouse: and Toxicokinetic Study with ITI-007 in • Study was terminated at Week 89 for male mice Mice (Study No. 8328210) and as early as Week 91 for high-dose female mice. • The NOAEL for neoplastic lesions in male and female mice was 21/14 mg/kg/day. • This dose is ~1.6 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

Figure 5. Putative Lumateperone Metabolic Scheme

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Figure 6. Putative Mechanism for Aniline Metabolite Formation

Figure 7. Putative Mechanism for Metabolic Activation of Anilines

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Table 8. TK of Lumateperone and Metabolites in Rats Following 26-Weeks Oral Administration Dose Parameter Sex Lumateperone IC200131 IC200161 IC200565 IC201308 IC201309 IC201337 IC201338 (mg/kg) 0.8 M 268 3.30 789 8.01 -- -- 4.8 Cmax (BLOQ) (ng/mL) 0.3 42 F 266 3.52 741 5.91 -- -- 1.7 (BLOQ) AUC0-24 M 2000 54.2 5800 103 -- -- 11 48 (ng·hr/mL) F 1830 57.8 6660 99 -- -- 4 25 0.4 M 101 2.33 537 8.57 -- -- 3.1 Cmax (BLOQ) (ng/mL) 0.2 21 F 314 3.09 600 4.87 67.1 6.9 1.6 (BLOQ) AUC0-24 M 572 38.9 1870 19.9 -- -- NC 14 (ng·hr/mL) F 1380 50.2 3780 16.6 1060 121 NC 16 Cmax M 15.4 1.87 114 2.69 ------(ng/mL) F 61.5 2.06 197 1.70 82.9 9.6 -- -- 10.5 AUC0-24 M 131 5.45 185 4.38 ------(ng·hr/mL) F 299 6.35 698 5.48 1090 123 -- -- Cmax M 3.32 1.81 6.57 BLOQ 9.8 0.8 BLOD 0.3 (ng/mL) F 10.9 1.60 33.0 BLOQ 48.8 3.8 BLOD 1.1 3.5 AUC0-24 M 5.52 5.87 8.90 BLOQ 85.4 7.7 NC 0.5 (ng·hr/mL) F 86.9 5.48 42.8 BLOQ 464 41.5 NC 2.1 Cmax,ss < 0.1 < 0.1 Human M/F 19.7 26.4 19.1 24.8 9.3 26.3 (ng/mL) (BLOQ) (BLOQ) Exposure AUCtau 42 mg M/F 64.2 260.7 66.5 261.8 54.4 361.9 NC NC (ng·hr/mL) BLOQ = Below Limit of Quantitation BLOD = Blow Limit of Detection NC = Not Calculated -- = Not Measured Exposures for lumateperone, IC200131, IC200161, and IC200565 obtained from Week 26 of the 26- Week rat general toxicology study (No. 11220) Exposures for IC201308 and IC201309 were obtained from the rat carcinogenicity study (No. 8328209)

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Table 9. TK of Lumateperone and Metabolites in Dogs Following 39-weeks Oral Administration Dose Parameter Lumateperone IC200131 IC200161 IC200565 IC201308 IC201309 IC201337 IC201338 (mg/kg) Cmax 127 40.1 183 50.0 ------(ng/mL) 10.5 AUC0-24 707 205 907 423 ------(ng·hr/mL) Cmax 30.2 6.58 57.6 27.6 0.870 3.01 3.3 2.1 (ng/mL) 7 AUC0-24 225 37.4 332 170 3.83 52.9 61 37 (ng·hr/mL) Cmax 9.66 3.29 22.1 13.1 1.59 2.69 1.6 1 (ng/mL) 3.5 AUC0-24 49.4 13.5 84.7 51.6 5.76 38.9 27 15 (ng·hr/mL) Cmax 0.8 2.67 2.05 11.2 8.52 1.67 3.01 0.5 (ng/mL) (BLOQ) 1.75 AUC0-24 6.44 7.46 20.5 17.7 3.20 52.9 13 6 (ng·hr/mL) Cmax,ss < 0.1 < 0.1 Human 19.7 26.4 19.1 24.8 9.3 26.3 (ng/mL) (BLOQ) (BLOQ) Exposure AUCtau 42 mg 64.2 260.7 66.5 261.8 54.4 361.9 NC NC (ng·hr/mL) BLOQ = Below Limit of Quantitation -- = Not Measured

Toxicology

General Toxicology

The doses of lumateperone in the nonclinical study reports were expressed as mg of lumateperone tosylate. To maintain consistency with the clinical doses in the label, these doses have been converted to the free base form of lumateperone throughout this review.

The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively. The carcinogenic potential of lumateperone was studied following oral administration for up to 94 weeks in rats and up to 91 weeks in mice. Although lumateperone was not associated with an increased incidence in neoplasms in rats or mice, these studies provide further information on its toxicological profile and, therefore, are reviewed here.

Study title/ number: A 6 Month (180 Day) Oral Repeat Dose Toxicity and Toxicokinetic Study of ITI-007 in Sprague Dawley Rats with a 30-Day Recovery

• Adverse lumateperone treatment-related effects were observed at doses ≥ 21 mg/kg/day with females generally more sensitive than males. • Adverse clinical signs consisted of body shakes, ataxia, hind paw/limb splay, walking on tip toes, unsteady gait, and flaccid body and occurred primarily at 42 mg/kg/day in males and females and occasionally 21 mg/kg/day in females. • Adverse ocular findings (retinal degeneration, inflammation, pigment accumulation) were observed in males and females at 42 mg/kg/day.

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• Hematology findings consistent with a systemic inflammatory response were observed at doses ≥ 10.5 mg/kg/day. • Gross pathology and weight changes in numerous organs consistent with significant intracellular accumulation of pigmented material and infiltrating macrophages at doses ≥ 21 mg/kg/day. • Systemic pigment accumulation, including tissues with low regenerative capacity, at doses ≥ 10.5 mg/kg/day in females and 21 mg/kg in males and associated degenerative changes and signs of an inflammatory response at doses ≥ 21 mg/kg/day in males and females. • The NOAEL for degenerative changes and inflammation was 10.5 mg/kg/day in male and female rats, which is ~2.4 times the MRHD of 42 mg lumateperone on a mg/m2 basis. • The NOAEL for pigment accumulation in tissues with low regenerative capacity was 10.5 mg/kg/day in males and 3.5 mg/kg/day in females, which are ~ 2.4 and 0.8 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: 0, 3.5, 10.5, 21, and 42 mg/kg/day Route of administration: Oral Gavage Formulation/Vehicle: 0.5% methylcellulose (400 centipoise) suspension in deionized (DI) water Species/Strain: Sprague Dawley [Crl:CD®(SD)] rat Number/Sex/Group: See Table 10 below Age: 8 weeks Satellite groups/ unique design: See Table 10 below Histopathology evaluation includes electron microscopy and neuropathology reports Deviation from study protocol affecting interpretation of results: No

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Table 10. Study Design, 6 Month Rat Toxicology Study Number of Rats Lumateperone Lumateperone Dose Volume Group Male Female Dose (mg/kg/day) Concentration (mg/mL) (mL/kg) Toxicology Rats Control 15 15 0 0 10 Low Dose (LD) 10 10 3.5 0.5 10 Mid-Dose 1 (MD-1) 10 10 10.5 1.5 10 Mid-Dose 2 (MD-2) 10 10 21 3.0 10 High Dose (HD) 15 15 42 6 10 Toxicokinetic Rats Control 3 3 0 0 10 Low Dose (LD) 9 9 3.5 0.5 10 Mid-Dose 1 (MD-1) 9 9 10.5 1.5 10 Mid-Dose 2 (MD-2) 9 9 21 3.0 10 High Dose (HD) 9 9 42 6 10 Recovery Rats Control 5 5 0 0 10 High Dose (HD) 5 5 42 6 10

Observations and Results: changes from control Parameters Major findings Mortality Lumateperone treatment cannot be ruled out as causing mortality or toxicity leading to moribund sacrifice for 2 HD male or 2 MD-2 and 2 HD female rats. Clinical Signs Adverse lumateperone treatment-related effects consisted of body shakes, ataxia, hind paw/limb splay, walking on tip toes, unsteady gait, and flaccid body primarily in HD male and female and occasionally in MD-2 female rats.

Although effects on gate and posture are known to occur following administration of antipsychotic drugs, these clinical signs were observed throughout recovery in HD female rats indicating an irreversible effect and correlated with lesions in the sciatic nerve in HD male and female rats.

Other treatment-related effects (e.g., hypoactivity, lethargy, head tilt, salivation, pale body, lacrimation, miscellaneous staining, and dehydration) are consistent with the primary pharmacology of lumateperone and were not considered adverse. Body Weights Males: Decreased bodyweight gain was observed at the MD-2 (-17%) and HD (-31%) throughout the dosing period. Decreased bodyweight gain continued to be observed at the HD (-31%) throughout the recovery period. Females: Slight decreases in bodyweight gain were observed at the HD (-6 to -10%) during the last month of the study and continued to be decreased during the recovery period (-10 to -12%).

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Ophthalmoscopy Bilateral yellow discoloration (minimal to moderate) of the retina was observed in HD male and female rats at the end of both the dosing and recovery periods. This finding correlated with histopathology findings of retinal degeneration and pigmentation and is considered adverse. Hematology Males: LD: +30% white blood cells, +25% neutrophils, +32% lymphocytes, +72% basophils. MD-1: +25% white blood cells, +87% neutrophils, +14% lymphocytes, +40% basophils. MD-2: +43% white blood cells, +121% neutrophils, +28% lymphocytes, +36% monocytes, +53% basophils, +54% large unstained cells. HD: +74% white blood cells, +232% neutrophils, +44% lymphocytes, +65% monocytes, +138% basophils, +198% large unstained cells, +16% reticulocytes. Females: LD: No significant effects MD-1: +27% white blood cells, +51% neutrophils, +20% lymphocytes, +35% monocytes, +41% basophils, +33% large unstained cells, +23% reticulocytes. MD-2: +50% white blood cells, +62% neutrophils, +47% lymphocytes, +30% monocytes, +88% basophils, +118% large unstained cells, +33% reticulocytes. HD: +121% white blood cells, +311% neutrophils, +69% lymphocytes, +93% monocytes, +147% basophils, +272% large unstained cells, +25% reticulocytes. Recovery Males: No effects were observed in males at the end of the recovery phase. Recovery Females: HD: +103% white blood cells, +121% neutrophils, +95% lymphocytes, +122% monocytes.

Changes in hematology parameters correlated with varying degrees of inflammatory reaction or infiltration of inflammatory cells, pigmentation of parenchymal cells, pigment laden macrophage infiltrates, necrosis, and/or degeneration in multiple organs observed during histopathology evaluation.

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Clinical Chemistry Males: LD: No significant effects. MD-1: No significant effects. MD-2: +276% alanine aminotransferase, +129% aspartate aminotransferase. HD: +337% alanine aminotransferase, +248% aspartate aminotransferase. Females: LD: No significant effects. MD-1: No significant effects. MD-2: No significant effects. HD: +87% alanine phosphatase, +126% aspartate aminotransferase. Recovery Males: HD: -40% creatine kinase. Recovery Females: HD: +55% alanine phosphatase, +76% aspartate aminotransferase.

Changes in clinical chemistry parameters correlated with histopathology changes in the skeletal muscle (degeneration/necrosis, intracellular pigment accumulation) and liver (vacuolar degeneration, hepatocellular necrosis, intracellular pigment accumulations [Kupffer cells, hepatocytes, bile duct epithelium], and proliferation of bile duct epithelium). Urinalysis No lumateperone treatment-related effects Gross Pathology Dark brown or red discoloration was noted in multiple organs (lungs, lymph nodes, seminal vesicles, testes, thymus, thyroid glands, uterus, and zymbal’s glands) in MD and HD male and female rats at the end of the treatment and recovery phases. Corresponding histopathology findings included intracellular pigment accumulation and/or pigment laden macrophages in these organs. Organ Weights Males: Absolute and relative organ weight changes were noted in the adrenal glands (↑; MD-2, HD), spleen (↑; HD), and thymus (↓; HD). Females: Absolute and relative organ weight changes were noted in the adrenal glands (↑;HD), heart (↑; LD, MD-1, MD-2, HD), liver (↑; MD-1, MD-2, HD), lungs (↑; MD-1, MD-2, HD), spleen (↑; MD-1, MD- 2, HD), thymus (↓; HD), and uterus (↓; MD-2, HD).

Increases in organ weights are likely due to the significant intracellular pigment accumulation and pigment laden macrophages observed in these organs.

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Histopathology The most prominent finding was a dose-related increase in the Adequate battery: Yes presence of a red/eosinophilic intracellular substance termed “pigment” in numerous tissues at all doses except the LD (Table 101 in Appendix). The presence of intracellular pigment accumulation correlated with macroscopic findings of dark brown or red organ discoloration and increased organ weights. Of particular concern is the presence of intracellular accumulation of pigmented material in tissues with low regenerative capacity (brain, spinal cord, retina, and heart) (Table 11, Table 12, and Table 13).

In the brain and spinal cord, accumulation of pigmented material did not appear to be associated with any degenerative or inflammatory changes. According to the study pathologist, intracellular accumulation of pigmented material was most prominent in neurons in the brain stem (medulla oblongata, pons, and midbrain), ventral horns in the spinal cord, cerebellum (scattered Purkinje neurons), and cerebral cortex (scattered individual neurons in the parietal and piriform cortex) of MD-2 and HD male and female rats and a few MD- 1 female rats (Table 11). Following a 30-day recovery period, the incidence and severity of intracellular accumulation of pigmented material was similar to rats examined at the end of the dosing phase indicating no reversal during this time frame. The Applicant does not consider the intracellular accumulation of pigmented material in the brain and spinal cord adverse as they were not associated with degeneration, necrosis, or inflammatory reactions in these tissues. Reviewer Note: The presence and apparent persistence of these pigment accumulations in the brain, which has limited regenerative capacity, together with the presence of degenerative changes in tissues with significant intracellular accumulations (Table 12, Table 13, Table 14 and Table 101 in Appendix) suggests they may be adverse (Lenz, Braendli-Baiocco et al. 2018). In addition, the sciatic nerve degeneration (Table 14) and adverse effects on gate and posture observed in this study may be linked to the intracellular accumulation of pigmented material in the ventral horns of the spinal cord.

In the peripheral nervous system, there was an increase in the incidence and severity of axonal degeneration in the sciatic nerve; however, the Applicant considers this effect an exacerbation of a spontaneous background lesion and, therefore, not clinically relevant. Reviewer Note: Axonal degeneration in the sciatic nerve occurs commonly in aging rats (Cotard-Bartley, Secchi et al. 1981, Kaufmann, Bolon et al. 2012); however, the dose-related increase in incidence and severity indicate it may be lumateperone-related (Table 14). In addition, the location of lysosomal pigment accumulation in motor neurons in the ventral horn of the spinal cord could be associated with a disruption of neuronal homeostasis that results in axonal degeneration but not neuronal necrosis or degeneration.

In the eye, accumulation of pigmented material was associated with a significant increase in the incidence and severity of chronic active inflammation and retinal degeneration (Table 12); however, the Applicant considers this effect an exacerbation of a spontaneous

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background lesion and, therefore, not clinically relevant. Reviewer Note: Retinal degeneration can be a common background lesion in albino rats (Yamashita, Hoenerhoff et al. 2016); however, retinal degeneration was observed in 100% of HD male and female rats, but not in vehicle control. In addition, degenerative changes were only noted in the presence of significant accumulation of pigmented material in the eye and in the presence of chronic active inflammation (Table 12). Therefore, a causal role of intracellular pigment accumulation is likely.

In the heart, accumulation of pigmented material was associated with inflammation, degeneration and/or necrosis; however, the Applicant considers this effect an exacerbation of a spontaneous background lesion and, therefore, not clinically relevant. Reviewer Note: Progressive cardiomyopathy occurs commonly in aging rats (Bradley, Fant et al. 2015); however, degenerative changes were only noted in the presence of significant accumulation of pigmented material in cardiomyocytes (Table 13). Degeneration/necrosis was noted in the heart of 40% (4/10) of MD-2 male and 80% (8/10) of MD-2 female rats and 100% (15/15) of HD male and female rats. Conversely, degeneration/necrosis was observed in only 6% (1/15) of male rats and no female rats administered vehicle control. It should be noted that the significant accumulation of pigmented macrophages and accumulation of extracellular pigmented material within alveoli of the lung (Table 101 in appendix) may also have contributed to the progression of cardiomyopathy.

Although the toxicological significance of the intracellular accumulation of pigmented material is unclear at this time, a causal role in the adverse degenerative changes noted in MD-2 and/or HD male and/or female rats in the epididymis, esophagus, eyes, heart, larynx, liver, skeletal muscle, sciatic nerve, testes, thymus, and tongue or hypertrophic changes in the adrenal glands, lungs, and thyroid gland cannot be ruled out.

In addition, the magnitude of pigment accumulation and/or presence of significant numbers of pigment laden macrophages was considered adverse in MD-2 and/or HD male and/or female rats in the , lymph nodes, mammary glands, ovaries, pituitary gland, and spleen.

At the end of the recovery period, the histopathology changes noted in HD male and female rats were still present with a similar incidence and severity indicating a lack of reversibility.

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Electron Microscopy TEM was performed on the liver from HD male and female rats to further characterize the light microscopy findings of intracellular accumulation of pigmented material. TEM analysis identified lysosomes within cells (primarily Kupffer cells and macrophages but occasionally hepatocytes) containing medium sized, round, electron dense bodies that occasionally coalesced into larger amorphous structures. The exact nature of the electron dense material was not clear; however, it appeared to be material exogenous to the cell. The study pathologist made no direct statement about the adversity of these findings based on TEM analysis; however, they did note the formation of autolysosomes, which may indicate a response to sublethal cellular injury. LD: low dose (3.5 mg/kg); MD-1: mid dose-1 (10.5 mg/kg); MD-2: mid dose-2 (21 mg/kg) HD: high dose (42 mg/kg). +: indicates increase in parameters compared to vehicle control. -: indicates decrease in parameters compared to vehicle control.

Table 11. Incidence of Neuronal Pigmentation in the Brain and Spinal Cord Following Administration of Lumateperone to Rats for 6-Months. Male Female Dose (mg/kg) 0 10.5 21 42 0 10.5 21 42 Brain – Number Examined 15 10 10 15 15 10 10 15 Neuronal Pigmentation Cerebellum 0 0 0 6 0 0 0 12 Brain Stem 0 0 10 15 0 4 10 15 Cerebral Cortex 0 0 0 13 0 0 0 15 Gliosis Cerebral Cortex 0 0 0 1 0 0 0 0 Spinal Cord – Number Examined 15 10 10 15 15 10 10 15 Neuronal Pigmentation Cervical 0 0 9 14 0 2 9 15 Lumbar 0 0 9 13 0 2 9 15 Thoracic 0 0 9 14 0 2 9 15 The 3.5 mg/kg/day dose was included in the table as no effects were observed.

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Table 12. Incidence and Severity of Lesions in the Eye Following Administration of Lumateperone to Rats for 6-Months. Male Female Dose (mg/kg) 0 10.5 21 42 0 10.5 21 42 Eyes (Retina) – Number Examined 15 10 10 15 15 10 10 15 Degeneration 0 0 1 15 0 0 2 15 Minimal - - - 1 - - 2 - Mild - - - 2 - - - - Moderate - - 1 4 - - - 14 Marked - - - 8 - - - 1 Inflammation – chronic/active 0 0 0 14 0 0 0 15 Minimal - - - 5 - - - 14 Mild - - - 9 - - - 1 Pigmentation 0 0 0 15 0 0 1 15 Minimal - - - 3 - - 1 - Mild - - - 12 - - - 15 The 3.5 mg/kg/day dose was included in the table as no effects were observed. Table 13. Incidence and Severity of Lesions in the Heart Following Administration of Lumateperone to Rats for 6-Months. Male Female Dose (mg/kg) 0 10.5 21 42 0 10.5 21 42 Heart – Number Examined 15 10 10 15 15 10 10 15 Inflammation – chronic/active 0 0 0 15 0 0 1 15 Minimal - - - 1 - - - 1 Mild - - - 5 - - - 9 Moderate - - - 9 - - 1 5 Degeneration/necrosis 1 1 4 15 0 1 8 15 Minimal 1 - 2 1 - 1 5 1 Mild - 1 2 4 - - 2 2 Moderate - - - 10 - - 1 12 Pigmentation 0 0 4 15 0 0 8 15 Minimal - - 4 3 - - 7 1 Mild - - - 12 - - 1 14 The 3.5 mg/kg/day dose was included in the table as no effects were observed. Table 14. Incidence and Severity of Lesions in the Sciatic Nerve Following Administration of Lumateperone to Rats for 6-Months. Male Female Dose (mg/kg) 0 10.5 21 42 0 10.5 21 42 Sciatic Nerve – Number Examined 15 10 10 15 15 10 10 15 Degeneration 1 0 0 4 0 0 0 15 Minimal 0 - - 4 - - - 14 Mild 1 - - 0 - - - 1 The 3.5 mg/kg/day dose was included in the table as no effects were observed.

Study title/ number: 104-Week Oral Gavage Carcinogenicity Study in Rats with ITI-007

• Adverse lumateperone treatment-related effects were observed at doses ≥ 7 mg/kg/day with females generally more sensitive than males.

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• Adverse clinical signs consisted of ataxic and hypoactive behavior, splayed gait, splayed posture, and limited use of the hind legs, and occurred primarily at 14 mg/kg/day in males and ≥ 10.5/7 mg/kg/day in females. • Systemic pigment accumulation, including tissues with low regenerative capacity, at doses ≥ 3.5 mg/kg/day in males and females. • Adverse ocular findings (retinal degeneration, inflammation) were observed in males at 14 mg/kg/day and females at ≥ 10.5/7 mg/kg/day. • Adverse cardiovascular findings (cardiomyopathy, atrial thrombus) at 14 mg/kg/day in males and ≥ 10.5/7 mg/kg/day in females. • Gliosis and infiltrating macrophages in the brain at 14 mg/kg/day in males and ≥ 10.5/7 mg/kg/day in females. • Axonal degeneration in the spinal cord at doses ≥ 7 mg/kg/day in males and ≥ 10.5/7 mg/kg/day in females. • Histiocytic inflammation in the dorsal root ganglia, spinal roots, and peripheral nerves, and axonal degeneration in peripheral nerves particularly at doses ≥ 7 mg/kg/day in males and ≥ 10.5/7 mg/kg/day in females. • The NOAEL for degenerative changes and inflammation was 3.5 mg/kg/day in male and female rats, which is ~0.8 times the MRHD of 42 mg lumateperone on a mg/m2 basis. • A NOEL for pigment accumulation in tissues with low regenerative capacity (e.g., neurons) was not established. The LOEL for pigment accumulation was 3.5 mg/kg/day in males and females, which is ~ 0.8 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: See Table 15 below Route of administration: Oral Gavage Formulation/Vehicle: 0.5% methylcellulose (400 centipoise) suspension in DI water Species/Strain: Sprague Dawley [Crl:CD®(SD)] rat Number/Sex/Group: See Table 15 below Age: 5-7 weeks Satellite groups/ unique design: See Table 15 below Histopathology evaluation includes neuropathology reports Deviation from study protocol affecting interpretation of results: No

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Table 15. Study Design, Rat Carcinogenicity Study Lumateperone Dose Volume Group Number of Rats Dose (mg/kg/day) (mL/kg) Toxicology Rats Male 55 0 10 Control Female 55 0 10 Low Dose Male 55 3.5 10 (LD) Female 55 3.5 10 Mid-Dose Male 55 7 10 (MD) Female 55 10.5 (Day 1 – 385) 7 (Day 386 – end) 10 High Dose Male 55 14 10 (HD) Female 55 21 (Day 1 – 385) 14 (Day 386 – end) 10 Toxicokinetic Rats Male 3 0 10 Control Female 3 0 10 Low Dose Male 9 3.5 10 (LD) Female 9 3.5 10 Mid-Dose Male 9 7 10 (MD) Female 9 10.5 (Day 1 – 385) 7 (Day 386 – end) 10 High Dose Male 9 14 10 (HD) Female 9 21 (Day 1 – 385) 14 (Day 386 – end) 10

Observations and Results: changes from control Parameters Major findings Mortality Lumateperone treatment caused a significant increase in mortality or toxicity leading to moribund sacrifice in HD male and female rats. The survival rates at the time of group termination in the control, LD, MD, and HD groups were 33%, 35%, 25%, and 24% for male rats and 31%, 27%, 55%, and 22% in female rats.

In particular, lumateperone treatment-related cardiopulmonary disease was considered the cause of death by the study pathologist for 36 HD female rats and 20 HD male rats. The presence of cardiopulmonary disease was determined by the severity of progressive cardiomyopathy, and the apparent lung functional reserve indicated by the severity of infiltrates of pigmented macrophages and of free pigment within alveoli. In many animals pigmented macrophages and free pigment occupied a large portion of the lung tissue examined. The Applicant noted that the causes of death not attributed to cardiopulmonary disease were those commonly noted in Crl:CD(SD) rats of this age (Ettlin, Stirnimann et al. 1994). Clinical Signs Adverse lumateperone treatment-related effects consisted of thin appearance, ataxic and hypoactive behavior, splayed gait, splayed posture, limited use of the hind legs, and dark red eyes (Table 16).

Table 16. Incidence of Adverse Clinical Signs Following Administration of Lumateperone in the Rat Carcinogenicity Study Male (n = 55) Female (n = 55)

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Dose (mg/kg) 0 3.5 7 14 0 3.5 10.5/7 21/14 Clinical Sign Hypoactive 8 2 16 53 6 4 55 55 Gait, Splayed 0 1 1 21 0 0 10 34 Posture, Splayed 0 1 1 26 0 0 6 34 Ataxic 0 0 1 0 2 3 2 42 Limited Use, Hind 0 2 0 0 0 1 3 44 Limbs Dark Red Eyes 0 0 0 0 0 0 0 50

Reviewer Note: Although effects on activity, gate, and posture are known to occur following administration of antipsychotic drugs, these clinical signs tend to be observed early during the treatment phase and tolerance is usually established after a couple of weeks. In contrast, these clinical signs worsened or were first observed after Week 52 following administration of lumateperone indicating a non- pharmacologically mediated effect. In addition, these clinical signs are correlated with lesions in the spinal cord and sciatic nerve (Table 19 and Table 20) and, therefore, a toxicological effect cannot be ruled out.

The incidence of dark red eyes in HD females correlated with histopathological findings of pigmented material in the choroid, retina, sclera, and retinal pigment epithelium of the eye (Table 17).

Gross Pathology Dark brown or red discoloration was noted in multiple organs (e.g., lungs, thyroid, heart, adrenals, liver, brain, spinal cord, and eye) in rats at all dose levels. Corresponding histopathology findings included intracellular pigment accumulation and/or pigment laden macrophages in these organs. Histopathology The most prominent finding was a dose-related increase in the Adequate battery: Yes presence of a red/eosinophilic intracellular substance termed “pigment” in numerous tissues at all dose levels. The presence of intracellular pigment accumulation correlated with macroscopic findings of dark brown or red organ discoloration. Of particular concern is the presence of intracellular accumulation of pigmented material in tissues with low regenerative capacity (brain, spinal cord, retina, and heart) (Table 17, Table 18, Table 19, Table 20).

The histopathology findings in the brain, spinal cord, and peripheral nervous system are reviewed in the next section.

In the eye, accumulation of pigmented material was observed in multiple structures and was associated with a significant increase in the incidence and severity of retinal degeneration in HD rats (Table 17). Degenerative changes were most prominent in the outer retina and were typical of those observed with outer retinal derangements. Aside from accumulation of pigmented material the inner retinal ganglion cell complex, the inner limiting membrane appeared unaffected. The optic nerve head and immediately adjacent optic nerve appeared unaffected. In the retina, cells with intracellular

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accumulation of pigmented material were so distorted by intracytoplasmic pigment aggregates that their exact identity could not be determined; thus, it was unclear if the cells were retinal neurons, retinal glial cells, reactive immigrant retinal pigmented epithelium cells, or immigrant systemic macrophages (histiocytes). Reviewer Note: The Applicant considers the retinal degeneration an exacerbation of a spontaneous background lesion and, therefore, not clinically relevant. Retinal degeneration can be a common background lesion in albino rats (Yamashita, Hoenerhoff et al. 2016); however, the incidence and severity of retinal degeneration had a clear dose response and was only noted in the presence of significant accumulation of pigmented material in the eye (Table 12). Therefore, a causal role of intracellular pigment accumulation cannot be ruled out.

In the heart, accumulation of pigmented material was associated with a significant increase in the incidence and severity of cardiomyopathy in HD males and MD and HD females. In addition, atrial thrombus was observed in HD female rats. Reviewer Note: The Applicant considers this effect an exacerbation of a spontaneous background lesion and, therefore, not clinically relevant. Progressive cardiomyopathy occurs commonly in aging rats (Bradley, Fant et al. 2015); however, degenerative changes were only noted in the presence of significant accumulation of pigmented material in cardiomyocytes and the incidence and severity of cardiomyopathy were clearly dose-related (Table 18). In addition, cardiopulmonary disease was listed as the cause of unscheduled deaths in 48% and 84% of HD male and female rats, respectively. Cardiopulmonary disease is not a common cause of death in rat carcinogenicity studies (Ettlin, Stirnimann et al. 1994). It should be noted that the significant accumulation of pigmented macrophages and accumulation of extracellular pigmented material within alveoli of the lung may also have contributed to the progression of cardiomyopathy.

Targeted Secondary Because of the intracellular accumulation of pigmented material in Neuropathology Evaluation of the the CNS and eye and potential association with degenerative changes, Brain, Spinal Cord, and Sciatic targeted evaluations of tissues from the rat carcinogenicity study Nerve and Primary Evaluation of were performed. A targeted secondary evaluation of sections from the Right Side Dorsal Root Ganglia the brain and spinal cord and a primary evaluation of the right side and Nerves peripheral nervous system was performed by (b) (4) . A targeted secondary evaluation of sections from the optic nerves, eyes, and left side sciatic nerve was performed by (b) (4) . In addition, a consultative review was performed by internal FDA pathologists on sections of the brain and spinal cord (Appendix: CFSAN Pathology Consult).

According to the reviewing pathologist (b) (4) , intracellular accumulation of pigmented material in the brain and spinal cord did not appear to be directly associated with any overt degenerative changes; however, axonal degeneration in the dorsal and ventral funiculus of the spinal cord white matter tracts was reported in MD and HD male and female rats (Table 20). Reviewer Note: Although the

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reviewing pathologist (b) (4) did not directly link axonal degeneration with neuronal accumulation of pigmented material, the axonal degeneration in the white matter tracts may be associated with the observed neuronal pigment accumulation in the spinal cord gray matter. Furthermore, axonal degeneration and neuronal accumulation of pigmented material were clearly dose responsive.

The reviewing pathologist (b) (4) did not report reactive (gliosis) or inflammatory (histiocytic inflammation) changes in the spinal cord; however, pigmented infiltrating macrophages and gliosis were reported in the brain, particularly at the HD with females more affected than males (Table 19). Reviewer Note: The internal FDA pathologists further reported a subtle increase in the numbers of activated microglial cells and macrophages, sometimes containing pigmented material, that, in their opinion, constituted a low grade reactive inflammatory response in the spinal cord consistent with that described in the rat brain by the study pathologists (Appendix: CFSAN Pathology Consult).

In addition, the internal FDA pathologists considered the infiltrating macrophages observed in the brain consistent with a diagnosis of histiocytic inflammation, and could not rule out the possibility that neuronal injury and loss occurred at an earlier timepoint. In particular, following review of the cerebellar cortex, the internal FDA pathologists made the following observations: • Red pigment accumulations in Purkinje cells. • Macrophages containing pigmented materials located adjacent to pigmented Purkinje cells (histiocytic inflammation). • A subtle decrease in the number of Purkinje cells (neuronal loss). Therefore, the internal FDA pathologists concluded that the histiocytic inflammation and neuronal loss are adverse biological consequences of accumulation of the pigmented material (Appendix: CFSAN Pathology Consult).

In the peripheral nervous system, lumateperone administration was associated with increased numbers of satellite glial cells (SGCs) in the dorsal root ganglia (DRG), histiocytic inflammation, matrix accumulation among nerve fibers in nerves, and intracellular accumulation of pigmented material in neurons and macrophages, particularly in MD and HD rats.

In the DRG, according to the reviewing pathologist (b) (4) , “In many instances the increased SGC clusters occurred in the absence of a centrally placed neuron, while in a few cases the cores of such SGC clusters consisted of large pigment blocks that were identical to that seen in the peri-nuclear cytoplasm of nearby intact neurons.” The review pathologist (b) (4) considered these findings representative of reactive proliferation of glia associated with neuron degeneration and, therefore, adverse in MD and HD rats.

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In the peripheral nerves and spinal nerve roots, an increased incidence and severity of histiocytic inflammation containing macrophages and multinucleated giant cells was observed in HD rats. These inflammatory foci contained sterol clefts and were associated with myelin debris indicating these regions were destroying the myelin of adjacent nerve fibers. The reviewing pathologists (b) (4) considered this finding adverse. In addition, matrix accumulation consisting of granular to fibrillar pale blue material was often observed as a “small lake beneath the epineurium” or scattered among nerve fibers in MD and HD rats. The toxicological significance of these findings is unclear as the impact of this material on nerve fiber structure and function is unknown. Finally, the incidence of axonal degeneration was increased in peripheral nerves (both proximal and distal samples) arising from the cervical and lumbar DRG, particularly at the HD. In hard plastic-embedded tibial nerve sections, there was a dose-dependent reduction in the numbers of nerve fibers and an associated increased in Schwann cell nuclei at the MD and HD. These findings were considered adverse.

Reviewer Note: The Applicant considers the degenerative effects in the spinal cord and peripheral nervous system to be an exacerbation of a spontaneous background lesions and, therefore, not clinically relevant. Axonal degeneration occurs commonly in aging rats (Cotard- Bartley, Secchi et al. 1981, Kaufmann, Bolon et al. 2012); however, the dose-related increase in incidence and severity indicate it may be lumateperone-related. In addition, a reactive inflammatory response to the accumulation of this pigmented material could not be ruled out based on the evaluations conducted by the secondary reviewing pathologists and the internal reviewing pathologists. LD: low dose (3.5 mg/kg); MD: mid dose (Male, 7 mg/kg; Female, 10.5/7 mg/kg); HD: high dose (Male, 14 mg/kg; Female, 21/14 mg/kg).

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Table 17. Incidence and Severity of Lesions in the Eye Following Administration of Lumateperone (b) (4) to Rats in the Carcinogenicity Study . Male Female Dose (mg/kg) 0 3.5 7 14 0 3.5 10/7 21/14 Eyes – Number Examined 55 55 55 55 55 55 55 55 Autolytic – Not Readable 10 5 9 5 4 3 3 3 Retina, Degeneration 5 4 3 35 11 12 23 41 Minimal 4 3 0 6 9 8 10 1 Slight - 1 2 9 1 3 7 4 Moderate 1 - 1 6 1 3 7 4 Marked - - - 10 - - 5 13 Severe - - - 4 - - - 14 Retina, Pigmentation 0 0 1 14 - - 3 40 Minimal - - 1 13 - - 3 28 Slight - - - 1 - - - 10 Moderate ------2 Retinal Pigmented Epithelium, Pigmentation 0 5 18 47 0 0 48 51 Minimal - 5 17 12 - - 45 2 Slight - - 1 34 - - 3 49 Moderate - - - 1 - - - - Retinal Pigmented Epithelium, 0 0 0 29 0 0 2 39 Hyperplasia/Hypertrophy Minimal - - - 26 - - 2 39 Slight - - - 1 - - - - Moderate - - - 2 - - - - Iris, Pigmentation 0 0 0 9 0 0 0 25 Minimal - - - 9 - - - 25 Choroid, Mononuclear Cell Infiltrate 0 0 1 6 0 0 0 5 Minimal - - 1 6 - - - 5 Choroid, Pigmentation 0 0 0 19 0 0 4 33 Minimal - - - 17 - - 4 30 Slight - - - 2 - - - 3 Ciliary Body, Pigment 0 0 1 35 0 0 12 41 Minimal - - 1 34 - - 12 40 Slight - - - 1 - - - 1

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Table 18. Incidence and Severity of Lesions in the Heart Following Administration of Lumateperone to Rats in the Carcinogenicity Study. Male Female Dose (mg/kg) 0 3.5 7 14 0 3.5 10/7 21/14 Heart – Number Examined 55 55 55 55 55 55 55 55 Cardiomyopathy, Progressive 40 46 47 54 29 23 43 53 Minimal 31 39 33 13 28 22 38 - Slight 9 7 14 30 1 1 4 23 Moderate - - - 11 - - 1 28 Marked ------2 Thrombus, Atrium 0 0 1 0 0 0 0 14 Minimal - - 1 - - - - 3 Slight ------3 Moderate ------6 Marked ------2 Pigmentation, Myocardiocytes 0 0 16 19 0 0 48 53 Minimal - - 14 19 - - 40 7 Slight - - 2 30 - - 8 41 Moderate ------5 Pigmentation, Infiltrating Macrophages 0 4 18 47 0 1 29 53 Minimal - 4 18 16 - 1 26 3 Slight - - - 30 - - 3 26 Moderate - - - 1 - - - 24

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Table 19. Incidence of Neuronal Pigmentation in the Brain and Spinal Cord Following (b) (4) Administration of Lumateperone to Rats in the Carcinogenicity Study . Male Female Dose (mg/kg) 0 3.5 7 14 0 3.5 10/7 21/14 Brain – Number Examined 55 55 55 55 55 55 55 55 Neuronal Pigmentation 0 42 44 51 0 40 53 54 Minimal - 42 33 11 - 40 11 6 Slight - - 11 34 - - 41 31 Moderate - - - 6 - - 1 17 Infiltrating Macrophages, Pigmentation 0 0 1 26 0 0 8 39 Minimal - - 1 24 - - 8 31 Slight - - - 2 - - - 8 Gliosis, Focal 0 0 0 0 1 0 1 3 Minimal - - - - 1 - 1 3 Gliosis, Multifocal - - - - 0 0 0 1 Minimal ------1 Spinal Cord – Number Examined 55 55 55 55 55 55 55 55 Neuronal Pigmentation 0 25 41 53 0* 22 53 54 Minimal - 25 40 20 - 22 27 8 Slight - - 1 30 - - 26 41 Moderate - - - 3 - - - 5 Dorsal Funiculus, Axonal Degeneration 0 0 3 19 0 0 4 17 Minimal - - 3 5 - - 2 8 Slight - - - 9 - - 2 7 Moderate - - - 5 - - - 2 Ventral Funiculus, Axonal Degeneration 2 3 2 0 1 0 3 13 Minimal 2 3 2 - 1 - 2 7 Slight ------1 5 Moderate ------1 *Both the original study pathologist and the targeted review pathologist noted pigment in the neurons of 2 or 1 control female rats, respectively. The FDA pathologists did not observe pigment in any control animals.

Table 20. Incidence and Severity of Selected Lesions in the Peripheral Nervous System Following (b) (4) Administration of Lumateperone to Rats in the Carcinogenicity Study . Male Female Dose (mg/kg) 0 3.5 7 14 0 3.5 10/7 21/14 Dorsal Root Ganglia – Number Examined 47 45 39 43 40 36 50 26 Increased Cellularity, Satellite Glial Cells 8 11 24 43 15 17 50 26 Minimal 8 16 16 5 15 15 14 1 Slight - 1 5 23 - 2 18 5 Moderate - - 2 11 - - 10 10 Marked - - 1 2 - - 6 4 Severe - - - 2 - - 2 6 Pigmented Macrophages 0 0 0 5 0 1 4 12 Minimal - - - 5 - 1 4 12 Neuronal Pigmentation 0 37 38 43 0 33 48 26 Minimal - 37 28 - - 33 36 0 Slight - - 10 37 - - 11 23 Moderate - - - 6 - - 1 3

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Male Female Dose (mg/kg) 0 3.5 7 14 0 3.5 10/7 21/14 Spinal Root – Number Examined 47 45 39 43 40 36 49 26 Increased Cellularity, Schwann Cell 4 1 2 35 0 0 1 26 Minimal 3 - 2 18 - - 1 13 Slight 1 1 - 15 - - - 10 Moderate - - - 2 - - - 3 Axonal Degeneration 29 17 32 42 31 29 47 26 Minimal 29 17 31 41 31 29 45 26 Slight - - 1 1 - - 2 - DRG Nerve – Number Examined 47 45 39 43 40 36 49 26 Increased Cellularity, Schwann Cell 0 0 0 5 0 0 0 4 Minimal - - - 4 - - - 3 Slight - - - 1 - - - 1 Axonal Degeneration 29 17 32 31 12 11 43 25 Minimal 29 17 31 41 12 11 43 25 Slight - - 1 1 - - - - Sciatic Nerve – Number Examined 55 55 55 55 55 55 55 55 Axonal Degeneration 44 52 44 54 43 49 55 53 Minimal 38 41 27 22 43 48 28 33 Slight 6 9 17 24 - 1 27 20 Moderate - 2 - 7 - - - - Marked - - - 1 - - - - Histiocytic Inflammation 7 19 16 31 6 6 41 33 Minimal 7 19 16 19 6 6 41 29 Slight - - - 5 - - - 4 Moderate - - - 4 - - - - Marked - - - 2 - - - - Severe - - - 1 - - - - Matrix Accumulation 0 1 1 27 0 2 21 41 Minimal - 1 1 12 - 2 17 14 Slight - - - 12 - - 4 14 Moderate - - - 3 - - - 12 Marked ------1 Pigmentation 0 0 0 0 0 0 0 7 Minimal ------7 Spinal Nerve Root (Tibia) – Number Examined 47 45 39 43 40 36 49 26 Reduced Nerve Fiber Numbers 44 52 44 54 43 49 55 53 Minimal 7 10 8 4 0 3 7 - Slight 2 6 4 8 - - 14 2 Moderate - - 1 19 - - 10 10 Marked - - 2 6 - - - 11 Severe - - - 2 - - - 2

Study title/ number: 90-Day Oral Toxicology and Toxicokinetic Study of ITI-007 in Beagle Dogs with 45-Day Recovery Period

• Adverse lumateperone treatment-related effects were observed at doses ≥ 3.5 mg/kg/day.

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• Adverse clinical signs consisted of whole body and seizures at doses ≥ 21 mg/kg/day. • Systemic pigment accumulation at doses ≥ 1.75 mg/kg/day in males and females. • Pigment accumulation in neurons in the brain and spinal cord at 21 mg/kg/day in males and females. • Neuronal degeneration and necrosis in the brain and spinal cord at doses ≥ 21 mg/kg/day in males and females. • The NOAEL for degenerative changes and inflammation was 3.5 mg/kg/day in males and females, which is ~2.8 times the MRHD of 42 mg lumateperone on a mg/m2 basis. • The NOAEL for pigment accumulation in neurons was 3.5 mg/kg/day in males and females, which is ~ 2.8 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: 0, 1.75, 3.5, 7→14→21 mg/kg/day Dose escalation for HD group dogs occurred at 7-day intervals Route of administration: Oral gavage Formulation/Vehicle: Suspension with 0.5% w/v methylcellulose Species/Strain: Dog/Beagle Number/Sex/Group: 3 Age: 6 to 7 months Satellite groups: Recovery – 2 vehicle control and HD Deviation from study protocol affecting interpretation of results: Yes Dosing was discontinued for HD dogs, including the recovery group, on study Day 75 due to the emergence of severe neurological signs. The HD main study group dogs were sacrificed on study Day 76 and the recovery group dogs were sacrificed on study Day 133 (actual duration of the recovery period was 58 days).

Observations and Results: changes from control Parameters Major findings Mortality Although no mortality occurred during the course of the study 3 HD group dogs (1M, 2F) were sacrificed due to the emergence of severe neurological signs (seizures).

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2 HD dogs (1 M and 1 F) were sacrificed due to the emergence of seizures on study Days 74 or 75. Due to the presence of whole body tremors in the remaining HD group dogs dosing was discontinued on study Day 75 and the remaining HD main group dogs were sacrificed on study Day 76.

Two days after treatment discontinuation (study Day 77) one female HD recovery group dog was sacrificed due to the emergence of seizures. Clinical Signs Adverse lumateperone treatment-related effects were noted in HD male and female dogs.

Early in the dosing period clinical signs observed in all dose groups were similar to those observed with other atypical antipsychotics (hypoactivity/lethargy and unsteadiness), associated with tmax, were most prominent during the first 1-2 weeks, and decreased in incidence and severity as the study progressed.

Later in the dosing period, adverse CNS-related clinical signs (whole body tremors and seizures) appeared in HD dogs. Seizures were observed beginning on study Day 74, including one dog in which seizures were observed 2 days after discontinuation of treatment. The emergence of seizures led to sacrifice of the affected dogs and dose cessation for the remaining dogs. Body Weights No lumateperone treatment-related effects. Ophthalmoscopy No lumateperone treatment-related effects. ECG No lumateperone treatment-related effects. Hematology No lumateperone treatment-related effects. Clinical Chemistry No lumateperone treatment-related effects. Urinalysis No lumateperone treatment-related effects. Gross Pathology Dark brown or red discoloration was noted in HD dogs in the following organs: Lungs (M/F), intestine (F).

Corresponding histopathology findings included intracellular pigment accumulation and/or pigment laden macrophages in these organs. Organ Weights No lumateperone treatment-related effects. Histopathology The most prominent findings were a dose-related increase in the Adequate battery: Yes presence of a red/eosinophilic intracellular substance termed “pigment” in numerous tissues at all doses and neuronal necrosis/degeneration in the spinal cord and/or brain in 1 MD female dog and most HD male and female dogs (Table 21 and Table 22).

In the CNS, the cerebral cortex, midbrain, brainstem, and all levels of the spinal cord contained significant amounts of intracellular pigmented material. Degeneration was characterized by neurons swollen with eosinophilic cytoplasm, which displaced the Nissl substance to the periphery. Necrosis was characterized by neurons with irregularly smudged, basophilic, shrunken, and wrinkled chromatin or eosinophilic amorphous cytoplasm.

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Outside of the CNS, the presence of intracellular pigment accumulation correlated with macroscopic findings of dark brown or red organ discoloration in several organs. The study pathologist considered the intracellular accumulation of pigmented material in the gall bladder, kidney, liver, lung, lymph nodes, spleen, thymus, tonsil, ureter, and urinary bladder as adverse findings. Accumulation of pigmented material in all other tissues was not considered adverse due to low incidence/severity and absence of adverse gross or histopathology findings. LD: low dose (1.75 mg/kg); MD: mid dose (3.5 mg/kg); HD: high dose (7 mg/kg).

Table 21. Incidence and Severity of Lesions in the Brain Following Administration of Lumateperone to Dogs for 3-Months. Male Female Male Female (Rec) (Rec) Dose (mg/kg) 0 1.75 3.5 21 0 21 0 1.75 3.5 21 0 21 Brain – Number examined 3 3 3 3 2 2 3 3 3 3 2 2 Neuronal Pigmentation 0 0 0 3 0 2 0 0 0 3 0 2 Minimal - - - 2 ------1 Slight - - - 1 - 2 - - - 3 - 1 Neuronal Necrosis 0 0 0 2 0 1 0 0 1 3 0 1 Minimal - - - 2 - - - - 1 2 - - Slight - - - - - 1 - - - 1 - 1 Neuronal Degeneration 0 0 0 3 0 2 0 0 0 3 0 1 Minimal - - - 2 - 1 ------Slight - - - 1 - 1 - - - 3 - 1 Perivascular cuffing 0 0 0 0 0 2 0 0 0 1 0 1 Minimal - - - - - 2 ------Slight ------1 - 1

Table 22. Incidence and Severity of Lesions in the Spinal Cord Following Administration of Lumateperone to Dogs for 3-Months. Male Female Male Female (Rec) (Rec) Dose (mg/kg) 0 1.75 3.5 21 0 21 0 1.75 3.5 21 0 21 Spinal Cord - Number Examined 3 3 3 3 2 2 3 3 3 3 2 2 Neuronal Pigmentation 0 0 0 3 0 2 0 0 0 3 0 2 Minimal - - - 2 - 1 - - - 1 - 1 Slight - - - 1 - 1 - - - 2 - 1 Neuronal Necrosis 0 0 0 2 0 1 0 0 0 2 0 1 Minimal - - - 2 - 1 - - - 2 - 1 Neuronal Degeneration 0 0 0 2 0 2 0 0 0 3 0 1 Minimal - - - 1 - 1 - - - 3 - - Slight - - - 1 - 1 - - - - - 1

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Study title/ number: 9-Month Oral Toxicology and Toxicokinetic Study of ITI-007 in Beagle Dogs

• Adverse lumateperone treatment-related effects were observed at doses ≥ 3.5 mg/kg/day. • Adverse clinical signs consisted of hypoactivity/lethargy, muscle fasciculation, tremors, unsteadiness, reluctance/inability to stand and/or walk, and rigid limbs at doses ≥ 3.5 mg/kg/day. • Systemic pigment accumulation, including neurons in the brain and spinal cord, at doses ≥ 1.75 mg/kg/day in males and females. • Axonal degeneration in the brain and spinal cord at doses ≥ 7 mg/kg/day in males and females. Evidence of an adverse inflammatory reaction (perivascular cuffing, microglial activation) in the brain and spinal cord at doses ≥ 3.5 mg/kg/day in males and females. • The NOAEL for degenerative changes and inflammation was 1.75 mg/kg/day in males and females, which is ~1.4 times the MRHD of 42 mg lumateperone on a mg/m2 basis. • A NOEL for pigment accumulation in neurons was not established. The LOEL for pigment accumulation was 1.75 mg/kg/day in males and females, which is ~ 1.4 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

(b) (4) Conducting laboratory and location GLP compliance: Yes

Methods Dose and frequency of dosing: 0, 1.75, 3.5, 7, and 10.5 mg/kg/day Route of administration: Oral Capsules Formulation/Vehicle: Empty capsule Species/Strain: Dog/Beagle Number/Sex/Group: 4 Age: 6 to 7 months Satellite groups: None Deviation from study protocol affecting interpretation of results: Yes Beginning on study Day 122, HD animals were given dosing holidays when adverse clinical signs were observed. Dosing of all HD dogs was stopped on study Day 135 due to deteriorating condition and emergence of unacceptable clinical observations. All HD dogs were sacrificed on study Day 143 (4.8 months).

Observations and Results: changes from control

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Parameters Major findings Mortality Although no mortality occurred during the course of the study, all HD male and female dogs were sacrificed early on study Day 143 (4.8 months) due to the emergence of unacceptable clinical signs. Clinical Signs Adverse lumateperone treatment-related effects were noted in MD-1, MD-2, and HD dogs with incidence, severity, and time course clearly related to dose and male dogs more affected than females. Adverse clinical signs consisted of hypoactivity/lethargy, muscle fasciculation, tremors, unsteadiness, reluctance/inability to stand and/or walk, and rigid limbs.

Early in the dosing period these clinical signs were similar to those observed with other atypical antipsychotics (hypoactivity/lethargy and unsteadiness), associated with tmax, were most prominent during the first 1-2 weeks, and decreased in incidence and severity as the study progressed. Later in the dosing period; however, other CNS-related clinical signs appeared or became more prominent. These late developing clinical signs included tremors and rigid limbs. Tremors and rigid limbs were first observed or significantly worsened after approximately 3 to 4 months of dosing. The incidence and severity of rigid limbs increased rapidly in dogs in the HD group after about 4 months and generally did not resolve during the dose interval or following cessation of dosing for 9 days. As a result, all HD dogs were sacrificed on study Day 143 (4.8 months). Body Weights No lumateperone treatment-related effects. Ophthalmoscopy No lumateperone treatment-related effects. ECG No lumateperone treatment-related effects. Hematology No lumateperone treatment-related effects. Clinical Chemistry No lumateperone treatment-related effects. Urinalysis No lumateperone treatment-related effects. Gross Pathology Dark brown or red discoloration was noted in the following organs: LD: Lungs (F), (F), salivary gland (F), thyroid glands (M/F) MD-1: Lungs (F), lymph node (M/F), salivary gland (M/F), thymus (F), thyroid glands (M/F) MD-2: Lungs (M/F), lymph node (M/F), pancreas (M/F), salivary gland (M/F), thymus (M/F), thyroid gland (M/F) HD: Gall bladder (M/F), intestine (M/F), lungs (M/F), lymph node (M/F), ovaries (F), pancreas (M/F), salivary gland (M/F), thymus (M/F), thyroid glands (M/F), uterus (F)

Corresponding histopathology findings included intracellular pigment accumulation and/or pigment laden macrophages in these organs. Organ Weights No organ weights were obtained for HD group dogs. No clearly adverse lumateperone treatment-related organ weight effects were noted for LD, MD-1, or MD-2 group dogs. Effects on organ weights were limited to MD-1 and MD-2 dogs: Males: MD-1: Prostate – 26 (absolute) & -23% (relative BW) MD-2: liver; +19 (absolute) & +23% (relative BW), prostate; -29 (absolute) & -26% (relative BW) Females:

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MD-2: thymus; -35 (absolute) & -29% (relative BW) Histopathology The most prominent findings were a dose-related increase in the Adequate battery: Yes presence of a red/eosinophilic intracellular substance termed “pigment” in numerous tissues at all doses (Table 23, Table 24, and Table 102 in Appendix), and axonal degeneration and signs of an inflammatory response (increased GFAP and IBA-1 staining, and perivascular cuffing) in the brain and/or spinal cord in MD-1, MD-2, and/or HD dogs (Table 23 and Table 24). It should be noted that the slightly lower incidence and severity of histopathology findings in HD dogs is likely due to the preterminal sacrifice of these animals on study Day 143 (4.8 months) opposed to the terminal sacrifice of all other dogs on study Day 282 (~9 months).

In the CNS, larger neurons in the midbrain, medulla oblongata, and ventral horns of the spinal cord contained the most significant amounts of intracellular pigmented material (Table 23 and Table 24). Axonal degeneration occurred in MD-2 and HD male and female dogs and was characterized by vacuolated axons containing cellular debris. The incidence of axonal degeneration was highest in the cerebrum and midbrain, although the medulla oblongata and all three sections of the spinal cord were also affected. An increase in the incidence of perivascular cuffing (mononuclear inflammatory cells surrounding small vessels) occurred in MD-1, MD-2, and HD male and female dogs with a distribution similar to axonal degeneration.

In addition to standard histopathology IBA-1 and GFAP staining was performed on sections of the midbrain and cerebrum to assess microglial and astrocyte activity, respectively. In MD-1, MD-2, and HD group dogs IBA-1 positive staining was increased in a diffuse pattern throughout the cerebrum and midbrain with some sections displaying foci of intense IBA-1 positive staining. IBA positive cells were also often concentrated around small and medium sized vessels and described as having a perivascular distribution. GFAP positive staining was increased in the midbrain of MD-2 and HD group dogs indicating an increased in activated astrocytes.

Reviewer Note: The study pathologist did not consider the pigment accumulation in the neurons adverse based on the following assessment: “The material did not appear to alter the morphology of the neuron. There was no detectable swelling of neurons and no inflammatory response associated with intracytoplasmic accumulation of eosinophilic material. The eosinophilic material occurred at all dose levels and the severity was dose dependent; however, there was no evidence of adversity.” Although the study pathologist stated there was not an inflammatory response associated with the pigment accumulations, the presence of perivascular cuffing and increased IBA-1 staining are clear indicators of inflammation in the brain and spinal cord. Therefore, a causal role in the adverse degenerative and inflammatory changes noted in the brain and spinal cord of MD-1, MD-2, and/or HD male and female dogs cannot be ruled out. Furthermore, the presence of these pigment accumulations in a tissue

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with limited regenerative capacity may be considered adverse (Lenz, Braendli-Baiocco et al. 2018).

Outside of the CNS, the presence of intracellular pigment accumulation correlated with macroscopic findings of dark brown or red organ discoloration in several organs. The study pathologist considered the intracellular accumulation of pigmented material in the gall bladder of MD-2 and HD male and female dogs adverse based on the incidence and severity of these accumulations. All other histopathology findings were not considered adverse due to low incidence/severity and absence of adverse gross or histopathology findings. Transmission Electron Microscopy TEM was performed on MD-2 and HD male and female dogs to (TEM) further characterize the light microscopy findings of intracellular accumulation of pigmented material in the brain. TEM analysis identified lysosomes within neurons containing material of medium to marked electron density forming tightly packed lamellations or whorls. The exact nature of the electron dense material was not clear; however, it appeared to be material exogenous to the cell. In addition, the study pathologist did not consider the findings consistent with drug-induced phospholipidosis. According to the study pathologist the material appeared to distend the lysosome but did not otherwise affect it and the presence of lysosomes did not appear to affect adjacent organelles. Therefore, the study pathologist did not consider the presence of electron dense material in the lysosomes adverse. Reviewer Note: Although the accumulation of pigmented material in the lysosomes was not associated with lysosomal bursting it may be a sign of lysosomal dysfunction, which could cause adverse cellular effects. Therefore, a causal role in the adverse effects observed in the CNS cannot be ruled out at this time.

LD: low dose (1.75 mg/kg); MD-1: mid dose-1 (3.5 mg/kg); MD-2: mid dose-2 (7 mg/kg) HD: high dose (10.5 mg/kg). GFAP, glial fibrillary acidic protein; IBA-1, ionic calcium binding adapter molecule 1

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Table 23. Incidence and Severity of Lesions in the Brain Following Administration of Lumateperone to Dogs for 9-Months. Male Female Dose (mg/kg) 0 1.75 3.5 7 10.5 0 1.75 3.5 7 10.5 Midbrain – Number Examined 4 4 4 4 4 4 4 4 4 4 Neuronal Pigmentation 0 4 4 4 4 0 1 4 4 4 Minimal - 4 3 - - - 1 4 - - Slight - - 1 - 1 - - - - - Moderate - - - 4 3 - - - 4 4 Axonal Degeneration 0 0 0 4 3 0 0 0 4 4 Minimal - - - 4 3 - - - 4 4 Perivascular cuffing 1 1 2 4 4 0 0 1 4 4 Minimal 1 1 2 2 4 - - 1 3 2 Slight -- - - 2 - - - - 1 2 ↑ GFAP Positivity Diffuse 0 0 0 3 2 0 0 0 3 2 Minimal - - - 3 2 - - - 3 2 ↑ IBA-1 Positivity Diffuse 0 0 0 3 2 0 0 0 3 2 Minimal - - - 3 2 - - - 3 2 Foci 1 0 3 4 4 0 0 4 4 4 Minimal 1 ------1 Slight - - 3 3 3 - - 4 1 2 Moderate - - - 1 1 - - - 3 1 Perivascular location 0 0 3 4 4 0 0 4 4 2 Minimal ------2 0 2 Slight - - 2 4 4 - - 2 4 - Moderate - - 1 ------Cerebrum – Number Examined 4 4 4 4 4 4 4 4 4 4 Neuronal Pigmentation 0 1 4 4 4 0 0 4 4 4 Minimal - 1 4 - - - - 4 - - Slight - - - - 4 - - - - 4 Moderate - - - 4 - - - - 4 - Axonal Degeneration 0 0 0 4 4 0 0 0 3 4 Minimal - - - 3 4 - - - 3 4 Slight - - - 1 ------Perivascular cuffing 1 0 3 4 4 0 0 3 4 3 Minimal 1 - 3 2 4 - - 3 1 3 Slight - - - 2 - - - - 3 - ↑ IBA-1 Positivity Diffuse 0 0 3 4 4 0 0 3 4 4 Minimal - - 2 - - - - 2 2 - Slight - - 1 4 4 - - 1 2 4 Foci 1 2 4 4 4 - 3 4 4 4 Minimal 1 2 1 - - - 3 1 - - Slight - - 3 4 2 - - 3 4 2 Moderate - - - - 2 - - - - 2 Perivascular location 0 0 3 4 4 0 0 4 4 1 Minimal - - 1 1 - - - - - 1 Slight - - 2 3 4 - - 4 3 - Moderate ------1 -

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Male Female Dose (mg/kg) 0 1.75 3.5 7 10.5 0 1.75 3.5 7 10.5 Medulla Oblongata – Number 4 4 4 4 4 4 4 4 4 4 Examined Neuronal Pigmentation 0 1 4 4 4 0 1 4 4 4 Minimal - 1 3 1 1 - 1 4 - - Slight - - 1 ------Moderate - - - 4 4 - - - 4 4 Axonal Degeneration 0 0 0 2 0 0 0 0 1 1 Minimal - - - 2 - - - - 1 1 Perivascular cuffing 0 0 0 3 2 0 0 1 4 2 Minimal - - - 2 2 - - 1 3 2 Slight - - - 1 - - - - 1 - Cerebellum – Number Examined 4 4 4 4 4 4 4 4 4 4 Neuronal Pigmentation 0 0 2 4 4 0 0 3 4 4 Minimal - - 2 4 4 - - 3 4 4 Axonal Degeneration 0 0 0 1 0 0 0 0 0 0 Minimal - - - 1 ------Perivascular cuffing 0 0 1 0 0 0 0 1 1 0 Minimal - - 1 - - - - 1 1 -

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Table 24. Incidence and Severity of Lesions in the Spinal Cord Following Administration of Lumateperone to Dogs for9-Months. Male Female Dose (mg/kg) 0 1.75 3.5 7 10.5 0 1.75 3.5 7 10.5 Spinal Cord (Cervical) – Number 4 4 4 4 4 4 4 4 4 4 Examined Neuronal Pigmentation 0 0 4 4 4 0 0 4 4 4 Minimal - - 4 - - - - 4 - - Slight - - - - 1 - - - - - Moderate - - - 4 3 - - - 4 4 Axonal Degeneration 0 0 0 1 2 0 0 0 1 2 Minimal - - - 1 2 - - - 1 2 Perivascular cuffing 0 0 1 1 0 0 0 0 3 1 Minimal - - 1 1 - - - - 2 1 Slight ------1 - Spinal Cord (Lumbar) – Number 4 4 4 4 4 4 4 4 4 4 Examined Neuronal Pigmentation 0 1 4 4 4 0 0 4 4 4 Minimal - 1 4 - - - - 4 - - Slight - - - - 1 - - - - - Moderate - - - 4 3 - - - 4 4 Axonal Degeneration 0 0 0 1 3 0 0 0 2 0 Minimal - - - 1 3 - - - 2 - Perivascular cuffing 0 0 0 1 0 0 0 0 1 1 Minimal - - - 1 - - - - 1 - Slight ------1 Spinal Cord (Thoracic) – Number 4 4 4 4 4 4 4 4 4 4 Examined Neuronal Pigmentation 0 0 4 4 4 0 0 4 4 4 Minimal - - 4 - - - - 4 - - Slight - - - - 1 - - - - - Moderate - - - 4 3 - - - 4 4 Axonal Degeneration 0 0 0 1 4 0 0 0 1 1 Minimal - - - 1 4 - - - 1 1 Perivascular cuffing 0 0 1 2 0 0 0 0 2 1 Minimal - - 1 2 - - - - 1 1 Slight ------1 -

General toxicology; additional studies In addition to the general toxicology studies conducted in rat and dog, 3-month general toxicology (study No. 11217) and 2-year carcinogenicity (study No. 8328210) studies were conducted in mice.

In the mouse 3-month general toxicology study (No. 11217) oral administration of lumateperone was generally well tolerated at doses up to 21 mg/kg/day, the mid-dose in this study. At the high dose of 42 mg/kg/day, lumateperone treatment-related mortality and adverse clinical signs (tremors, prostrate condition, flaccidity, lysing on side, ataxia) were observed in males and females. These adverse clinical signs were observed throughout the dosing phase and into the recovery period. A dose responsive increase in non-adverse clinical

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signs consistent with the known pharmacology of lumateperone (hypoactivity, ptosis, lethargy) was observed at doses ≥ 10.5 mg/kg/day. In general, these clinical signs were observed around Tmax primarily during the first 2-weeks of the dosing phase. Consistent with findings in dogs and rats, the most prominent gross pathology findings in mice was a dose-responsive dark discoloration of numerous organs, which correlated with intracellular accumulation of pigmented material in the adrenal glands, brain, gall bladder, liver, lungs, lymph nodes, spinal cord, spleen, thymus ovaries, and uterus. Intracellular accumulation of pigmented material was still present in these organs following a 30 day recovery period. Of particular concern is the apparently irreversible intracellular accumulation of pigmented material in multiple areas of the brain (predominantly thalamus, pons, medulla oblongata) and spinal cord (cervical, thoracic, lumbar) observed at doses ≥ 21 mg/kg/day in males and ≥ 10.5 mg/kg/day in females (Table 25). The pigment was predominantly located within neurons and occasionally in the neuropil. The exact location of pigment accumulation within the neuropil was not identified by the study pathologist; however, given the probable lysosomal location it was likely present in glial cells. The study pathologist did not consider the intracellular accumulation of pigmented material in any organ adverse based on the following assessment: 1) There was no indication of tissue destruction; and 2) there were no clinical pathology or gross pathology changes that were directly or indirectly related to lumateperone administration. Based on adverse clinical signs and mortality at the 42 mg/kg/day dose, the NOAEL in this study is 21 mg/kg/day, which is ~2.4 times the MRHD of 42 mg lumateperone on a mg/m2 basis. The NOEL for intracellular accumulation of pigmented material in the brain and spinal cord is 3.5 mg/kg/day (females), which is ~0.4 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

Table 25. Incidence of Intracellular Pigment Accumulation in the Brain and Spinal Cord Following Administration of Lumateperone to Mice for 3-Months. Male Female Dose (mg/kg) 0 3.5 10.5 21 42 0 3.5 10.5 21 42 Brain – Number Examined 15 15 15 14 14 15 15 14 15 14 Neuronal Pigmentation 0 0 0 7 14 0 0 13 15 12 Minimal - - - 7 1 - - 13 15 - Slight - - - - 13 - - - - 12 Spinal Cord – Number Examined 15 15 15 14 15 15 15 15 15 15 Neuronal Pigmentation 0 0 0 6 13 0 0 13 15 12 Minimal - - - 6 - - - 13 15 - Slight - - - - 13 - - - - 12

In the mouse carcinogenicity study, lumateperone was administered via oral gavage at doses of 3.5, 10.5, and 21 mg/kg/day for the first 36 days, at which time the doses were lowered to 1.4, 4.9, and 14 mg/kg/day for the remainder of the study. Although the Applicant did not indicate why the doses were lowered, this was likely done to bring the study in-line with eCAC recommendations. The higher doses were only administered for 1 month; therefore, the lower dose levels will be referenced throughout the remainder of this section. Lumateperone administration caused a significant increase in early deaths at 14 mg/kg/day in both male and female mice. Doses ≤ 4.9 mg/kg/day were generally well tolerated in this study. Clinical signs observed at all dose levels were generally consistent with those expected based on the known pharmacology of lumateperone or were not significantly different from those observed in 99 Version date: October 12, 2018

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vehicle controls and likely age related. Consistent with findings in the 3-month mouse general toxicology study and findings in dogs and rats, the most prominent histopathology findings in the carcinogenicity study was a systemic dose-responsive intracellular accumulation of pigmented material in the adrenal glands (females only), brain, esophagus (females only), eye (infiltrating macrophages, females only), gall bladder, kidney, liver, lung, lymph nodes, spinal cord, spleen, thymus ovaries, and uterus. Of particular concern is the intracellular accumulation of pigmented material in tissues with low regenerative capacity (e.g., neurons). Although the exact location of the pigment accumulations in the brain and spinal cord was not identified by the study pathologist, based on the 3-month mouse study, it is likely that multiple areas were affected. Neuronal accumulation of pigmented material was observed at doses ≥ 4.9 mg/kg/day in males and ≥ 1.4 mg/kg/day in females (Table 26). The study pathologist did not consider the intracellular accumulation of pigmented material in any organ adverse based on the following assessment: Degenerative or inflammatory lesions did not accompany the pigment. In addition to the accumulation of pigmented material in neurons, an increase in the incidence and severity of sciatic nerve axonal degeneration was observed at 14 mg/kg/day in males and ≥ 4.9 mg/kg/day in females (Table). Sciatic nerve axonal degeneration is a common age-related background lesion in the mouse; however, based on the increased incidence and severity, together with the presence of neuronal accumulation of pigmented material in neurons and similarity to findings observed in the rat, a causal role of lumateperone cannot be ruled out. In the eye pigment accumulation was observed in infiltrating macrophages in 3 of 55 females at 14 mg/kg/day. The significance of this finding is unclear at this time and no increase in the incidence or severity of retinal degeneration was observed in mice in this study; however, given the findings in the eye of rats, this observation should not be dismissed. The NOAEL for sciatic nerve axonal degeneration in this study is 1.4 mg/kg/day (females), which is ~0.2 times the MRHD of 42 mg lumateperone on a mg/m2 basis. A NOEL for intracellular accumulation of pigmented material in the brain and spinal cord was not achieved in female mice in this study. The LOEL is 1.4 mg/kg/day (females), which is ~0.2 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

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Table 26. Incidence of Intracellular Pigment Accumulation in the Brain and Spinal Cord Following Administration of Lumateperone to Mice in the Carcinogenicity Study. Male Females Dose (mg/kg) 0 1.4 4.9 14 0 1.4 4.9 14 Brain – Number examined 55 54 54 55 55 55 55 55 Neuronal Pigmentation 0 0 9 45 0 8 35 54 Minimal - - 9 20 - 7 33 24 Slight - - - 23 - 1 2 30 Moderate - - - 2 - - - - Spinal Cord – Number examined 55 54 55 54 55 55 55 54 Neuronal Pigmentation 0 0 0 41 0 3 26 52 Minimal - - - 28 - 3 26 30 Slight - - - 12 - - - 22 Moderate - - - 1 - - - -

Table 27. Incidence and Severity of Sciatic Nerve Axonal Degeneration Following Administration of Lumateperone to Mice in the Carcinogenicity Study. Male Females Dose (mg/kg) 0 1.4 4.9 14 0 1.4 4.9 14 Sciatic Nerve – Number examined 55 55 55 55 55 55 55 54 Axonal Degeneration 23 28 23 35 36 31 47 49 Minimal 19 21 22 28 30 19 35 30 Slight 4 7 1 7 6 12 12 19

Genetic Toxicology

In Vitro Reverse Mutation Assay in Bacterial Cells (Ames) Study title/ number: Bacterial Reverse Mutation Assay (Ames test), AB34LX.503.BTL Key Study Findings: • Lumateperone was positive (3.3-fold maximum increase) for mutagenicity in bacterial cells (TA1537) in the presence of S9 metabolic activation. • Lumateperone was negative for mutagenicity in bacterial cells without S9 metabolic activation. GLP compliance: Yes Test system: Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain WP2 urvA; doses ≤ 5000 μg/plate in DMSO; +/- S9. Study is valid: Yes

Study title/ number: Bacterial Reverse Mutation Assay (Ames test), AE54JU.502ICH.BTL Key Study Findings: • Lumateperone was negative for mutagenicity in bacterial cells with and without S9 metabolic activation. GLP compliance: Yes Test system: Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain WP2 urvA; doses ≤ 5000 μg/plate in DMSO; +/- S9. Study is valid: Yes

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In Vitro Assays in Mammalian Cells Study title/ number: In Vitro Mammalian Cell Gene Mutation Test (L5178Y/TK+/- Mouse Lymphoma Assay), AB34LX.704.BTL Key Study Findings: • Lumateperone was positive for mutagenicity in mouse lymphoma TK+/- cells in the presence of S9 metabolic activation at a few concentrations (non-concentration-related) that were associated with inhibition of cell growth. • Lumateperone was negative for mutagenicity in mouse lymphoma TK+/- cells in the absence of S9 metabolic activation. GLP compliance: Yes Test system: L5178Y/TK+/- mouse lymphoma cells Study is valid: Yes

In Vivo Clastogenicity Assay in Rodent Study title/ number: Mammalian Erythrocyte Micronucleus Test, AB43RT.125.BTL Key Study Findings: • Lumateperone was negative for clastogenicity in a valid in vivo micronucleus assay at doses up to 70 mg/kg GLP compliance: Yes Test system: Rat, bone marrow micronuclei; Single oral administration of 7, 21, or 70 mg/kg; bone marrow was collected 24 or 48 hr after the dose. Study is valid: Yes

Study title/ number: In Vivo Comet Assay Key Study Findings: • Lumateperone was negative in a valid in vivo comet assay at doses up to 70 mg/kg GLP compliance: Yes Test system: Rat, liver; two oral doses of 7, 21, or 70 mg/kg separated by 21 hr; liver was collected 3 hr after the second dose. Study is valid: Yes

Other Genetic Toxicity Studies The mutagenic potential of several lumateperone metabolites (IC201314, IC201309, IC201308, IC200565, IC200161, IC200131) was investigated using the in vitro reverse mutation assay in bacterial cells. These metabolites were negative for mutagenicity with and without S9 metabolic activation with the exception of IC200161, which was judged to be equivocal (dose responsive increase 1.6 to 1.8-fold) in the presence of S9 metabolic activation.

The mutagenic potential of two lumateperone metabolites (IC200131, IC200161) was investigated using the in vitro L5178Y/TK+/- mouse lymphoma assay. Both metabolites were negative for mutagenicity with and without S9 metabolic activation.

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Carcinogenicity

There were no statistically significant lumateperone treatment-related neoplasms observed in male or female Sprague-Dawley rats following daily oral gavage administration under the conditions of this study. The rat carcinogenicity protocol was submitted for review and concurrence, which was granted by the executive Carcinogenicity Assessment Committee (eCAC). The lumateperone doses selected were 0, 3.5, 7, and 14 mg/kg/day for male rats and 0, 3.5, 10.5, and 21 mg/kg/day for female rats. Following a decreasing trend in body weight gain and increasing mortality in female rats, the MD and HD were lowered during Week 54 to 7 and 14 mg/kg/day, respectively. The study was terminated early at Week 75 for HD female rats and at Week 94 for all male rats due to moribundity. The MD and low dose (LD) group female rats were terminated at Week 92. There were no statistically significant lumateperone treatment- related neoplastic lesions observed in male or female rats at any dose level. The NOAEL for neoplastic lesions was the HD of 14 mg/kg/day in male rats and 10.5/7 mg/kg/day in female rats. For the label: “In a two-year carcinogenicity study conducted in Sprague-Dawley rats, lumateperone did not cause any increase in tumors when dosed orally up to a maximum daily dose of 14 mg/kg/day in male rats and up to 10.5/7 mg/kg/day in female rats. This dose is approximately 3.2 and 1.6 times the MRHD of 42 mg/day for adult male and adult females, respectively, on a mg/m2 basis.”

There were multiple non-neoplastic lesions observed in multiple organ systems including the brain, spinal cord, peripheral nervous system, eye, and heart. These findings are reviewed in detail under the General Toxicology section above. Briefly, consistent with findings in other repeat dose toxicology studies, intracellular accumulation of pigmented material was observed in multiple tissues within parenchymal cells, infiltrating macrophages, and occasionally in the extracellular space. The accumulation of intracellular pigmented material was consistently associated with degenerative changes in these tissues and is considered adverse. These intracellular pigment accumulations occurred at all dose levels in this study and therefore a NOAEL based on non-neoplastic lesions could not be established. The LD of 3.5 mg/kg/day is 0.8 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

There were no statistically significant lumateperone treatment-related neoplasms observed in male or female Crl:CD-1(ICR) mice following daily oral gavage administration under the conditions of this study. The mouse carcinogenicity protocol was submitted for review and concurrence by the eCAC. The lumateperone doses selected by the Applicant were 0, 3.5, 10.5, and 21 mg/kg/day for male female mice. The eCAC recommended doses of 1.4, 4.9, 14 mg/kg/day. The final doses selected by the Applicant were the same originally proposed; however, the doses were reduced to those recommended by the eCAC starting on Day 36. It is not clear why the doses were reduced; however, it is likely that the Applicant initiated dosing prior to receiving eCAC concurrence and reduced the doses to those recommended by the eCAC. The study was terminated early at Week 89 for all male mice and at Week 91 for HD female mice due to moribundity. The MD and LD group female mice were terminated at Week 98 and 99, respectively. There were no statistically significant lumateperone treatment-related

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neoplastic lesions observed in male or female mice at any dose level. The NOAEL for neoplastic lesions was the HD of 21/14 mg/kg/day in both male female mice. For the label: “In a two-year carcinogenicity study conducted in Crl:CD-1(ICR) mice, lumateperone did not cause any increase in tumors when dosed orally up to a maximum daily dose of 21/14 mg/kg/day. This dose is approximately 2 times the MRHD of 42 mg/day on a mg/m2 basis.”

There were multiple non-neoplastic lesions observed in multiple organ systems in mice, including the brain and spinal cord. These findings are reviewed in detail in the General Toxicology section above. Briefly, consistent with findings in other repeat dose toxicology studies, intracellular accumulation of pigmented material was observed in multiple tissues in mice, similar to those seen in rats and dogs. Pigmented material was observed within parenchymal cells and infiltrating macrophages. The accumulation of intracellular pigmented material was not associated with degenerative changes in these tissues under the conditions of this study; however, as previously noted, degenerative changes were observed in rats and dogs. The accumulation of pigmented material in organs with low regenerative capacity (e.g., brain) is considered adverse. These intracellular pigment accumulations occurred at all dose levels in female mice and at the MD and HD in male mice in this study. Therefore, a NOAEL based on non-neoplastic lesions could not be established for female mice. The LD of 3.5/1.4 mg/kg/day is 0.4/0.16 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

Reproductive and Developmental Toxicology

The doses of lumateperone in the nonclinical study reports were expressed as mg of lumateperone tosylate. To maintain consistency with the clinical doses in the label, these doses have been converted to the free base form of lumateperone throughout this review.

Fertility and Early Embryonic Development Study title/ number: Study of Fertility and Early Embryonic Development in Sprague Dawley Rats After Daily Oral Administration of ITI-007/ Study 11051 Key Study Findings • Dose-dependent increase in clinical signs of ptosis, hypoactivity, and lacrimation in both sexes. These are likely due to the anti- activity of the drug. • Dose-dependent decreases in body weight in males during the entire treatment period and dose-dependent decreases in body weight gain in females during the gestation period. • Abnormal estrous cycle (increased number of acyclic animals and prolonged estrous cycle length) in females at all doses. • Testicular toxicity in males at doses ≥ 21 mg/kg/day, evidenced by decreased sperm counts and motility, reduced testicular/epididymal size and weight, and histopathological findings of atrophy or degeneration of the seminiferous tubules. • Decreases in the number of corpora lutea and implantation sites at 42 mg/kg/day.

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• Decreases in mating and fertility indices at all doses, when treated males were paired with treated females. At doses ≤10.5 mg/kg/day, mating performance of treated males was not significantly impaired when paired with untreated naïve females. • Based on the testicular toxicity findings, the NOAEL for male fertility is 10.5 mg/kg/day lumateperone tosylate, which is approximately 2.3 times the MRHD of 42 mg lumateperone on a mg/m2 basis. • Based on the effects on female estrous cycle and decreased mating and fertility indices at all doses, a NOAEL could not be established for the effect on female fertility. The LOAEL for female fertility is 3.5 mg/kg/day lumateperone, which is approximately 0.8 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: Once daily of 0 (vehicle control), 3.5 (LD), 10.5 (MD-1), 21 (MD-2), and 42 (HD) mg/kg/day Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose [400 centipoise (cp)] in DI water Species/Strain: Sprague Dawley [Crl:CD®(SD)] rat Number/Sex/Group: N=25/sex/group (5 of which were also used for TK analysis) Satellite groups: NA Study design: Males were orally administered with lumateperone tosylate once daily at 0, 3.5, 10.5, 21, and 42 mg/kg/day for at least 9 weeks (pre-mating, during mating, and post-mating till the day prior to scheduled necropsy). Females were orally administered with lumateperone tosylate once daily at 0, 3.5, 10.5, 21, and 42 mg/kg/day for 2 weeks prior to mating, during mating, and until gestation day (GD) 7. In addition, because of increased time to mating and decreased fertility indices, a second pairing was performed using untreated naïve females with treated males that did not mate with their corresponding treated females. However, no cesarean evaluation was performed for these untreated females.

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Deviation from study protocol No affecting interpretation of results:

Observations and Results

Parameters Major findings Mortality No drug-related mortality was observed in the study. Clinical Signs Dose-dependent increases in ptosis, hypoactivity, and lacrimation (at all doses in both sexes); salivation (HD in both sexes); splayed hindlimbs (HD females), reluctance to walk (LD and HD males); nasal discharge (LD and MD-1 males), and rales in one HD male. In addition, dose-dependent increases in various staining (nasal, oral, perigenital, perinatal, lacrimal, etc.) were observed and were most marked in HD animals (Table 28). Body Weights During the pre-mating and mating treatment period, dose-dependent decreases in mean body weight were observed in HD males (↓~6- 22%), MD-2 males (↓~5-15%), and MD-1 males (↓~6-7%). No effect was seen in LD males. These decreases in body weight did not correlate with food consumption. Body weight was not affected in females at any dose. During the gestation period, compared to the controls, slight but dose-dependent decreases in the mean body weights were observed in MD-2 females (↓~5-6%) and HD females (↓~7-9%) from GDs 6-14. Dose-dependent decreases in body weight gain were observed in MD- 1 females, MD-2 females, and HD females (↓30, 40, and 43%, respectively, relative to controls). These decreases correlated with decreases in food consumption. Body weight or food consumption were not affected in LD females. Necropsy findings Estrous Cycle: abnormal estrous cyclicity at all doses. Specifically, [Mating/Fertility Index, Corpora there were 3/9, 4/10, 4/10, 4/10 females that were acyclic (did not Lutea, Preimplantation Loss, etc.] complete one full estrous cycle) in LD, MD-1, MD-2, and HD groups, respectively, whereas all 10/10 control females completed at least 1 cycle and 9/10 control females completed 2 or 3 cycles. This was also reflected by the decreased mean number of cycles (Table 29). In addition, for females that completed at least 1 cycle, prolongation of the estrous cycle length was observed at all doses (5.0, 6.0, 5.5, and 6.8 days in LD, MD-1, MD-2, and HD, respectively, compared to 4.7 days in controls, Table 29). Male Sperm Analysis: dose-dependent decreases in sperm motility and epididymal sperm count were observed in MD-1 males and HD males (Table 30). A slight decrease in sperm count was also observed in MD-1 males (↓~14% relative to concurrent controls); however, the value was within the historical control range at the test facility provided by the Applicant and, therefore, were not considered to be drug-related. Mating and Fertility Indices: Treated males paired with treated females: decreased mating index in MD-1 and HD; dose-dependent increases in the number of days for

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males to inseminate females in MD-1, MD-2, and HD (6.1, 8.4, and 8.2 days, respectively, compared to 2.8 days in controls, Table 31); decreased fertility index at all doses (75%, 85.7%, 75%, and 54.5% in LD, MD-1, MD-2, and HD, respectively, compared to 96% in controls, Table 31). Treated males paired with untreated naïve females: Because of the decreases in mating and fertility indices, males that failed to inseminate their corresponding treated females were paired with a new set of untreated naive females. Most of the males successfully mated with the untreated females and the time to mating were comparable to control values (Table 32). However, a few males failed to inseminate untreated females (Table 32). The treated males had correlative findings of small or no sperm cloud, reduced testis size, and very low epididymal sperm count. The 2 MD-2 males also had histopathology findings of testicular atrophy/degeneration. These findings are consistent with the findings of impaired sperm parameters and histopathology changes in the testis in MD-2 and HD males. Therefore, the inability of these 2 MD-2 males to inseminate was most likely drug-related and adverse. In contrast, the only control male that failed to inseminate had normal sperm parameters and normal histopathology findings in the testis. Therefore, its failure to inseminate the female is considered to be incidental. Based on the additional data from the second pairing, it appears that at lower doses (≤10.5 mg/kg/day), the decrease in mating and/or fertility indices were likely due to effects on females (dysregulated estrous cycle, etc.), whereas at higher doses (≥ 21 mg/kg/day), both males and females seem to be affected. Female Cesarean Data: Compared to controls, HD females had significantly decreased number of corpora lutea (15 compared to 20 in controls, ↓25%) and implantation sites (12 compared to 15 in controls, ↓20%). These changes correlated with the abnormalities in the estrous cycle. LD, MD-1, and MD-2 groups were not affected. Gross Pathology: MD-2 and HD males had reduced size of testes and/or epididymis, which correlated with histopathological findings of atrophy/degeneration of the seminiferous tubules (bilateral) and decreased epididymal weights. Females had dose-dependent increases in “patent” (open or unobstructed) uterus/cervix, which correlated with the increases in the number of non-gravid females with drug treatment (Table 33). Organ Weights: HD males had decreases in epididymis weights (↓~10%), which correlated with findings of impaired sperm motility, gross pathology of reduced testis/epididymis size, and histopathology of atrophy or degeneration in the seminiferous tubules. Histopathology: drug-related findings suggestive of testicular toxicity in MD-2 and HD males, including bilateral atrophy/degeneration of seminiferous tubules in 3/22 MD-2 and 6/20 HD males; hypospermia in the epididymal ducts in 2/22 MD-2 and 2/22 HD males; cell debris in 2/22 MD-2 males; and exfoliated germ cells in 5/20 HD males (Table 34); dose-dependent increases of pigmentation (pigment laden macrophages) in the ovaries and uterus in MD-1, MD-2, and HD females (Table 34).

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Toxicokinetics After 96/28 (M/F) days of repeat dosing, the exposures (AUC) to lumateperone were (M/F, ng·h/mL): LD: 83.4/28.1; MD-1: 121/338; MD-2: 249/1995; HD: 1661/1652. . LD: low dose (3.5 mg/kg/day); MD-1: mid dose-1 (10.5 mg/kg/day); MD-2: mid dose-2 (21 mg/kg/day); HD: high dose (42 mg/kg/day)

Table 28: Drug-related Clinical Observations during the Pre-mating Treatment Period in the Rat Fertility Study Number of Animals with Observation Males (mg/kg/day) Females (mg/kg/day) Clinical Observation 0 3.5 10.5 21 42 0 3.5 10.5 21 42 Ptosis - 17 25 25 25 - 17 25 25 25 Lacrimation - 9 23 25 25 1 18 25 25 25 Hypoactive - 4 24 25 25 - - 22 25 25 Splayed limbs ------12 Reluctant to walk - - 1 - 5 ------= no observation at this dose level; n = 25/sex/dose

Table 29: Drug-related Abnormal Female Estrous Cycles in the Rat Fertility Study Dose Level (mg/kg/day) Parameter 0 3.5 10.5 21 42 No. Females Analyzed 10 9 10 10 10 Mean No. of Cycles 2.0 0.89 0.70 0.70 0.80 No. Females Analyzed 10 6 6 6 6 Mean Cycle Length 4.7 5.0 6.0 5.5 6.8

Table 30: Drug-related Decreases in Sperm Parameters in the Rat Fertility Study Dose Level (mg/kg/day) Sperm Analysis Parameter 0 3.5 10.5 21 42 % Motile 90.5 88.3 90.4 81.9 79.8 Motility (%) % Progressive 70.2 68.5 68.1 64.1 59.8 Counts (sperm/gram) Epididymal Counts 232.9 NP 199.9 145.8 185.8 Normal 197.7 NP 193.8 185.0 182.8 Morphology Abnormal 1.7 NP 5.0 6.0 3.3 (# in 200 sperm) Detached Head 0.6 NP 1.3 0.8 4.6 NP = Not Performed; n = 19-20/dose

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Table 31: Drug-related Decreases in Mating and Fertility Indices in the Rat Fertility Study Dose Group (mg/kg/day) Parameter 0 3.5 10.5 21 42 Females Placed with males n 25 25 25 25 25 Total number inseminated n 23 24 21 24 22 Female mating index % 92 96 84 96 88 Pregnant females n 22 18 18 18 12 Female fertility index % 96 75 85.7 75 54.5 Days until mating Mean 2.8 2.7 6.1 8.4 8.2 n 21 20 10 7 7 Day 1 to 4 % 87.5 87 47.6 30.4 31.8 n 2 2 5 3 5 Day 5 to 8 % 8.3 8.7 23.8 13 22.7 n 1 1 6 13 10 Day 9 to 14 % 4.2 4.3 28.6 56.5 45.5 Mating index = No. of females sperm positive/No. females co-housed x 100Fertility index = No. of females pregnant (with implants)/ No. of animals inseminated x 100

Table 32: Mating Performance to Untreated Naive Females in the Rat Fertility Study Dose Group No. of Males Time to Mating (days) 0 2 4 3.5 1 na 10.5 6 3.2 21 6 2.5 42 10 2.9 na = single male did not impregnate a female

Table 33: Drug-related Gross Pathology Findings in the Rat Fertility Study 0 3.5 10.5 21 42 Dose (mg/kg/day) Number of Animals Affected Reduced Epididymis/Testis (with 1 1 0 2 2 histopathology) Patent Uterus 4 6 6 7 12

Table 34: Drug-related Histopathology Findings in the Rat Fertility Study Sex and Dose Group (mg/kg/day) Males Females Organ Finding 0 3.5 10.5 21 42 0 3.5 10.5 21 42 Number examined 20 20 21 22 20 25 25 25 25 25 Epididymis Cell Debris 0 1 0 2 0 - - - - - Hypospermia 0 1 0 2 2 - - - - - Exfoliation 1 0 0 0 5 - - - - - Testes Atrophy/degeneration 1 1 0 3 6 - - - - - Ovaries Pigmentation - - - - - 0 0 8 16 21 Uterus Pigmentation - - - - - 0 0 0 1 7 Non-gravid - - - - - 4 7 8 8 13

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Embryo-Fetal Development Study title/ number: An Oral (Gavage) Embryo-Fetal Developmental Toxicity Study of ITI-007 in the Sprague-Dawley Rat/ Study 11053 Key Study Findings • Dose-dependent increases in clinical signs of hypoactivity, ptosis, and lacrimation in the dams at all doses. These clinical signs could be due to the anti-serotonergic activity of the drug • Decreases in maternal weight gain at ≥ 21 mg/kg/day • Decreases in fetal weight at ≥ 21 mg/kg/day • No increases in fetal malformation at doses up to 63 mg/kg/day. At 63 mg/kg/day, lumateperone caused increases in fetal variations, including dilated ureter, incomplete ossification or unossified bone with cartilage present. • Based on the decreases in both maternal and fetal weight gain, the NOAELs for maternal and embryofetal toxicity are both 10.5 mg/kg/day lumateperone tosylate, which is approximately 2.3 times the MRHD of 42 mg lumateperone on a mg/m2 basis.

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: Once daily of 0 (control), 3.5 (LD), 10.5 (MD-1), 21 (MD-2), and 63 (HD) mg/kg/day Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose (400 cp) suspension in DI water Species/Strain: Sprague-Dawley [Crl:CD®(SD)] Rat Number/Sex/Group: N=20/group Satellite groups: TK, n=6 for treated groups and n=3 for control Study design: Time-pregnant rats were orally administered with lumateperone tosylate at 0, 3.5, 10.5, 21, and 63 mg/kg/day from GDs 6 to 17. Necropsy/cesarean was performed on GD 21. Parameters evaluated include mortality, clinical signs, body weight, food consumption, necropsy, and cesarean evaluation. Dose selection was based on a preliminary dose range finding study (Study 11052), in which pregnant rats were orally administered with lumateperone tosylate at 0, 3.5, 10.5, 21, and 42 mg/kg/day. At ≥ 10.5 mg/kg/day, lumateperone dose-dependently induced pharmacology-related clinical signs of hypoactivity, ptosis, and salivation. Maternal toxicity of decreased body weight gain (↓~23-30%) was also observed at ≥ 10.5 mg/kg/day and decreased fetal weight was observed at 60 mg/kg/day. In a separate single dose

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study (Study 06-A12-FE), lumateperone at 70 mg/kg/day led to decreased food and water intake in non-pregnant rats. Based on these findings, 63 mg/kg/day was selected as the high dose Deviation from study protocol affecting interpretation of results: No

Observations and Results

Parameters Major findings Mortality No lumateperone-related mortality Clinical Signs Dose-dependent increases in clinical signs of hypoactivity, ptosis, and lacrimation at all doses; splayed hindlimbs and various staining at ≥ 10.5 mg/kg/day; and prostration and lethargy at ≥ 21 mg/kg/day . Body Weights HD: decreased body weight (↓~9%) and weight gain (↓~58%) in; MD- 2: decreased weight gain (↓~21%). These decreases were partially recovered during the treatment-free period. Changes in body weight and weight gain correlated with food consumption. Necropsy findings Gross pathology: Cesarean Section Data HD: decreased gravid uterine weight (↓27%), likely due to decreased maternal and fetal weight. Cesarean: HD: increased post-implantation loss and resorption (32 compared to 7 in controls), mainly due to complete resorption in 2/20 HD dams. No drug-related findings at lower doses (≤ 21 mg/kg/day). Necropsy findings Fetal Weight: Offspring HD: decreased litter size (11.4 compared to 12.9 in controls) and decreased fetal weight ([4.7/4.4g (M/F) compared to 5.9/5.7 in controls, ↓~20%, Table 35]); MD-2: a trend towards decreased fetal weight (↓~7%, Table 35); Malformations: No drug-related increases in fetal malformation at any doses. Variations: HD: increased incidence of dilated ureters (visceral, 7.2% and 33.3% when counted by fetal and litter, respectively, compared to 2.5% and 10.5% in controls); increased incidence of incomplete ossification or unossified bone with cartilage present, likely secondary to decreased fetal and maternal weight. Toxicokinetics On GD 17, the exposure (AUC) to lumateperone were (ng·h/mL): LD: 590; MD-1: 847; MD-2: 1120; HD:1420. LD: low dose (3.5 mg/kg/day); MD-1: mid dose-1 (10.5 mg/kg/day); MD-2: mid dose-2 (21 mg/kg/day); HD: high dose (63 mg/kg/day)

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Table 35: Drug-related Decreases in Fetal Weight in the Rat Embryo-fetal Developmental Toxicity Study Difference from Controls (%) Parameter 21 mg/kg/day 63 mg/kg/day Mean Fetal Weight – Males -7% -20% Mean Fetal Weight – Females -7% -23% Mean Fetal Weight – combined -7% -22%

Study title/ number: An Oral (Gavage) Embryo-Fetal Developmental Toxicity Study of ITI-007 in the New Zealand White Rabbit (Study 11055) Key Study Findings • No overt maternal or fetal toxicity at doses up to 21 mg/kg/day. • Exposure to lumateperone plateaued at ≥ 7 mg/kg/day, which was likely due to increased metabolic conversion to the metabolites. • Based on the minimal maternal and fetal toxicity, the NOAELs for both maternal and fetal toxicity are 21 mg/kg/day lumateperone, which is approximately 9.7 times the MRHD of 42 mg lumateperone on a mg/m2 basis

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: Once daily of 0 (control), 2.1 (LD), 7 (MD), and 21 (HD) mg/kg/day Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose (400 cp) suspension in DI water Species/Strain: New Zealand White (albino) SPF rabbit Number/Sex/Group: N=20/group Satellite groups: TK, n=3/group Study design: Pregnant rabbits were orally administered with lumateperone tosylate at 0, 2.1, 7, and 21 mg/kg/day once daily from GDs 7 to 19. Necropsy/cesarean was performed on GD 28. Parameters evaluated included mortality, clinical signs, body weight, food consumption, necropsy, and cesarean evaluation. Dose selection was based on a dose range finding study (Study 11054), in which pregnant rabbits were orally administered with lumateperone at 0, 1.75, 7, 14, and 21 mg/kg/day. No signs of maternal toxicity were observed at doses up to 21 mg/kg/day. At 14 mg/kg/day, slightly decreased fetal weight was observed; however, it was likely due to higher litter size, instead of a direct drug effect on fetal weight

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(*For the 21 mg/kg/day group, cesarean was performed on GD 27 instead of GD 28; therefore, the fetal data at 21 mg/kg/day were not evaluated). Deviation from study protocol No affecting interpretation of results:

Observations and Results

Parameters Major findings Mortality No lumateperone-related mortality Clinical Signs MD and HD had increased incidence of swollen vulva; however, the overall health of the animals was not affected, and these findings are not considered to be adverse. Body Weights No drug-related changes in body weights, weight gain, or food consumption. Necropsy findings No drug-related abnormal findings at necropsy. Cesarean data were Cesarean Section Data comparable across all groups, including the controls. Necropsy findings No drug-related abnormal fetal findings. No drug-related fetal Offspring malformations or variations.

Toxicokinetics Exposure to lumateperone plateaued at doses ≥ 7 mg/kg/day whereas the exposure to metabolites continued to increase with increasing doses, suggesting increased conversion/metabolism of lumateperone. On GD 19, exposure levels to lumateperone were (ng*h/mL): LD: 450, MD: 538, and HD: 537. LD: low dose (2.1 mg/kg/day); MD: mid dose (7 mg/kg/day); HD: high dose (21 mg/kg/day) Study title/ number: An Oral Embryo-Fetal Developmental Toxicity Study of IC200131 in the Sprague-Dawley Rat / Study 11865 Key Study Findings • One potentially drug-related mortality in the TK group at 100 mg/kg/day • Dose-dependent increases in clinical signs of hypoactivity, ataxia, splayed hindlimbs, ptosis, and lacrimation at all doses • Decreases in maternal body weight, weight gain, and food consumption at ≥ 60 mg/kg/day. Decreases in fetal weight at ≥ 60 mg/kg/day. • Increases in fetal visceral malformation (cleft palate) at 100 mg/kg/day; increases in skeletal malformations at ≥ 60 mg/kg/day, including missing and fused ribs, missing thoracic arches and centra, 21 unaligned thoracic centra, fused 3rd and 4th sternebrae, and missing lumbar arches. • Based on decreased maternal weight, the NOAEL for maternal toxicity is 15 mg/kg/day IC200131. Based on decreased fetal weight and fetal malformations, the NOAEL for fetal toxicity is also 15 mg/kg/day IC200131. The corresponding exposure to IC200131 on GD 17 was 321 h*ng/mL, which is approximately equal to human exposure at the MRHD of 42 mg (lumateperone).

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(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: Once daily of 0 (control), 15 (LD), 60 (MD), and 100 (HD) mg/kg/day Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose (400 cp) suspension in DI water Species/Strain: Sprague-Dawley [Crl:CD®(SD)] Rat Number/Sex/Group: N=25/group Satellite groups: TK, n=8/group for treatment groups and n=4 for controls Study design: Time-pregnant rats were orally administered with lC200131 at 0, 15, 60, and 100 mg/kg/day from GDs 6 to 17. Necropsy/cesarean was performed on GD 21. Parameters evaluated include mortality, clinical signs, body weight, food consumption, necropsy, and cesarean evaluation. Dose selection was based on a preliminary dose range finding study (Study 11864), in which pregnant rats were orally administered with IC200131 at 0, 15, 100, and 150 mg/kg/day. Premature deaths occurred at 150 mg/kg/day, indicating that MTD was exceeded. At 100 mg/kg/day, the drug caused maternal toxicities of decreased weight gain (↓~39%) with correlative decreased food consumption (↓~19-38%) and fetal toxicities of decreased fetal weight (↓~22%). No overt maternal or fetal toxicities were observed at 15 mg/kg/day. Based on these findings, 100 mg/kg/day was selected as the high dose and 15 mg/kg/day as the low dose. Deviation from study protocol No affecting interpretation of results:

Observations and Results

Parameters Major findings Mortality Potentially IC200131-related premature death in 1/8 HD TK animal. Moribund condition included cold to touch and pale. These findings were similar to the premature death conditions observed in the dose range finding study at 150 mg/kg/day; therefore, are considered to be drug-related.

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Clinical Signs Dose-dependent increases in hypoactivity, ataxia, splayed hindlimbs, ptosis, and lacrimation at all doses; body shakes, salivation, and splayed limbs and various staining at ≥ 60 mg/kg/day; splayed forelimbs and cool to touch at 60 mg/kg/day; and rough coat at 100 mg/kg/day (Table 36). Body Weights MD and HD had decreases in body weight (↓up to 13% and 20%, respectively) and weight gain (↓ 51% and 77%, respectively) compared to control group. These decreases correlated with decreases in food consumption in MD and HD (↓up to 24% and 40%, respectively). Necropsy findings Gross pathology: HD had decreases in gravid uterine weight (↓~13%), Cesarean Section Data which was likely secondary to decreases in maternal and fetal weight. No other abnormal findings were observed. [*Two HD dams were not pregnant (not due to resorption) and were excluded from the evaluation]. Cesarean: No drug-related changes in the number of corpora lutea, implantation sites, resorptions (early or late), or in pre- or post- implantation loss. Necropsy findings Fetal weight: MD and HD had decreases in fetal weight (↓12% and Offspring 18%, respectively, Table 37), which correlated with decreases in maternal weight. Malformations: HD had increases in the incidence of visceral malformations, which was mainly due to increases in the incidence of cleft palate (8.3% and 26.1% fetal and litter incidences, respectively, compared to 1.4% and 8.0% in controls, Table 38). MD and HD had increases in the incidence of skeletal malformations, including missing and fused ribs; missing thoracic arches and centra; unaligned thoracic centra, and fused 3rd and 4th sternebrae, and missing lumbar arches (Table 38). LD was not affected. Variations: MD and HD also had increases in the incidences of incomplete ossification (31 and 38 for fetal incidence, compared to 25 in controls; and 16 and 16 litter incidences, compared to 12 in controls, respectively). These could be secondary to decreases in fetal weight, rather than a direct drug effect. Toxicokinetics Exposure to IC200131 was generally higher than its downstream metabolites. Repeat dosing lead to slight accumulation of IC200131. On GD17, the exposure to IC200131 were (ng·h/mL): LD: 321, MD: 5070, and HD: 7030. LD: low dose (15 mg/kg/day); MD: mid dose (60 mg/kg/day); HD: high dose (100 mg/kg/day)

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Table 36: Drug-related Clinical Signs in the Rat Embryo-fetal Developmental Toxicity Study with the Metabolite IC200131

Table 37: Drug-related Decreases in Fetal Weights in the Rat Embryo-fetal Developmental Toxicity Study with the Metabolite IC200131

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Table 38: Drug-related Fetal Visceral and Skeletal Malformations in the Rat Embryo-fetal Developmental Toxicity Study with the Metabolite IC200131.

Prenatal and Postnatal Development Study title/ number: Study for Effects on Prenatal and Postnatal Development Following Daily Oral Dosing of ITI-007 to Sprague Dawley Rats (Study 11627) Key Study Findings • Dose-dependent increases in clinical signs of hypoactivity, ataxia, lacrimation, and ptosis at all doses in F0 dams.

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• Decreases in body weight and food consumption in F0 dams at 30 mg/kg/day • Increases in early deaths of the F1 pup (increased number of pups missing, found dead, cannibalized, or stillborn prior to postnatal day [PND4]) at ≥ 15 mg/kg/day. • Decreases in F1 pup body weight during the pre-weaning and post-weaning period at 30 mg/kg/day. • No drug effect on F1 pup sexual maturation or learning and memory. • Based on decreases in maternal body weight and food consumption, the NOAEL for maternal toxicity is 15 mg/kg/day lumateperone tosylate, which is approximately 2.3 times the MRHD of 42 mg lumateperone. Based on decreased pup viability, the NOAEL for pup is 5 mg/kg/day lumateperone tosylate, which is approximately 0.8 times the MRHD; the NOAEL for pup sexual maturation, mating and fertility, and learning and memory is 30 mg/kg/day lumateperone tosylate, which is approximately 4.8 times the MRHD on a mg/m2 basis.

Reviewer Note: HD group had decreased viability of the F1 pups; MD and HD F1 pups also had decreased body weight. The Applicant attributed these findings to decreased nursing behavior of the F0 dams. This is a reasonable explanation given the hypoactivity observed in the dams; however, a direct drug effect in the F1 pups due to in utero exposure or exposure via lactational could not be excluded. The current study did not determine whether the drug is present in the milk.

(b) (4) Conducting laboratory and location: GLP compliance: Yes

Methods Dose and frequency of dosing: Once daily of 0 (control), 3.5 (LD), 10.5 (MD), and 21 (HD) mg/kg/day Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose in DI water Species/Strain: Sprague Dawley [Crl:CD®(SD)] Rat Number/Sex/Group: N=25/group Satellite groups: N/A (TK not performed) Study design: Pregnant rats were orally administered with lumateperone tosylate at 0, 3.5, 10.5, and 21 mg/kg/day from GD 6 to lactation day (LD) 20. Parameters evaluated include: F0 generation: mortality, clinical signs, body weight, food consumption, parturition, maternal behavior, and macroscopic observations; for F1 generation: viability, clinical signs, body weight, food consumption, developmental landmarks, neurobehavioral assessments (learning and memory using the M water maze conducted on PND 60), reproductive capacity,

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macroscopic findings and organ weights, and ovarian and uterine contents. Deviation from study protocol Yes affecting interpretation of results:

Observations and Results F0 Dams Survival: No mortality Clinical signs: In both gestational and lactational period, dose-dependent increases in hypoactivity, ptosis, lacrimation (all doses); lethargy and walking on tiptoes (HD); and oral stain (MD and HD). This is could be due to the anti- serotonergic activity of the drug Body weight and food During gestation: HD had slight decreases in body weight (↓~9%) and consumption: weight gain (↓~10-20%). During lactation: MD and HD had slight decreases in body weight (↓~5% and 5-8%, respectively); HD also had slight decreases in food consumption (↓~ 8%-12%). The decreases in MD were mild and considered to be non-adverse. Uterine content: no drug-related abnormal findings Necropsy observation: no drug-related abnormal findings. Toxicokinetics: not conducted; drug levels in the milk were not determined F1 Generation Survival: During the lactational period: MD and HD had decreases pup viability (increased number of pups missing, found dead, cannibalized, or stillborn pups), which occurred primarily before post-natal day (PND) 4. The lactation index (PNDs 4-21) was not affected (Table 39). LD was not affected. During the post-weaning period: no drug-related death in F1 offspring. Clinical signs: During the lactational (pre-weaning) period: HD had increases in the incidence of “no milk in stomach,” which correlated with the clinical observation of decreased nursing in the dams and higher pup mortality. During the post-weaning period: no drug-related clinical signs. Body weight and Food During the lactational (pre-weaning) period: dose-dependent decreases Consumption: in body weight in MD and HD (↓~5% and ~ 15%, respectively (Table 40). LD was not affected During the post-weaning period: decreases in body weight in HD male pups (↓7%-14% through PND 77) and HD female pups (↓6-13%, through PND 42). LD or MD was not affected. Physical development: no drug-related changes in physical development or sexual maturation landmarks (surface righting, testicular descent, vaginal patency, or balanopreputial separation). Neurological assessment: no drug-related changes in neurobehavioral evaluations (observational battery, motor and locomotor activity, and learning and memory). Reproduction: no drug-related changes in reproductive parameters (mating or fertility indices, time to mate, number of corpora lutea, implantation sites, resorption, pre- and post-implantation loss). Necropsy no drug-related necropsy findings. LD: low dose (3.5 mg/kg/day); MD: mid dose (10.5 mg/kg/day); HD: high dose (21 mg/kg/day)

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Table 39: Drug-related Decreases in F1 Pup Viability in the Rat Pre- and Post-natal Developmental Toxicity Study Dose level (mg/kg/day) Parameter 0 3.5 10.5 21 Total No. of Pups Born 316 288 331 312 No. of Pups Missing (No. of Litters) 0 (0) 1 (1) 5 (5) 6 (3) No. of Pups Found Dead (No. of Litters) 1 (1) 1 (1) 1 (1) 30 (12) No. of Pups Cannibalized (No. of Litters) 0 (0) 0 (0) 0 (0) 2 (2) No. of Stillborn Pups (No. of Litters) 0 (0) 2 (1) 19 (5) 28 (3) Live Birth Index (%) 100 99.4 94.3 90.8 Viability Index (%) 99.3 99.3 99.1 86.7 Lactation Index (%) 95.8 91.3 99.5 90.3

Table 40: Decreases in F1 Pup Body Weight Relative to Vehicle Control in the Rat Pre- and Post- natal Developmental Toxicity Study Both Sexes Male Female (Combined) Dose level (mg/kg/day) 10.5 21 10.5 21 10.5 21 Postnatal Day 0 -6% -11% -6% -12% -6% -12% 4 (Pre-culling) -5% -16% -6% -19% -5% -17% 4 (Post-culling) -6% -17% -5% -18% -5% -17% 7 -5% -15% ------17% ------16% 14 -6% -15% -5% -17% -5% -16% 21 -5% -15% -5% -17% -5% -16% ----- = No change

Other Toxicology Studies

The identity of the constituents(s) that make up the intracellular pigmented material observed in the toxicology studies was not fully characterized by the Applicant; however, it is not consistent with common endogenous intracytoplasmic pigments (e.g., hemosiderin, calcium, lipofuscin) and, based on electron microscopy, it appears to be localized within the lysosomes of cells. Therefore, the Applicant conducted a series of in vitro assays to: 1) assess the potential for lumateperone and several metabolites to become trapped in the lysosome (study Nos. XT168007 and XT17A067); and 2) assess whether lumateperone and several metabolites are capable of forming a pigmented material consistent with the intracellular accumulations (study Nos. ITI-007-CHEM-1902 and ITI-007-CHEM-1904).

The Applicant assessed the potential for lumateperone and the metabolites IC200161, IC200131, IC200565, IC201308, and IC201309 (study No. XT168007) as well as the aniline metabolites IC201337 and IC201338 (study No. XT17A067) to be taken up and trapped in the lysosomes of immortalized hepatocytes (Fa2N-4 cells). Consistent with other compounds possessing a weakly basic functional amine group and a hydrophobic aromatic ring structure (also known as cationic amphiphilic amines), lumateperone and all the assessed metabolites accumulated in Fa2N-4 cells. In addition, the accumulation of IC201337 and IC201338 was

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inhibited (73.6% and 72.7%, respectively) by coincubation with 50 mM ammonium chloride used to neutralize the pH of the lysosome, suggesting this accumulation occurred in acidic organelles. It should be noted that the inhibition of uptake by ammonium chloride was not assessed for lumateperone or the other metabolites; however, the uptake of these compounds was significantly inhibited by coincubation with propranolol (300 μM), a compound known to inhibit the lysosomal uptake of cationic amphiphilic amines. The Applicant also noted that lumateperone, IC200161, IC200131, IC200565, IC201308, and IC201309 significantly inhibited the uptake of LysoTracker Red (Table 41), a lysosome specific probe that has been used to characterize the potential for drugs to be trapped in lysosomes (Kazmi, Hensley et al. 2013); however, IC201337 only weakly inhibited (IC50 = 219 μM) and IC201338 did not significantly inhibit (IC50 > 500 μM) the uptake of LysoTracker Red.

Reviewer Note: Although the Applicant concluded, based on this result, that IC201337 and IC201338 are not trapped in lysosomes, two known phospholipidosis-inducing agents, cariprazine and aripiprazole, did not significantly inhibit (IC50 > 500 μM) the uptake of LysoTracker Red under the same conditions as this study (No. XT17A067). Therefore, it is not clear if this assay is useful for predicting the potential for drugs that are known to accumulate in lysosomes to cause lysosomal disfunction.

Table 41. Lysosomal Trapping Potential of Lumateperone and Metabolites Inhibition of LysoTracker Red Accumulation Compound IC50 (μM) Lumateperone 9.46 IC200161 28.1 IC200131 11.7 IC200565 94.1 IC201308 146 IC201309 189

The Applicant assessed the potential for lumateperone and the metabolites IC200161, IC200131, IC200565, IC201308, and IC201309 (study No. ITI-007-CHEM-1904) as well as the aniline metabolites IC201337 and IC201338 (study Nos. ITI-007-CHEM-1902 and ITI-007-CHEM- 1904) to undergo chemical changes and produce pigmented material consistent with the intracellular accumulations observed in the toxicology studies. The Applicant proposed that the aniline metabolites IC201337 and IC201338 may be responsible for the pigmented material accumulations and the formation of these pigments may be the result of the fixation process used for histopathological evaluation. To support this hypothesis the Applicant added sodium iodate (an oxidative reagent used in the H&E staining process) to acidic aqueous solutions containing either IC201337 or IC201338. Both IC201337 and IC201338 were chemically unstable under these conditions with only 11% of IC201337 and no IC201338 remaining 3 minutes following addition of sodium iodate. Based on UPLC-ESI-TOF-MS analysis, IC201337 and IC201338 were rapidly converted to relatively high molecular weight compounds (~1400 Daltons) that the Applicant proposes are polymers of IC201337 or IC201338. In addition, the originally clear solutions of IC201337 and IC201338 underwent rapid color changes resulting in light pink to red solutions 1 minute and dark red solutions 3 minutes following addition of

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sodium iodate. These color changes are consistent with the color of the pigmented material observed in toxicology studies. In contrast, lumateperone and the non-aniline metabolites were relatively stable following addition of sodium iodate with minimal chemical modifications, mainly consisting of dehydrogenated analogues or other oxidized derivatives observed after 5 minutes. The formation of relatively high molecular weight compounds was not observed indicating the lack of polymerization of these compounds. Importantly, although color changes were observed for some of the solutions of these compounds, they were blue or yellow and, therefore, not consistent with the pink to red color of the pigmented material observed in the toxicology studies.

Reviewer Note: These data suggest that the aniline metabolites IC201337 and IC201338 are responsible for the pigmented material observed in the toxicology studies and that the H&E staining procedure may stain these metabolites; however, this should not be taken to conclude that this is an artifact of the fixation process and of no toxicological significance. First, these in vitro data, if representative of the in vivo situation, suggest that significant quantities of the anilines are present in the lysosomes of cells. Second, the lysosome provides an oxidative and acidic environment. Therefore, it is likely that the polymerization reactions observed in vitro are capable of taking place in the lysosome, thus resulting in trapping and significant accumulation of these polymers in the lysosome. Although the toxicological significance of these accumulations has not been definitively established, their colocalization in tissues with significant degenerative changes and/or signs of an inflammatory response strongly suggest they are contributing factors.

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6 Clinical Pharmacology

Executive Summary

Intra-Cellular Therapies, Inc. (ITI) is seeking approval of lumateperone for the treatment of schizophrenia in adult patients via the 505b (1) pathway. The proposed therapeutic dose of lumateperone is 42 mg for once daily oral administration. Dose titration is not required. Lumateperone was granted Fast Track Designation in 2017.

Lumateperone is a serotonin 5-HT2A and postsynaptic dopamine D2 receptor antagonist. In addition, lumateperone displays relatively high affinity for the serotonin transporter (SERT). The mechanism of action of lumateperone in schizophrenia is not fully understood. The drug product is formulated as a capsule.

The clinical pharmacology development program for lumateperone included trials to evaluate: 1) the absolute bioavailability and metabolite profiles; 2) single ascending dose and multiple ascending dose pharmacokinetics (PK); 3) the effect of intrinsic factors (e.g., hepatic impairment, and renal impairment) on the PK; 4) the drug-interaction potential of lumateperone with inducers, inhibitors, or substrates of CYP3A4. Additional studies were conducted to evaluate brain receptor occupancy and the effects of lumateperone on corrected QT (QTc) intervals.

The safety and efficacy of lumateperone (14, 28, 42 and 84 mg) in treating patients with schizophrenia was evaluated in three studies (ITI-007-005, ITI-007-301, and ITI-007-302). In Studies ITI-007-005 and ITI-007-301, lumateperone dose of 42 mg showed statistically significant benefits versus placebo, and in Study ITI-007-302, lumateperone failed to demonstrate effectiveness. Risperidone showed statistically significant benefit versus placebo in studies ITI-007-005 and ITI-007-302. At doses of 14, 28, and 84 mg, lumateperone did not demonstrate statistically significant benefit over placebo using total PANSS score as the primary endpoint. For more details, refer to the clinical review section.

Two key clinical pharmacology review issues are identified for this application: (1) Dose adjustment strategies in the presence of intrinsic and extrinsic factors (2) Aniline metabolites in humans

In this review, the term lumateperone is used interchangeably with ITI-007 and IC200056.

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6.1.1 Recommendations Review Issue Recommendations and Comments General dosing instructions The recommended dose of lumateperone is 42 mg. Administer orally once daily with food. Dose titration is not required. Dosing in patient subgroups Dosage adjustment of lumateperone is considered (intrinsic and extrinsic factors) necessary in certain subgroups of patients based on relevant PK studies and the dose/exposure-response relationships. However, because the unavailability of appropriate strengths, OCP recommends avoid use of lumateperone in the following scenarios: - Moderate and severe hepatic impairment (Child- Pugh score: ≥7) - Weak, moderate, or strong CYP3A inducers - Moderate or strong CYP3A inhibitors Bridge between the to-be- The formulation used in the clinical trials was the same marketed and as the to-be-marketed formulation. formulations

6.1.2 Post-Marketing Requirements and Commitments Key PMC or Key Issue(s) to be Considerations Rationale PMR Addressed for Design Features Glucuronidated An in vivo drug metabolites interaction represented about 50% study to of total plasma quantify the radioactivity after a impact of UGT single dose inhibition on the administration of 14C- PK of the parent labeled ITI-007. In vitro, compound and Effect of UGT enzymes PMC multiple UGT enzymes major Inhibition on the exposure of PMR are found to be involved metabolites, as ITI-007 and its metabolites in the metabolism of ITI- well as aniline 007 and its metabolites. metabolites Therefore, it is clinically IC201337 and meaningful to quantify IC201338. The the effect of UGT effect of a enzyme inhibition on general inhibitor the PK and help of UGTs (e.g., determine an valproic acid)

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appropriate dosing dosed to steady recommendation. state should be evaluated. • Substrate potential of ITI- Lumateperone is Standard in vitro 007 for OATP1B1/1B3; extensively assay • Inhibitor potential of ITI- metabolized; at steady 007 towards P-gp and state, these metabolites BCRP; circulate at a • Inhibition potential of all concentration similar to major metabolites or greater than the (IC200131, IC200161, parent. The required IC200565, IC201308, studies will provide IC201309, and IC200056- information of potential PMC drug-drug interactions PMR enol-glu), if have not been evaluated, towards with other drugs. 1) transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, and MATE2K; 2) inhibition/induction potential towards major CYPs, except CYP3A (in vivo study with midazolam has been conducted).

Summary of Clinical Pharmacology Assessment

6.2.1 Pharmacology and Clinical Pharmacokinetics

Following once daily oral administration, lumateperone steady state is reached in about 5 days. Steady-state exposure increases approximately dose proportionately over a dosage range from 21 mg to 56 mg. A large inter-subject variability in lumateperone PK parameters was observed, with coefficients of variation for Cmax (peak plasma concentration) and AUC (area under the concentration vs time curve) ranging from 68% to 97% at the therapeutic dose.

The following is a summary of the clinical pharmacokinetic features of lumateperone:

Absorption: Lumateperone has an absolute bioavailability of 4.4%. The peak lumateperone plasma concentration (Cmax) is reached approximately 1-2 hours after oral dosing. Distribution: Protein binding of lumateperone is 97.4% at 5 µM (about 70-fold higher than therapeutic concentrations) in human plasma. The volume of distribution of lumateperone following intravenous (IV) administration is about 4.1 L/kg.

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Elimination: The clearance of lumateperone is approximately 27.9 L/hour, and the terminal half-life is about 18 hours after IV administration. - Metabolism: Lumateperone is extensively metabolized with more than twenty metabolites identified in vivo. After a single oral dose of 14C-labeled lumateperone, lumateperone and glucuronidated metabolites represent about 2.8% and 51% of the total plasma radioactivity, respectively. In vitro studies show that multiple enzymes including but not limited to uridine 5'- diphospho-glucuronosyltransferases (UDP-glucuronosyltransferase, UGT) 1A1, 1A4, and 2B15, aldo-keto reductase (AKR)1C1, 1B10, and 1C4, and cytochrome P450 (CYP) 3A4, 2C8, and 1A2, are involved in the metabolism of lumateperone.

- Excretion: In a human mass-balance study, 58% and 29% of the radioactive dose was recovered in the urine and feces, respectively. Less than 1% of the dose was excreted as unchanged lumateperone in the urine.

6.2.2 General Dosing and Therapeutic Individualization

General Dosing The recommended dose of lumateperone is 42 mg once daily. Dose titration is not required. Lumateperone should be administered with food.

Therapeutic Individualization Hepatic Impairment Compared to healthy controls, the pharmacokinetic change in patients with hepatic impairment following a single dose of 14 mg lumateperone are as follows: based on the geometric mean ratios, the AUC of lumateperone was increased by 14%, 137%, and 80%, respectively, in subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment. Similar effects were observed for Cmax of lumateperone. A dosage reduction to 21 mg seems appropriate for patients with moderate or severe hepatic impairment. However, because no appropriate strength is available for dose adjustment, use of lumateperone is not recommended in patients with moderate or severe hepatic impairment.

Renal Impairment Following a single dose of 14 mg, lumateperone Cmax and AUC in patients with renal impairment (mild, moderate, or severe) are not clinically significantly different from subjects with normal renal function. The mean T1/2 of lumateperone was comparable among groups. Dosage adjustment is not considered necessary for patients with impaired renal function.

Age, Race and Sex Dose adjustment on the basis of age, race, and sex is not necessary. No significant differences in plasma levels of lumateperone are observed by age, race, and sex.

Weak, Moderate, or Strong CYP3A Inducers

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Coadministration of lumateperone 28 mg with rifampin 600 mg (a strong CYP3A4 inducer) reduced lumateperone Cmax to 7.7% and AUC to 2.1% of the levels when lumateperone was administered alone in healthy subjects. Given the magnitude of effect, concomitant use of lumateperone with weak, moderate, or strong CYP3A inducers is not recommended.

Strong CYP3A Inhibitors Coadministration of lumateperone 14 mg with itraconazole 200 mg (strong CYP3A4 inhibitor) increased lumateperone exposure approximately 4-fold in patients with schizophrenia. Dosage adjustment to 10.5 mg seems appropriate for patients taking a strong CYP3A inhibitor concomitantly. However, because no appropriate strength is available for dose adjustment, concomitant use of strong CYP3A inhibitors with lumateperone is not recommended.

Moderate CYP3A Inhibitors Coadministration of lumateperone 14 mg with diltiazem 240 mg (moderate CYP3A4 inhibitor), increased lumateperone exposure approximately 2-fold in patients with schizophrenia. Dosage adjustment to 21 mg seems appropriate for patients taking a moderate CYP3A inhibitor concomitantly. However, because no appropriate strength is available for dose adjustment, concomitant use of moderate CYP3A inhibitors with lumateperone is not recommended. Given the expected smaller effect from a weak CYP3A inhibitor compared to a moderate or strong CYP3A inhibitor, dosage adjustment for lumateperone when used concomitantly with a weak CYP3A inhibitor is not necessary.

Food Effect Ingestion of a high-fat meal with lumateperone resulted in an ~33% decrease in mean Cmax, and a 9% increase in mean AUCinf of lumateperone. A delay of approximately 1 hour was observed in Tmax. Given that a higher incidence rate of gastrointestinal (GI) effects was observed in the higher dose groups than the lower dose groups in the clinical trials, a decreased Cmax with food may cause fewer GI effects, and doses were administered with food in registration trials, we recommend administration of lumateperone with food.

Summary of Labeling Recommendation

The Office of Clinical Pharmacology recommends the following labeling concepts be included in the final package insert: • Lumateperone should be taken with food. • Patients should avoid concomitant use with weak, moderate, or strong CYP3A inducers. • Patients should avoid concomitant use with moderate or strong CYP3A inhibitors. Dosage adjustment is not considered necessary when used concomitantly with a weak CYP3A inhibitor. • For patients with moderate and severe hepatic impairment (Child-Pugh score: ≥7), usage of lumateperone is not recommended. • In general, no dose adjustment is necessary in patients based on race, age, sex, or renal impairment status.

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• No significant QTc prolongation effect of lumateperone at the therapeutic dose (42 mg) was detected in a thorough QT study.

Outstanding Issues

None

Comprehensive Clinical Pharmacology Review

6.3.1 General Pharmacology and Pharmacokinetic Characteristics

Pharmacology Mechanism of Action Lumateperone is a serotonin 5-HT2A and postsynaptic dopamine D2 receptor antagonist. In addition, lumateperone displays relatively high affinity for the serotonin transporter (SERT). The mechanism of action of lumateperone in schizophrenia is not fully characterized.

Active Moieties Lumateperone, metabolite IC200161, IC201308, and IC200131 possibly active QT Prolongation The effect of lumateperone on the QT/QTcF interval was investigated in patients with schizophrenia following once daily oral administration. The placebo-corrected change from baseline QTcF (90% two-sided upper confidence interval) values of 4.9 (8.9) and 15.8 (19.8) ms for the 42 mg and the supratherapeutic dose of 126 mg lumateperone, respectively. General Information Bioanalysis Lumateperone and metabolites IC200131, IC200161, IC201308, IC201309 and IC200565 concentrations were measured using LC- /MS/MS methods in clinical trials. A summary of the respective method deployed in each study was included in the individual study review. Drug exposure at The following PK parameters are from the TQT study in which steady state patients received 42 mg lumateperone once daily for 5 days.

following the PK Parameters IC200056 IC200131 IC200161 IC200565 IC201308 IC201309 therapeutic dosing Cmax,ss (ng/mL) 19.7 (19.1) 26.4(12.8) 19.1(10.7) 24.8(9.7) 9.3 (7.0) 26.3(13.9) AUCtau (hr*ng/mL) 64.2 (43.1) 260.7(147.5) 66.5 (39.9) 261.8(120.3) 54.4(30.1) 361.9(202) regimen T1/2 (hr) 3.1 (1.5) 7.9(3.2) 2.7(0.9) 8.8 (2.9) 4.6(1.6) 11.8(3.9) Data are presented as mean (SD) source: Table 6-Table 11 CSR Study ITI-007-017 Maximum Single Dose Not Available tolerated dose or Multiple Dose Not Available

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Dose Proportionality Lumateperone exposure is approximately dose-proportional over the dose range of 21 to 56 mg. Accumulation Accumulation factor: ~1.4 Absorption - Absolutely bioavailability: ~ 4.4% - Tmax (median): 1 hour post dose - Food effect (high-fat/high-calorie): ingestion of a high-fat/high-calorie meal resulted in about 33% decrease in Cmax and 9% increase in AUCinf; a delay of approximately 1 hour in Tmax was observed. Distribution - Volume of distribution: 4.1 L/kg - Plasma protein binding: > 90% Elimination: - Clearance: ~ 27.9 L/hour following intravenous (IV) administration - Mean terminal elimination T1/2: ~18 hours following IV administration - Metabolism: extensively metabolized with more than twenty metabolites identified. - Transporters substrate: lumateperone does not appear to be a substrate of P-gp or BCRP. - Transporter inhibitor: lumateperone did not or weakly inhibit OCT2, OAT1, OAT3, OATP1B3, or OATP1B1. Significant drug interactions at clinically relevant concentrations are not expected. - CYP /inducer: lumateperone did not or weakly inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. It did not induce CYP1A2, CYP2B6, or CYP3A4. Significant drug interactions at clinically relevant concentrations are not expected.

6.3.2 Clinical Pharmacology Questions

Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought? Yes. The clinical studies included doses of 14, 28, 42 and 84 mg. Doses less than 42 mg did not show significant improvement in psychotic symptoms (PANSS scores) compared to placebo. Interestingly, the higher dose (84 mg) did not show significant improvement in PANSS scores compared to placebo. Analysis of sub-components of total PANSS score suggest that patients treated with 84 mg have poor attention compared to 42 mg dose. It is not clear whether this aspect is contributing to the observed dose-response for benefit. In terms of risk, greater proportion of patients in 84 mg reported events like sedation compared to that in 42 mg. Therefore, the proposed dosing regimen appears to be appropriate for the general patient population.

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Figure 8. Relationships of Dose-Benefit (Left) and Dose-Risk (Right)

Benefit Risk Source: Reviewer’s analysis and findings reported by applicant in Table 6-4 on page 90 in iss-iss-1.pdf

What are the strategies utilized when considering dosage adjustment in the presence of certain intrinsic/extrinsic factors? Given the specific properties of lumateperone and its metabolites, together with the clinical findings from clinical programs, the following factors were taken into account when considering dosage adjustment in the presence of intrinsic/extrinsic factors:

1) Potential involvement of multiple receptors in mediating the pharmacological effects of lumateperone Lumateperone is a serotonin 5-HT2A and postsynaptic dopamine D2 receptor antagonist. In addition, lumateperone displays relatively high affinity for the serotonin transporter (SERT). However, the mechanism of action for lumateperone in treatment of schizophrenia is not fully understood.

2) Receptor binding of lumateperone metabolites In addition to lumateperone, in vitro studies also showed that there are several metabolites that demonstrated binding affinity towards the receptors that are thought to be involved in the pharmacological effects following lumateperone administration (Table 42). Therefore, it is likely that these metabolites might contribute to the pharmacological effects after lumateperone administration.

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Table 42: Binding Affinities of ITI-007 and Its Major Metabolites

Source: Table 3 Applicant’s response to IR (metabolism information) received on Dec 7, 2018

3) Relative abundance of metabolites to lumateperone at steady state Following once daily administration of 42 mg lumateperone in patients with schizophrenia, there are several metabolites that circulate at levels similar to or higher than the parent lumateperone, as shown in Table 43 below.

Table 43: Relative Abundance of Metabolite to ITI-007 Following Administration of 42 mg ITI-007 for 5 Days Moiety ITI-007 IC200161 IC201308 IC200131 Relative Abundance to Parent 1.0 1x 1x 5x Source: Table 6-Table 10 CSR for study ITI-007-017

4) There are only two lower strengths developed for lumateperone, i.e., 14 mg and 28 mg, which are 1/3 and 2/3 of the recommended therapeutic dose of 42 mg, respectively.

5) The observed exposure changes in each specific scenario Clinically meaningful changes in lumateperone exposure are observed 1) for patients with moderate to severe hepatic impairment; 2) when lumateperone is coadministered with a CYP3A strong or moderate inhibitor; 3) when lumateperone is coadministered with a strong CYP3A inducer. For details of the exposure changes, refer to pertinent subsections below.

To summarize, lumateperone 42 mg was identified as the only effective dose in the clinical program. No specific concentration threshold for lumateperone could be identified that is associated with loss of efficacy. Taking all the factors described above, the proposed strategy for dose adjustment for various intrinsic/extrinsic factors is such that steady-state lumateperone AUC and Cmax would be comparable with those from 42 mg.

Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors? Yes, an alternative dosing regimen is required for the following subpopulations:

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Hepatic Impairment In subjects with mild hepatic impairment, there was a <1.4 fold increase in lumateperone Cmax and AUC. A greater increase of lumateperone in Cmax (up to 2.5-fold) and AUC (up to 2.4-fold) was observed in subjects with moderate or severe hepatic impairment (Table 44). In general, systemic exposure to metabolites IC200161and IC200131 was higher in all hepatic impairment groups, and the difference was generally most pronounced in subjects with moderate impairment. Exposure to metabolites IC201308 was consistently lower in all hepatic impairment groups compared with healthy subjects. Table 44: Statistical Comparisons of Plasma PK Parameters for Lumateperone, IC200161, IC201308 and IC200131: Hepatic Impairment versus Normal Function (%Geomean Ratio [90% CI]) Parameter Comparison Cmax AUC Lumateperone (IC200056) Mild vs Normal 138.3 (84.1, 227.3) 113.9 (75.3, 172.2) Moderate vs Normal 195.5 (118.9, 321.4) 235.4 (155.6, 356.0) Severe vs Normal 155.9 (94.5, 256.3) 184.9 (122.2, 279.6) IC200161 Mild vs Normal 117.8 (73.1, 189.8) 102.8 (59.7, 176.9) Moderate vs Normal 120.3 (74.7, 193.9) 154.7 (89.9, 266.2) Severe vs Normal 98.7 (61.3, 159.1) 141.0 (81.9, 242.7) IC201308 Mild vs Normal 58.2 (35.9, 94.6) 27.8 (13.5, 57.1) Moderate vs Normal 78.3 (43.2, 141.7) 70.0 (29.0, 169.1) Severe vs Normal Not calculated Not calculated IC200131 Mild vs Normal 126.2 (77.9, 204.6) 108.6 (52.4, 224.8) Moderate vs Normal 115.0 (70.9, 186.4) 232.6 (112.3, 481.5) Severe vs Normal 38.3 (23.6, 62.0) 94.6 (45.7, 195.8) Source: Table 11-14 to Table 11-18 CSR for study ITI-007-010

Together with the known dose-response relationships for efficacy and safety and the factors discussed in previous section (strategies considered in the presence of intrinsic/extrinsic factors), no dose adjustment is needed in patients with mild hepatic impairment, whereas a lower dosage of lumateperone, such as 21 mg daily, should be considered in patients with moderate or severe hepatic impairment. However, because no appropriate strength is available for dose adjustment, use of lumateperone is not recommended in patients with moderate or severe hepatic impairment.

Renal Impairment

Compared to healthy subjects, Cmax and AUC of IC200056 and metabolites IC200161, IC201308 and IC200131 were, on average, higher (≤ 50% for the parent) in subjects with severe renal impairment. Cmax and AUC were comparable between subjects with moderate renal impairment (except for IC201308 ~ 77% higher), and lower (~ 40-60%) in subjects with mild renal impairment (except for IC201308 ~ 22-35% higher). Considering the inherent large PK variability (68-97% CV for exposure at steady state) and even larger variability observed in the study, the

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observed changes in exposure (~50% change for the parent) for patients with renal impairment does not warrant a dosage adjustment.

Table 45 : Statistical Comparisons of Plasma PK Parameters for Lumateperone, IC200161, IC201308 and IC200131: Renal Impairment versus Normal Function (%Geomean Ratio [90% CI]) Parameter Comparison Cmax AUC Lumateperone (IC200056) Mild vs Normal 62.0 (34.8, 110.5) 53.5 (31.2, 91.9) Moderate vs Normal 103.9 (58.3, 185.0) 104.7 (61.0, 179.7) Severe vs Normal* 140 (--) 150 (--) IC200161 Mild vs Normal 64.8 (32.9, 127.6) 48.9 (20.8, 114.9) Moderate vs Normal 94.2 (47.9, 185.5) 95.6 (40.7, 225.0) Severe vs Normal* 110 (--) 160 (--) IC201308 Mild vs Normal 134.5 (80.0, 226.2) 122.3 (63.0, 237.5) Moderate vs Normal 176.3 (103.0, 301.8) 177.3 (89.3 352.3) Severe vs Normal 120 (--) 130 (--) IC200131 Mild vs Normal 61.0 (40.0, 92.9) 41.8 (24.4, 71.5) Moderate vs Normal 98.4 (64.6, 149.9) 91.0 (53.2, 155.7) Severe vs Normal* 130 (--) 160 (--) (--): 90% CI not calculated; Source: Table 11-14 to Table 11-18 CSR for study ITI-007-011; *reviewer analysis,

Age, Race or Sex

No dose adjustments are required on the basis of age, race or sex.

• Figure 9 shows the mean (+/- SD) dose normalized concentrations by age. No differences in plasma levels of lumateperone are observed by age. The applicant’s population pharmacokinetic analysis also reports similar findings.

• Figure 10 shows the mean (+/- SD) dose normalized concentrations by race. No differences in plasma levels of lumateperone are observed in the Caucasian and black populations. The applicant’s population pharmacokinetic analysis also reports similar findings.

• Figure 11 shows the mean (+/- SD) dose normalized concentrations by sex. Lumateperone plasma concentrations are higher in female subjects compared to male.

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This is likely due to differences in body weight. The applicant’s population pharmacokinetic analysis also reports similar findings.

Figure 9. Mean (+/-) SD Dose Normalized Lumateperone Concentrations by Age (<50y, ≥50y) from Studies ITI-007-002, ITI-007-006 and ITI-007-009.

Source: Reviewer’s analysis

Figure 10. Mean (+/-) SD Dose Normalized Lumateperone Concentrations by Race (Caucasian, Black) from Studies ITI-007-002, ITI-007-006 and ITI-007-009.

Source: Reviewer’s analysis

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Figure 11. Mean (+/-) SD Dose Normalized Lumateperone Concentrations by Sex (Male, Female) from Studies ITI-007-002, ITI-007-006 and ITI-007-009.

Source: Reviewer’s analysis

Are there clinically relevant food-drug or drug-drug interactions, and what is the appropriate management strategy? Yes. Strong CYP3A Inducers: Coadministration of rifampin (600mg, once daily for 8 days) led to >90% decreases in Cmax and AUC for the parent compound, with variable decreases for the major metabolites (Table 46). Together with the known dose-response relationships for efficacy and safety and the factors discussed under Section 3.2.2, concomitant use of lumateperone with a strong CYP3A inducer should be avoided. Given the large magnitude of effect (>90% decrease) with coadministration of a strong CYP3A inducer (i.e., rifampin), the same recommendation (i.e., avoid concomitant use) should be extended to weak and moderate CYP3A4 inducers.

Table 46: Statistical Analysis of Plasma Pharmacokinetic Parameters of ITI-007 (IC200056) and Major Metabolites: Rifampin/ITI-007 vs ITI-007 (% geomean ratio [90%CI]) Parameters IC200056 IC200161 IC201308 IC200131 Cmax 7.7 (4.6,13.1) 76.0 (63.7,90.8) 27.5 (23.6,32.0) 8.3 (6.8,10.2) AUClast 2.1 (1.0,4.3) 52.5 (46.5,59.4) 19.1 (16.2,22.5) 1.1 (0.6,2.1) AUCinf ND 54.6 (47.6,62.7) 28.7 (23.7,34.8)* ND *n=11 for ITI-007+Rifampin; others n=19; ND: not determined; Source: Tables 11-8, 11-10, and 11-12 of CSR for study ITI-007-013.

Strong CYP3A Inhibitors: When administered as a single 14 mg ITI-007 after 5 consecutive days of itraconazole administration (200 mg, once daily for 5days), exposure of IC200056 was 319% and 381% of the exposure observed following ITI-007 administration alone, based on Cmax and

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AUCt, respectively. Variable increases were observed for the major metabolites (Table 47). Based on the findings on exposure change, together with the known dose-response relationships for efficacy and safety and the factors discussed under Section 3.2.2, a dosage of lumateperone such as 10.5 mg should be considered when used concomitantly with a strong CYP3A4 inhibitor. However, because no appropriate strength is available for dose adjustment, concomitant use of strong CYP3A inhibitors with lumateperone should be avoided.

Table 47: Statistical Analysis of Plasma PK Parameters of IC200056 and Major Metabolites: Itraconazole/ITI-007 vs ITI-007 (% geomean ratio [90%CI]) Parameters IC200056 IC200161 IC201308 IC200131 Cmax 319 (278,366) 125 (105,149) 108 (91.4,128) 291 (261,324) AUClast 381 (321,453) 149 (134,167) 128 (109,150) 523 (433,632) AUCinf 343 (279,421) 141 (117,170) 143 (120,169) 416 (333,521) NC: not calculated. Source: Tables 11-8, 11-10, and 11-12 of CSR for study ITI-007-012.

Moderate CYP3A Inhibitors: When lumateperone was administered as a single 14 mg dose after 5 consecutive days of diltiazem administration (240 mg, once daily for 5 days), exposure of IC200056 was 187% to 232% of the exposure observed following lumateperone administration alone. A varying magnitude of increase was observed with the major metabolites (Table 48). Based on the findings on exposure change, together with the known dose-response relationships for efficacy and safety and the factors discussed under Section 3.2.2, dosage of lumateperone such as 21 mg, should be considered when used concomitantly with a moderate CYP3A4 inhibitor. However, because no appropriate strength is available for dose adjustment, concomitant use of moderate CYP3A inhibitors with lumateperone should be avoided. In addition, based on the results, smaller increase in exposure is expected when lumateperone is used concomitantly with a weak CYP3A inhibitor, dosage adjustment is not considered necessary in this scenario.

Table 48: Statistical Analysis of Plasma PK Parameters of IC200056 and Major Metabolites: Diltiazem/Lumateperone vs Lumateperone (% geomean ratio [90%CI]) Parameters IC200056 IC200161 IC201308 IC200131 Cmax 187 (134,261) 106 (92.6,122) 119 (99.6,142) 213 (159,287) AUClast 232 (161,335) 133 (113,156) 134 (107,170) 344 (255,465) AUCinf 225 (68,301) 126 (101,157) 151 (150,152)* 212 (148,287) *n=2 for ITI-007+Diltiazem; n=4/ITI-007 only -Source: Table 11-21 to Table 11-24 of CSR for study ITI-007-012

Food Effect Based on the study results, ingestion of food with lumateperone decreased the Cmax of the parent compound and metabolites IC201308, IC200309, and IC200565 by some 30-50%. Though no significant effect on AUC of the parent was observed, food numerically decreased the AUC of metabolites by about 15-20%. Given that a higher incidence of GI effects was observed in the higher dose group than the lower dose group in the clinical trials and that a

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decreased Cmax with food may result in fewer GI effects, we recommend that lumateperone should be given with food.

Table 49: Summary Statistics of the Plasma PK Parameters of IC200056 and Metabolite IC200131, IC200161 and IC200565: Fed vs Fasted (%Geomean Ratio, [90%CI]) IC200056 IC200131 IC200161 IC201308

Cmax (ng/mL) 0.67 0.69 0.48 0.64 (0.57, 0.80) (0.60, 0.79) (0.41, 0.57) (0.55, 0.75)

AUCt 1.07 0.84 0.81 0.93 (hr*ng/mL) (0.95, 1.19) (0.74, 0.96) (0.73, 0.89) (0.83, 1.04)

AUCinf 1.09 0.86 0.85 0.96 (hr*ng/mL) (0.97, 1.22) (0.76, 0.97) (0.77, 0.94) (0.87, 1.06)

-Source: Table 14, 14.2.2.3.2, 14.2.3.3.2, and 14.2.5.3.2 of CSR #ITI-007-019

Effect of Lumateperone on Midazolam Though coadministration with multiple doses of 42 mg lumateperone affected the exposure of midazolam, the magnitude of change (~25% increase in midazolam exposure) is not considered clinically significant. This result indicates that lumateperone has no clinically significant effect on the activity of CYP3A4. No dosage adjustment is necessary when CYP3A4 substrates are used concomitantly with lumateperone.

Table 50: Statistical Analysis of Plasma PK Parameters of Midazolam and 1- Hydroxymidazolam: ITI-007/Midazolam vs Midazolam (% geomean ratio [90%CI]) Parameters Midazolam 1-Hydroxymidazolam Cmax 111.3 (100.1, 124.0) 103.9 (91.3, 118.3) AUClast 123.7 (113.2, 135.2) 103.0 (94.4, 112.4) AUCinf 126.2 (114.9, 138.6) 103.0 (94.2, 112.5) -Source: Table 11-4 to Table 11-5 of CSR #ITI-007-014

What Are the Circulation Levels of the Aniline Metabolites in Humans? Are There Any Safety Concerns? At the therapeutic dose of 42 mg lumateperone, plasma levels of the two aniline metabolites (IC201337 and IC201338) in patients were below 0.1 ng/mL (LLOQ of the deployed bioanalytical methods). However, we cannot completely rule out the presence of lower levels of aniline metabolites in humans that are not quantifiable with available bioanalytical methods. Safety signals should be monitored by postmarketing pharmacovigilance.

Lumateperone is extensively metabolized with more than 20 metabolites identified in humans. Glucuronidation of the parent and intermediate metabolites seems to be a major

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biotransformation pathway in humans, as the glucuronidated metabolites represented about 50% of total plasma radioactivity after a single dose administration of 14C-labeled lumateperone. About 38% or more of the excreted radioactivity in urine is glucuronidated metabolites.

Studies have shown that species differences in lumateperone metabolism exist between humans and animals. In dogs, it seems that a considerable amount of aniline metabolites and corresponding 2-carbon fragments (piperazine ring cleavage products) are formed. Concerning neuropathological changes have been observed in dogs after long-term exposure to lumateperone, and the nonclinical data provided by the Applicant suggest the aniline metabolites (IC201337 and IC201338) are associated with the canine neurotoxicities/ findings.

The neuropathological findings and clinical signs of neurotoxicity observed in dogs raise concerns about whether similar neurotoxicities might occur in humans after long-term exposure. To date, the long-term human studies have not revealed any pattern of unexpected neurological adverse events emerging over time. However, it is unclear whether humans might develop the neuropathological changes, remain clinically asymptomatic for months or years, but begin to show clinical signs of neurotoxicity in the longer-term. Because the neuropathologies cannot be assessed directly in humans without an autopsy, determining whether circulating levels of aniline metabolites can be detected in patients who have had long- term exposure to lumateperone was critical to the approval decision for this application.

Assessment of Aniline Metabolites in Humans

The Applicant made several attempts to measure the plasma levels of the aniline metabolites in humans. The first effort was to measure the aniline metabolite concentrations from plasma samples collected in the open-label long term safety Study ITI-007-303 (Study 303) in the original submission. Both aniline metabolites were found to be below the lower limit of quantification (LLOQ) of 1.0 ng/mL. However, because there was a gap in time from lumateperone administration in the evening to blood sample collection around noon the next day, there is a possibility that higher concentrations of aniline metabolites present sooner after lumateperone administration might be missed.

The Applicant then reanalyzed the frozen plasma samples from the Thorough QT study ITI-007- 017 (study completed in May 2018) in which a series of intensive PK samples were collected on Day 5 following once daily administration of lumateperone, and submitted the results in a major amendment. Unfortunately, the stored samples were out of the long-term storage stability windows for IC201337 (94 days) and IC201338 (50 days) at -80˚C, originally established in the methods validation. Upon the Agency’s inquiry, the Applicant submitted data to support an extended stability window to 171 days in the submission dated Sep. 17, 2019, and to 567 days in the submission dated Oct. 10, 2019. To ensure the validity of the newly-extended (b) (6) stability windows, FDA conducted an inspection/audit of the contracted bioanalytical site,

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(b) (6) The Agency identified no major issues that would have caused us to reject the stability data.

Per the Agency’s request, the Applicant improved their bioanalytical assay sensitivity to 0.1 ng/mL for both aniline metabolites; this improved assay was used to analyze the frozen TQT samples, with a caveat that the improved sensitivity (from 1.0 ng/mL to 0.1 ng/mL) was not fully validated. Another limit of the bioanalytical run is that all calibration curves and QC samples were run in duplicate, rendering challenges in evaluating the assay performance. With the two constraints acknowledged, results from the TQT frozen samples showed that plasma levels of both IC201337 and IC201338 were below 0.1 ng/mL for patients dosed to steady state with the therapeutic dose. However, peaks detected at the targeted retention times for the aniline metabolites in the chromatograms were noticeable in some patients, suggesting that the aniline metabolites might be formed in some patients though in limited quantities (at levels below 0.1 ng/mL).

The Applicant also collected new plasma samples for analysis from patients dosed to steady state in an ongoing clinical trial in order to measure the aniline metabolites in freshly-collected (no long-term storage) plasma. Results from 11 patients dosed at 42 mg lumateperone were submitted on Nov. 27, 2019, one month before the PDUFA Goal date Dec. 27, 2019. These patients had been treated with lumateperone 42 mg for 23 to 26 months in Study ITI-007-303. Unfortunately, the steady state of these patients had been disrupted by skipping the evening dose, based on instructions per the study protocol. Thus, patients had been dosed in the morning on the day of PK sample collection, after an overnight fast of at least 10 hours. Regardless of this disturbance in steady state condition, comparison of the parent and the other three major metabolites showed comparable levels between this study and the TQT study, suggesting at least for the parent and the measured major metabolites, a half-day delay does not seem to cause significant deviation from steady state measurements. The inherent PK characteristics of lumateperone (large PK variability with a coefficient of variation for exposure about 68-97% at steady state) might contribute to the finding of comparable circulation levels.

In sum, results from the new PK analysis showed that the plasma levels of the aniline metabolites IC201337 and IC201338 were below 0.1 ng/mL (LLOQ of partially validated bioanalytical methods) following administration of 42 mg lumateperone at different time points (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose). Visual assessment of chromatograms from the PK samples yielded two patterns: in some patients, peaks associated with IC201337 or IC201338 were more noticeable, above the background noise but below the LLOQ (top panels of A and B in Figure below); while in others, no chromatographic peaks associated with IC201337 or IC201338 could be clearly identified above the background noise level (lower panels of A and B in Figure below). These results are consistent with the findings from TQT plasma samples.

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Figure 12: Representative Chromatograms For IC201337(A) And IC201338(B)

A: IC201337 (Retention Time: ~3.44 min)

B: IC201338 (Retention Time: ~3.90 min)

x-axis: time (min); y-axis: intensity (cps); cal11-1/2/3 are calibration standards at 0.1ng/mL; all others are study subjects -Source: study report RIXA3

In conclusion, given the totality of data, available evidence showed that at the therapeutic dose of 42 mg lumateperone, plasma levels of the two aniline metabolites (IC201337 and IC201338) in patients were below 0.1 ng/mL (the LLOQ of the bioanalytical method). We cannot completely rule out the presence of lower levels of aniline metabolites in humans that are not quantifiable with available bioanalytical methods. Safety signals should be monitored through postmarketing pharmacovigilance.

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More details about species difference in lumateperone metabolism and aniline metabolites in humans are described in Appendices 19.4.2.

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7 Sources of Clinical Data and Review Strategy

Table of Clinical Studies

The Applicant has submitted results from three multicenter, US-only, randomized, placebo- controlled clinical trials to provide evidence of lumateperone’s effectiveness for the treatment of schizophrenia. The safety data from these studies were supplemented by data from a long- term, uncontrolled study of lumateperone in patients with schizophrenia. Table 51 summarizes the three controlled clinical trials submitted to support efficacy and the uncontrolled trial submitted to support safety.

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Table 51: Listing of Clinical Trials to Support Efficacy and Safety Trial NCT no. Trial Design Regimen/ schedule Study Endpoints Treatment No. of Study No. of Identity (all dosing is by mouth) Duration/ patients Population Centers and Follow Up enrolled Countries Controlled Studies to Support Efficacy and Safety ITI-007- NCT01499563 randomized, lumateperone 42 mg daily Primary: change 4 weeks 335 Adults with 8 centers in 005 double-blind, lumateperone 84 mg daily from baseline to inpatient acute the United placebo-controlled, risperidone 4 mg daily Week 4 on PANSS treatment; exacerbation States with active placebo daily total score 1 week of comparator stabilization schizophrenia prior to discharge; follow-up 2 weeks after discharge ITI-007- NCT02282761 randomized, lumateperone 28 mg daily Primary: change 4 weeks 450 Adults with 12 centers in 301 double-blind, lumateperone 42 mg daily from baseline to inpatient acute the United placebo-controlled placebo daily Week 4 on PANSS treatment; exacerbation States total score 5 days of stabilization schizophrenia prior to discharge; follow-up 2 weeks after discharge ITI-007- NCT02469155 randomized, lumateperone 14 mg daily Primary: change 6 weeks 696 Adults with 13 centers in 302 double-blind, lumateperone 42 mg daily from baseline to inpatient acute the United placebo-controlled, risperidone 4 mg daily Week 6 on PANSS treatment; exacerbation States with active placebo daily total score 5 days of comparator stabilization schizophrenia prior to discharge; follow-up 2 weeks after discharge

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Studies to Support Safety ITI-007------open-label, lumateperone 42 mg daily vital signs, clinical Up to 1 year 603 Adults with 40 centers in 303 uncontrolled study lab studies, adverse of outpatient stable the United event reports treatment schizophrenia States

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Review Strategy

The assessment of efficacy included review of the Clinical Study Reports (CSRs) and submitted datasets from the three placebo-controlled trials. The assessment of efficacy was a joint review between the clinical and biostatistics teams.

The assessment of safety included review of the CSRs and submitted datasets from the three placebo-controlled trials as well as from the long-term open-label safety trial.

As specified in the text, the presentation of efficacy and safety results includes analyses submitted by the Applicant as well as those performed by the review team.

Description of Efficacy and Safety Assessments

The following is a description of the important efficacy and safety assessments used in the trials submitted to support the efficacy and safety of lumateperone. Not all assessment tools described were used in all three studies.

Positive and Negative Syndrome Scale

The PANSS is a 30-item scale used to measure symptoms of schizophrenia. The scale has seven positive symptom items (P1 through P7), seven negative symptom items (N1 through N7), and 16 general psychopathology symptom items (G1 through G16). Each item is scored on a seven- point scale by the clinical rater based on a clinical interview with the patient. A score of 1 indicates the absence of symptoms, and a score of 7 indicates extremely severe symptoms. The range of the total PANSS score is from 30 to 210. A PANSS total score of 58 approximately corresponds to the Clinical Global Impression–Severity (CGI-S) category of “mildly ill,” a score of 75 to “markedly ill,” and a score of 116 to “severely ill” (Leucht, Kane et al. 2005). The mean change in total PANSS score from baseline to the end of treatment has been used frequently as a primary efficacy endpoint in clinical trials of drugs for the treatment of schizophrenia.

The PANSS Positive subscale score is the sum of the scores on the following seven items: delusions (P1), conceptual disorganization (P2), hallucinatory behavior (P3), excitement (P4), grandiosity (P5), suspiciousness (P6), and hostility (P7). The possible range for the Positive subscale score is from 7 to 49.

The PANSS Negative subscale score is the sum of the scores on the following seven items: blunted affect (N1), emotional withdrawal (N2), poor rapport (N3), passive/apathetic social withdrawal (N4), difficulty in abstract thinking (N5), lack of spontaneity and flow of conversation (N6), and stereotyped thinking (N7). The possible range for the Negative subscale score is from 7 to 49.

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The PANSS General Psychopathology subscale score is the sum of the scores on the following sixteen items: somatic concern (G1), anxiety (G2), guilt feelings (G3), tension (G4), mannerisms and posturing (G5), depression (G6), motor retardation (G7), uncooperativeness (G8), unusual thought content (G9), disorientation (G10), poor attention (G11), lack of judgment and insight (G12), disturbance of volition (G13), poor control (G14), preoccupation (G15), and active social avoidance (G16). The possible range for the General Psychopathology subscale score is from 16 to 112.

Several factor models of the PANSS have been proposed. Some factor models include all items of the PANSS, while some include a subset of the PANSS items. The PANSS Prosocial Factor Score is the sum of scores from six items: two positive (P6 and P3), three negative (N2, N4, and N7), and one general psychopathology (G16). The possible range for the Prosocial Factor Score is 6 to 42.

Several different five-factor models of the PANSS have been constructed. For each factor, the sum of a subset of items is used to generate a subscore. The models differ in the subset of items included in each factor. The two five-factor models used in the lumateperone clinical trials are the Van Der Gaag model (used in all three trials) and the Marder model (use in Studies ITI-007-301 and ITI-007-302).

Factors Marder model Van Der Gaag model Negative N1, N2, N3, N4, N6, G7, G16 N1, N2, N3, N4, N6, G7, G8, G16 Positive P1, P3, P5, P6, N7, G1, G9, G12 P1, P3, P5, P6, G9 Disorganization / P2, N5, G5, G10, G13, G15 P2, N5, N7, G10, G11 Cognition Excitement / P4, P7, G8, G14 P4, P7, G8, G14 Hostility Emotional Distress G2, G3, G4, G6 G2, G3, G4, G6

Clinical reviewer comment: The mean change from baseline in the PANSS total score is the primary efficacy endpoint for all three registration studies. The PANSS total score has been accepted in the past by the Division of Psychiatry as a primary efficacy measure for the majority of clinical trials of antipsychotic agents, and it is included in the Agency’s Clinical Outcome Assessment Compendium. Although the Applicant included PANSS five-factor models as secondary endpoints, these results did not factor into the overall assessment of efficacy.

Clinical Global Impression – Severity The CGI-S scale is a 7-point scale for rating symptom severity in patients with psychiatric disorders. The clinician rates the severity of the patient’s illness at the time of assessment, relative to the clinician’s past experience with patients who have the same diagnosis. Possible ratings are:

1. Normal; not at all ill

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2. Borderline mentally ill 3. Mildly ill 4. Moderately ill 5. Markedly ill 6. Severely ill 7. Among the most extremely ill patients

Brief Psychiatric Rating Scale

The Brief Psychiatric Rating Scale (BPRS) is a clinician-administered questionnaire comprised of 24 items covering a wide range of psychiatric symptoms, including anxiety, depression, suicidal ideation, elevated mood, unusual thought content, conceptual disorganization, and motor behavior. Items are rated on a scale from 1 (symptom is absent) to 7 (symptom is severe). The total score ranges from 24 (absence of any symptoms) to 168 (severe symptoms in all categories). A BPRS score of 31 approximately corresponds to the CGI-S category of “mildly ill,” a score of 41 to “moderately ill,” and a score of 53 to “markedly ill” (Leucht, Kane et al. 2005). The BPRS was not used as a primary or secondary efficacy endpoint for any of the registration studies, but a BPRS score ≥ 40 was one of the criteria for all three registration studies.

Pittsburgh Sleep Quality Index

The Pittsburgh Sleep Quality Index (PSQI) includes 19 questions for the person being evaluated and five questions for a bed partner or roommate. It evaluates sleep quality during the previous month and covers seven domains of sleep: Subjective Sleep Quality, Sleep Latency, Sleep Duration, Habitual Sleep Efficiency, Sleep Disturbances, Use of Sleep Medications, and Daytime Dysfunction. The PSQI generates a score for each domain. Each domain score ranges from 0 (no difficulty) to 3 (severe difficulty). The domain scores are summed to produce a global score with a range from 0 to 21. A PSQI global score > 5 is considered to be suggestive of significant sleep disturbance.

Personal and Social Performance Scale

The Personal and Social Performance Scale (PSP) is a clinician-rated measure of the severity of personal and social dysfunction that has been validated in subjects with acute exacerbation of schizophrenia. The scale is a 100-point rating scale based on ratings in four areas: [1] socially useful activities, [2] personal and social relationships, [3] self-care, and [4] disturbing and aggressive behavior. Higher scores represent better personal and social functioning.

Calgary Depression Scale for Schizophrenia

The Calgary Depression Scale for Schizophrenia (CDSS) was developed to assess the level of depression in patients with schizophrenia, separate from the positive, negative, and extrapyramidal symptoms associated with schizophrenia and with pharmacologic treatments

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used to treat the illness. The instrument has nine items rated from 0 (absent) to 3 (severe) by the investigator or a clinical rater based on a semi-structured clinical interview. The items rate a patient’s depression, hopelessness, self-deprecation, guilty ideas of reference, pathological guilt, morning depression, early wakening, suicidality, and observed depression over the previous two weeks. The CDSS depression score is obtained by adding each of the item scores. A score > 6 is estimated to have 82% specificity and 85% sensitivity for predicting the presence of a major depressive episode.

Barnes Akathisia Rating Scale

The Barnes Akathisia Rating Scale (BARS) is a rating scale for drug-induced akathisia, incorporating both clinician- and patient-rated items. It includes ratings for observable restless movements, subjective awareness of restlessness, and distress associated with the akathisia. There is also a global rating for severity. Objective akathisia, subjective awareness, and subjective distress are rated on a four-point scale from 0 to 3, yielding a total score from 0 to 9. The global clinical assessment of akathisia is rated separately, on a five-point scale from 0 to 4.

Simpson-Angus Scale

The Simpson-Angus Scale (SAS) is a clinician-rated measure of observed extrapyramidal adverse effects. It consists of ten items: gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, , and salivation. Items are rated on a scale from 0 (normal) to 4 (extreme).

Abnormal Involuntary Movement Scale

The Abnormal Involuntary Movement Scale (AIMS) is a clinician-rated measure of observed extrapyramidal adverse effects. It assesses facial and oral movements, extremity movements, and trunk movements. Seven items are rated on a scale from none (0) to severe (4). A score of mild (2) in two or more categories or a score of moderate or severe in any one category results in a positive AIMS score. Additionally, overall severity is scored on the basis of severity of abnormal movements and incapacitation due to abnormal movements. The patient’s awareness of and distress caused by the abnormal movements are also noted.

Columbia Suicide Severity Rating Scale

The Columbia Suicide Severity Rating Scale (C-SSRS) is a questionnaire used to assess suicidal ideation and behavior. Several versions have been developed including the “Baseline” and “Screening” versions and a combined “Baseline/Screening” version that assesses suicidal ideation and behavior in a patient’s lifetime and during a predefined time period. This version can assess a patient’s lifetime suicidal ideation and behavior as well as eligibility based on inclusion/exclusion criteria. A separate “Since Last Visit” version of the scale has been developed which is used to assess suicidal ideation and behavior since the patient’s last visit.

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This version is meant to assess patients who have completed at least one initial C-SSRS assessment and can be used at each subsequent visit. The “Since Last Visit” of the C-SSRS addresses any suicidal thoughts or behaviors the patient may have had since the last time the C-SSRS was administered in the study. Scoring on the C-SSRS ranges from 0 (absence of any suicidal ideation or behavior) to 5 (active suicidal ideation with specific plan and intent). A score of 4 or 5 indicates a clinical assessment of high risk for suicide, where 4 represents active suicidal ideation with some intent to act. For each of the three registration studies, patients with a C-SSRS score ≥ 4 were excluded from the study.

Subjective Well-being Under Neuroleptic Treatment, Short Version

The Subjective Well-being Under Neuroleptic Treatment (SWN-S) scale is a patient-rated measure of subjective well-being. The scale consists of 20 items, each of which is scored on a Likert scale with six response categories ranging from “not at all” to “very much.” The SWN-S has five subscales: [1] mental functioning, [2] self-control, [3] emotional regulation, [4] physical functioning, and [5] social integration. The SWN-S was administered in Study ITI-007-302 only.

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8 Statistical and Clinical Evaluation

Review of Relevant Individual Trials Used to Support Efficacy

Study ITI-007-005 (Study 005; ClinicalTrials.gov Identifier NCT01499563)

Overview and Objectives Study Title: “A Randomized, Double-blind, Placebo-controlled, Multi-center Study to Assess the Antipsychotic Efficacy of ITI-007 in Patients with Schizophrenia”

Primary Objective: To determine whether lumateperone administered to patients with acutely exacerbated schizophrenia demonstrates antipsychotic efficacy compared to placebo, as measured by change from baseline on the PANSS total score.

Secondary Objectives: To determine whether, compared to placebo, lumateperone administered to patients with acutely exacerbated schizophrenia:

• demonstrates antipsychotic efficacy as assessed by change from baseline on the CGI-S; • demonstrates antipsychotic efficacy as assessed by change from baseline on any of the individual PANSS subscales: Positive, Negative, and General Psychopathology; • demonstrates an improvement in patient-reported sleep as measured by the PSQI; • demonstrates an improvement in symptoms of depression as measured by the CDSS or by the depression/anxiety factor of the PANSS; • is safe and well-tolerated.

Trial Design Study Design Overview: Refer to Figure 13 for a schematic of the study design. Patients with an acute exacerbation of schizophrenia were randomized to receive lumateperone 42 mg daily, lumateperone 84 mg daily, risperidone 4 mg daily (active control), or placebo daily for four weeks. The study was conducted on an inpatient hospital unit.

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Figure 13: Study 005: Design Schematic

Source: ITI-007-005 Clinical Study Report, Figure 1, page 17.

Trial Location: The study was conducted at eight sites in the United States.

Diagnostic Criteria: Eligible patients had a diagnosis of schizophrenia according to criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV- TR) and confirmed by the Structured Clinical Interview for DSM Disorders – Clinical Trial Version (SCID-CT). The appropriateness of each patient was reviewed and approved by an independent Eligibility Adjudication Committee (EAC).

Key Inclusion Criteria: • Male or female, age 18-55 years. • Diagnosis of schizophrenia. • Acute exacerbation of schizophrenia where the following criteria were met: o BPRS score ≥ 40 at screening. o BPRS at screening includes a minimum score ≥ 4 on at least two of the following four positive symptom items: . suspiciousness;

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. conceptual disorganization; . hallucinatory behavior; . unusual thought content. o CGI-S score ≥ 4 at screening. o Current exacerbated episode has lasted no longer than four weeks. o Sufficient history and/or independent reporter (such as a family member, caregiver, outside practitioner) must verify that the current state is an exacerbated state for the individual patient. • History of at least three months’ exposure to one or more antipsychotic therapies. • A prior response to antipsychotic therapy within the previous five years, where response was defined as a clinically significant decrease in delusions and/or hallucinations during an exacerbated episode. • Body mass index (BMI) of 19 to 40 kg/m2 at screening. • Female patients must be of non-childbearing potential or must use effective methods of birth control from at least one month prior to randomization to the end-of-study visit.

Key Exclusion Criteria: • Female patients who are pregnant, breast-feeding, or have a positive urine pregnancy test at screening or on Day 1. • Concurrent dementia, , mental retardation, epilepsy, drug-induced psychosis, or history of significant brain trauma. • Diagnosis of schizoaffective disorder, bipolar disorder, acute , or major depression with psychotic features. Symptoms of depression were allowed. • Patient was considered to be an imminent danger to themselves or others. • C-SSRS score ≥ 4 within 30 days prior to screening or any suicidal behavior in the last two years prior to screening, as indicated by any “yes” answers on the suicidal behavior section of the C-SSRS. • Abnormal laboratory values or clinical findings on screening that were judged to be clinically significant. • Diagnosis of within the three months prior to screening, any disorder within the six months prior to screening, positive urine drug or test at screening, or evidence of acute intoxication or withdrawal at screening. • Prior history of neuroleptic malignant syndrome induced by any antipsychotic medication. • Any subject who was unable to be safely discontinued from current antipsychotic therapy, mood stabilizers, , , and medications.

Prohibited Concurrent Medications: • Use of any antipsychotic medication within the screening period through Day 1. • Use of depot antipsychotic medication within one treatment cycle prior to Day 1 (baseline).

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• Use of any of the following agents: , , , , or within 30 days prior to Day 1. • Medications other than lorazepam, such as zaleplon and zolpidem, to manage insomnia.

Allowable Concurrent Medications: • Lorazepam was allowed to help alleviate agitation or insomnia, not to be given within eight hours prior to PANSS, CGI-S, PSQI, or CDSS. • Benztropine was allowed for treatment of extrapyramidal adverse effects, not to be given within eight hours of SAS, BARS, or AIMS. • Propranolol was allowed for treatment of akathisia, not to be given within eight hours of SAS, BARS, or AIMS.

Study Treatments: Starting on the first day of screening, all antipsychotic and other psychotropic medications were stopped, with taper conducted as per investigator’s clinical judgment.

Lumateperone, risperidone, and placebo were administered in capsule form. Placebo capsules were given along with drug capsules to maintain study blinding. Study treatments were administered once daily in the morning. The lumateperone doses of 42 mg daily and 84 mg daily were chosen based on safety and tolerability demonstrated in a previous clinical study, ITI- 007-002. In addition, based on previous pharmacokinetic studies, the striatal D2 receptor occupancy for the 42-mg and 84-mg doses were expected to be approximately 50% and 70%, respectively. This range of D2 occupancy was expected to have antipsychotic efficacy, based on D2 occupancy levels of other marketed antipsychotic agents.

Risperidone was chosen as the positive control because it is approved for the treatment of schizophrenia in the United States and is one of the most commonly prescribed medications for this disorder. The recommended target dose of risperidone for the treatment of schizophrenia in adults is 4 to 8 mg daily. The dose of 4 mg daily was chosen because it was expected to be efficacious but have a lower potential for adverse effects that might unblind the study, as well as being less likely to cause early discontinuation.

Assignment to Treatment: Patients were randomized 1:1:1:1 to lumateperone 42 mg, lumateperone 84 mg, risperidone 4 mg, or placebo daily. As a one-day dose titration, patients in the risperidone group and the lumateperone 84-mg group received risperidone 2 mg and lumateperone 42 mg, respectively, on Day 1.

Procedures and Schedule: Total study duration was approximately eight weeks, including a screening period of two to seven days prior to Day 1, an inpatient treatment period of four weeks, a five-day inpatient stabilization period during which patients were stabilized on standard antipsychotic medication, and a safety follow-up approximately two weeks after the end of the stabilization period (see Study Schematic, Figure 13). At the end of the stabilization

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period, patients were continued on either inpatient or outpatient standard-of-care treatment as deemed necessary by the investigator.

Table 52: Study 005: Schedule of Assessments

Screening End of End of Event Baseline Study Treatment Period Period Restabilization Study Visit Number 1 2 3 4 5 6 7 8 9 Day -7 to -2 –1 1 8 15 22 28 33 47 ± 2 d Informed Consent X Admission to Inpatient X Medical History X Incl/Excl Criteria Review X SCID-CT, BPRS, C-VISA© 2 X Completion Modified Physical Exam X X Hepatitis/HIV Testing X Urine Drug and Alcohol X X Urine Pregnancy Test X X X 3 Clinical Laboratories X X X X X X 4 12-Lead ECG X X X X X X 5 Vital Signs X X X X X X X X Randomization X Study Drug Dosing X X X X X PK Sample Collection6 X X X X Samples for p11 X X Sample for genetic testing7 X (X6) PANSS8 X X X X X CGI-S2, 8 X X X X X X X X PSQI, CDSS X X SAS, BARS, AIMS9 X X X X X X C-SSRS X X X X X X X X AE Assessments10, Con X X X X X X X X X Con Medications X X X X X X X X X Restart Standard X Antipsychotics11 1 Upon signing the ICF, patients were admitted to the inpatient unit, if they were not inpatients already. 2 These assessments were performed using Clintara audio-digital pen and submitted to EAC for review. 3 Clinical Laboratory samples were taken after an overnight fast of at least 10 hours. 4 ECGs were triplicate 10 second epochs with 5 min between recordings. ECGs were done once during Screening and on Days -1 and 33. On Days 1, 8, and 28 ECGs were taken pre-dose, and 3-6 hr and 9-12 hr post-dose. In all cases ECGs were conducted prior to other pre-dose assessments and prior to other assessments scheduled 3-6 hr or 9-12 hr post-dose. 5 Respiratory rate, oral temperature, and 3-positional blood pressure and pulse (after 10 minutes lying down, after 1 minute sitting, immediately upon standing, and after 3 minutes standing) were taken at least once at all

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scheduled visits. On Days 1, 8, 15, 22, and 28 vitals were taken pre-dose, and 3-6 hr and 9-12 hr post-dose. Vitals were always taken after ECGs, as applicable, and prior to any other assessments scheduled in the same time window. 6 Samples were collected prior to dosing and then 3-6 hours after dosing on Days 1, 8, and 28 and then once on Day 33. 7 A blood sample was collected once for genetic testing, if the optional ICF addendum is signed. If the addendum was signed prior to Day 1 then the sample was taken on Day 1. If it was signed after Day 1, then the sample was taken on Day 28. It was not to be taken twice. 8 PANSS was conducted by a remote central rater. Due to potential limitations around scheduling of the remote rater, the PANSS may have been conducted within a 1-day window provided for this assessment. If it was not conducted on the day of the scheduled visit then the CGI-S should have been conducted on the same day as the PANSS rather than on the day of the scheduled visit. 9 On Days 1, 8, 15, 22, and 28, the SAS, BARS, and AIMS assessments were conducted 3-6 hours after the administration of study treatment. 10 The recording of adverse events was to start immediately after the ICF is signed and continue through Day 74. 11 On Day 28, after all study assessments have been completed, or on Day 29 patients were to be started on standard antipsychotic medication as prescribed by the Investigator. Source: ITI-007-005 Protocol and Amendments, Table 4, page 32-33.

Study Endpoints (see Section 0 for descriptions of study endpoints) Primary efficacy endpoint: • mean change in total PANSS score from baseline to the end of treatment (Week 4)

Secondary efficacy measures: • PANSS Positive subscale • PANSS Negative subscale • PANSS General Psychopathology subscale • PANSS five factors • CGI-S • PSQI • CDSS Reviewer's Comment: Comparisons between lumateperone and placebo for the secondary efficacy measures were considered supportive, and statistical tests for endpoints with these measures were not controlled for multiplicity.

Safety assessments: • reported and observed adverse events (AEs) • • body weight and waist circumference • vital signs • 12-lead electrocardiogram (ECG) • clinical laboratory values • SAS • BARS • AIMS

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• C-SSRS

Pharmacokinetic data: Blood samples were collected pre-dose and 3-6 hours post-dose on Days 1, 8, and 28 and once on Day 33 for determination of lumateperone and metabolite concentrations, or risperidone and metabolite concentrations, as applicable.

Statistical Analysis Plan The protocol for Study 005 was submitted on 11/21/2011. The Statistics team conveyed comments on 3/22/2012. Study 005 in its initial description was classified as “proof-of- concept.” The statistical advice pertained to the primary analysis, handling of missing data, the proposed interim analysis, and the multiple comparison procedure. Database lock for Study 005 occurred on 11/1/2013. The statistical analysis plan (SAP) and interim analysis plan (IAP) both dated 5/9/2012 were submitted as appendices to the 005 study report on 05/22/2015. The Applicant did incorporate advice provided by the agency into those documents (e.g., change of primary analysis from Analysis of Covariance using last observation carried forward (LOCF) to a mixed-effect model repeated measures (MMRM) approach). It would have been prudent to submit the SAP and IAP for agency review prior database lock, data analysis, and reporting of results.

Analysis Sets

The primary efficacy analysis population termed “ITT Population” includes all patients who received at least four doses of study medication, have a baseline measurement, and at least one valid post-baseline efficacy measurement.

Statistical reviewer note: The requirement for “at least four doses of study medication” in order to contribute to the primary efficacy analysis set is unusual. The Applicant conducted an exploratory analysis using the more conventional primary analysis set definition of “at least one dose of study medication” (analysis provided with Integrated Summary of Effectiveness) and the impact on the numeric results is minimal. The efficacy conclusions stand regardless of the definition of the primary analysis set (“ITT set” vs. “Modified ITT set”).

The Applicant also defined a per-protocol set. However, this analysis set is of no interest to the statistical reviewer due to the difficulty of interpreting the results in the likely event of absence of balanced covariates between the treatment arms due to distortion of the randomization by conditioning on post-randomization events.

Primary Analysis model

The change from baseline to Day 28 in PANSS total score was pre-specified as a MMRM with terms for treatment, baseline score, time point (treated as categorical variable), as well as

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interaction between treatment and time point. An unstructured covariance matrix was used to model the correlation among the repeated measures.

Sample Size determination

Using a standard deviation of 17.5 points, a sample size of 60 patients per group results in 90% power to detect a true difference of 10.5 points (effect size of 0.6) in the mean change from baseline on the PANSS total score at two-sided alpha=0.05. Accounting for some discontinuations, enrolling 67 patients per group led to a total planned enrollment of 268 patients.

Interim Analysis

An unblinded interim analysis was pre-specified to occur after approximately 50% of patients had completed the four week double-blind treatment period. The conditional power (CP) to achieve a statistically significant result at the completion of the study for each dose-placebo comparison was to be calculated using EAST5.4 (based on the estimated effect size for Day 28 in the interim and a range of slightly different treatment effects). A sample size increase could achieve that objective. Details were specified in the interim statistical analysis plan. The following four possible paths for the study post interim analysis are laid out as follows:

a) Continue study to completion (at least one lumateperone dose has acceptable conditional power); b) Terminate study for futility (both lumateperone doses unlikely to demonstrate clinically meaningful effect); c) Modify study by terminating one lumateperone dose arm; d) Modify study “if the treatment effect is promising, but with moderately low CP (e.g., CP is greater than 30% but lower than 70%) in at least one of the ITI-007 dose groups” (IAP page 13).

Multiple Comparisons

The testing of two doses (i.e., 42 mg and 84 mg of lumateperone) required the use of a multiple comparison procedure. The Applicant pre-specified the Bonferroni procedure to control the overall Type-I error rate at alpha=0.10 (two-sided). The comparison between each lumateperone dose and placebo was to be tested at the two-sided alpha=0.05 and Study 005 was to be viewed as providing favorable evidence if at least one dose was shown to be significantly superior to placebo.

Statistical reviewer note: Controlling the overall Type-I error rate at the two-sided 0.10 level is not the accepted standard for confirmatory studies in Psychiatry, or at FDA in general. However, application of the Bonferroni correction, and setting overall alpha=0.05 (two-sided) leads to

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individual dose-placebo comparisons at two-sided alpha=0.025, which is a valid approach for a confirmatory study.

Missing Data/Sensitivity Analyses

The pre-specified sensitivity analyses (i.e., analysis of covariance with last observation carried forward on intent-to-treat (ITT) set and per-protocol set) to investigate the impact of the method of choice for handling missing data in the primary analysis are not informative because they rely on the stricter assumption of missing completely at random data, whereas the primary analysis method (MMRM) uses the less strict assumption of missing at random (MAR) data. Note that missing primary efficacy data was not an issue in Study 005.

Protocol Amendments Original protocol date: November 2, 2011

Protocol Clarification #1: December 21, 2012 • A letter from the Applicant to the IRB stated that the interim analysis had been completed, that screening would resume in January 2013, and that no changes would be made to the protocol.

Protocol Clarification #2 and #3: February 8, 2013 • Letters from the Applicant to the IRB and the investigator stated that the interim analysis had been conducted, as per protocol, to inform effect size. As a result, the target sample size was increased from 268 to 320 randomized patients.

Study ITI-007-005 Results

Compliance with Good Clinical Practices, Section 5.2, page 27 of the Clinical Study Report states: “The study was conducted in compliance with the principles of the Good Clinical Practice (GCP) guidelines of the FDA and International Council for Harmonisation (ICH) and the ethical principles laid down in the current revision of the Declaration of Helsinki. The study was also carried out in keeping with local legal and regulatory requirements in the United States of America (USA).”

Financial Disclosure No disclosable financial interests or arrangements were reported for any of the investigators participating in this study. See Section 19.2, Financial Disclosures, for details.

Patient Disposition A total of 467 patients were screened for the study. Of those, 335 were randomized; 84 patients to lumateperone 42 mg, 84 to lumateperone 84 mg, 82 to risperidone 4 mg, and 85 to placebo. One randomized patient in the 84 mg group was discontinued from the study at the

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patient’s request prior to receiving study drug. Reasons for discontinuation of study drug and for discontinuing from the Study are summarized in Table 53. Patients may have discontinued from the study without discontinuing from study drug if the patient left the study after completing the study treatment. In the table, the discontinuation category of “Investigator Opinion” is used to denote that the investigator felt that continuation would be detrimental to the patient’s well-being. Discontinuations related to adverse events are discussed in more detail in Section 8.2.

Clinical reviewer comment: The frequencies of discontinuation are reasonably similar across the treatment arms. The discontinuation rate appears to be comparable to that seen in other antipsychotic efficacy studies.

Table 53: Study 005: Disposition of Randomized Patients Lumateperone Lumateperone Risperidone Placebo 42 mg 84 mg 4 mg (N=84) (N=84) (N=82) (N=85) Disposition n (%) n (%) n (%) n (%) Completed the Treatment Period 67 (79.8) 70 (83.3) 67 (81.7) 66 (77.6) Discontinued Study Drug 17 (20.2) 14 (16.7) 15 (18.3) 19 (22.4) At own request 9 (10.7) 9 (10.7) 8 (9.8) 6 (7.1) Investigator opinion 1 (1.2) 2 (2.4) 0 3 (3.5) Non-compliance with study drug 0 0 0 0 Specific request of Applicant or 2 (2.4) 0 0 1 (1.2) investigator Adverse event 2 (2.4) 0 3 (3.7) 0 Lack of efficacy 0 1 (1.2) 3 (3.7) 8 (9.4) Other 3 (3.6) 2 (2.4) 1 (1.2) 1 (1.2)

Completed the Study 60 (71.4) 64 (76.1) 63 (76.8) 61 (71.8) Discontinued from Study 24 (28.6) 20 (23.8) 19 (23.2) 24 (28.2) At own request 10 (11.9) 12 (14.3) 8 (9.8) 7 (8.2) Investigator opinion 2 (2.4) 1 (1.2) 0 3 (3.5) Specific request of Applicant or 2 (2.4) 0 1 (1.2) 1 (1.2) investigator Adverse event 2 (2.4) 0 3 (3.7) 1 (1.2) Lack of efficacy 0 1 (1.2) 3 (3.7) 6 (7.1) Other 8 (9.5) 6 (7.1) 4 (4.9) 6 (7.1) Source: based on Study ITI-007-005 Clinical Study Report, page 65, Table 4.

Protocol Violations/Deviations Five major protocol deviations occurred in the study. These are listed in Table 54. The assessment of the clinical reviewer is that the number of protocol deviations is small and unlikely to affect the analysis of the efficacy data. The frequency of major protocol deviations was highest in the placebo arm. There were no major protocol deviations in the lumateperone 42 mg arm.

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Table 54: Study 005: Major Protocol Deviations Patient ID Treatment Group Protocol Deviation (b) (6) lumateperone 84 mg baseline PANSS and CGI-S after the first dose of study drug risperidone 4 mg baseline PANSS after the first dose of study drug placebo disallowed concomitant medication placebo PANSS within one hour of lorazepam dosing placebo baseline PANSS and CGI-S after the first dose of study drug Source: Reviewer generated.

Table of Demographic Characteristics Table 55 presents the demographics of the ITT population. This population included all patients who received at least four doses of study drug and had both a baseline efficacy measurement and at least one valid post-baseline efficacy measurement. The majority of patients in all treatment groups were males. The mean age was 40.3. The majority of patients in each treatment group were African American or of African descent. Demographic characteristics were comparable across the four treatment groups.

Clinical reviewer comment: The maximum age in all treatment arms was 55 years, so generalization of results to the growing United States population aged 60 years and older will be limited. The mean and median age were both centered around 40 years, and the standard deviations of ages places the majority of patients in a range of 30 to 50 years. The inclusion criteria for the study were at least 3 months prior exposure to one or more antipsychotic medications, and a prior response to antipsychotic therapy within the previous five years. These criteria excluded patients experiencing a first episode of psychotic illness, which typically occurs during the early 20’s, so the number of patients in their early 20’s were expected to comprise a relatively small segment of the study population. The racial composition of the patient population was unbalanced, with approximately 60% patients of African descent in all treatment arms and no patients of Asian descent. Of note, only 1.8% of subjects (6) in this study were Caucasian females. However, the hypothesized mechanisms of action and metabolism of the drug do not suggest any reasons to expect differential efficacy or metabolism on the basis of race.

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Table 55: Study 005: Demographic Characteristics, Intent-to-Treat Population Lumateperone Lumateperone Risperidone Placebo 42 mg 84 mg 4 mg (N=76) (N=80) (N=75) (N=80) n (%) n (%) n (%) n (%) Age (years) n 76 80 75 80 Mean (SD) 38.3 (10.3) 41.4 (8.8) 40.7 (9.1) 40.6 (9.8) Median 38.5 43.5 42.0 42.5 Min, Max 21, 55 20, 55 20, 55 22, 55

Age (years), n (%) ≤ 40 42 (55.3) 34 (42.5) 34 (45.3) 37 (46.3) > 40 34 (44.7) 46 (57.5) 41 (54.7) 43 (53.8)

Gender, n (%) Male 61 (80.3) 69 (86.3) 67 (89.3) 62 (77.5) Female 15 (19.7) 11 (13.8) 8 (10.7) 18 (22.5)

Ethnicity, n (%) Hispanic or Latino 3 (3.9) 7 (8.8) 2 (2.7) 4 (5.0) Not Hispanic or Latino 73 (96.1) 73 (91.3) 73 (97.3) 76 (95.0)

Race, n (%) White 12 (15.8) 16 (20.0) 14 (18.7) 16 (20.0) American Indian / 1 (1.3) 1 (1.3) 0 0 Alaska Native Native Hawaiian / 0 1 (1.3) 0 0 Other Pacific Islander Black / African 63 (82.9) 59 (73.8) 59 (78.7) 61 (76.3) American / African Descent Other 0 3 (3.8) 0 2 (2.5)

BMI (kg/m2) n 76 80 75 80 Mean (SD) 28.9 (5.5) 28.5 (5.2) 28.3 (5.6) 29.8 (5.7) Median 28.1 27.6 28.7 29.1 Min, Max 19, 39 19, 40 19, 40 19, 40 Source: ITI-007-005 Clinical Study Report, page 68, Table 6.

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Other Baseline Characteristics (e.g., disease characteristics, important concomitant drugs) The most commonly used prior medication was lorazepam. Other commonly used prior medications were quetiapine, risperidone, olanzapine, and aripiprazole. Prior medication use was comparable across treatment groups.

The majority of patients in all treatment groups were diagnosed with the DSM-IV paranoid subtype of schizophrenia (note: the current DSM-5 omits subtype specification in schizophrenia). The mean time since first diagnosis of schizophrenia, mean baseline BPRS scores, PANSS total scores, PANSS subscores, and CGI-S scores were similar across treatment groups. The percentage of patients with symptoms of depression (defined as CDSS score >6) and the mean CDSS depression score at baseline were both lower in the 42 mg treatment group than in the other three treatment groups. Table 56 presents baseline clinical characteristics for patients in the ITT population.

Clinical reviewer comment: The study population’s mean BPRS score of 56, mean PANSS total score of 86, and mean PSQI score of 95 reflect severe symptoms of schizophrenia and significant sleep disturbance. These are consistent with an acute exacerbation of schizophrenia symptoms. Therefore, the baseline clinical characteristics of the study population reflect a clinical state for which a clinician would prescribe antipsychotic medication for acute control of symptoms.

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Table 56: Study 005: Baseline Clinical Characteristics, ITT Population Lumateperone Lumateperone Risperidone Placebo 42 mg 84 mg 4 mg (N=76) (N=80) (N=75) (N=80) Schizophrenia Diagnosis Type, n (%) Paranoid 74 (97.4) 76 (95.0) 71 (94.7) 78 (97.5) Disorganized 0 1 (1.3) 1 (1.3) 1 (1.3) Catatonic 0 0 0 0 Undifferentiated 2 (2.6) 3 (3.8) 3 (4.0) 1 (1.3) Time since First Diagnosis of Schizophrenia (Years) n 76 80 75 80 Mean (SD) 16.0 (9.4) 17.0 (10.2) 15.2 (9.4) 17.7 (10.4) Symptoms of Depression, n (%) Yes 15 (19.7) 23 (28.8) 21 (28.0) 20 (25.0) No 61 (80.3) 57 (71.3) 54 (72.0) 60 (75.0) BPRS Total Score n 76 80 75 80 Mean (SD) 55.6 (7.0) 55.5 (7.7) 56.6 (8.2) 56.5 (8.0) PANSS Total Score n 76 80 75 80 Mean (SD) 88.1 (11.0) 84.6 (11.6) 86.1 (12.2) 86.3 (13.1) PANSS Positive Subscale Score n 76 80 75 80 Mean (SD) 24.8 (4.2) 23.8 (4.5) 24.2 (4.1) 24.6 (4.6) PANSS Negative Subscale Score n 76 80 75 80 Mean (SD) 21.0 (4.1) 19.8 (4.1) 20.7 (5.1) 19.8 (4.8) PANSS General Psychopathology Subscale Score n 76 80 75 80 Mean (SD) 42.2 (7.0) 41.0 (6.9) 41.3 (6.6) 41.9 (7.0) CGI-S Score n 76 80 75 80 Mean (SD) 4.8 (0.5) 4.8 (0.5) 4.7 (0.6) 4.8 (0.6) PSQI Global Score n 73 80 74 78 Mean (SD) 9.8 (4.9) 9.3 (4.6) 9.2 (5.6) 9.6 (4.8) CDSS Total Score n 76 80 75 80 Mean (SD) 3.0 (2.6) 3.6 (3.2) 3.7 (3.6) 3.9 (3.5) Source: ITI-007-005 Clinical Study Report, page 69, Table 7.

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Treatment Compliance and Rescue Medication Use For the ITT population, the overall reported mean treatment compliance rate was greater than 99.8% and was similar across treatment groups. However, there were ten patients in the lumateperone 42 mg group, four in the lumateperone 120 mg group, and six in the risperidone group, who had low or zero blood drug levels at one or more time points during the study. The Applicant reports that it is not clear whether the zero or negligible blood drug levels were a result of lack of compliance, sample processing that prohibited proper analytical assessment, or very low exposure levels that were below the limits of detection. The Applicant noted that the low levels could indicate less actual compliance than was reported by the study site staff.

In addition, there were 17 patients randomized to placebo who had residual blood levels of risperidone and/or its metabolites. These residual plasma levels may have been the result of previous exposure to risperidone, which was one of the most common prior medications.

One patient randomized to placebo had measurable levels of lumateperone and its metabolites. The Applicant notes that this may have been due to a misassignment of study drug treatment kit or mislabeling of plasma sample.

During the study, as per instructions provided in the protocol, lorazepam may have been administered for agitation or to aid sleep, benztropine for extrapyramidal symptoms, and propranolol for akathisia. For the ITT Population, the number of patients administered lorazepam at least once during the treatment period was comparable across treatment groups. The use of benztropine for extrapyramidal symptoms was highest in the risperidone group. The use of propranolol for akathisia was low in all treatment groups, and lowest in the lumateperone 84 mg group. Use of these three medications is presented in Table 57.

Clinical reviewer comment: The most frequently used concomitant medication was lorazepam. This is expected considering that patients were entering the study during an acute exacerbation of psychotic symptoms. Given that lorazepam has no antipsychotic effects on its own and the protocol prohibited lorazepam use during the eight hours prior to a PANSS assessment, it is unlikely that per protocol use of lorazepam would confound the study results.

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Table 57: Study 005: Lorazepam, Benztropine, and Propranolol Use, ITT Population Lumateperone Lumateperone Risperidone Placebo 42 mg 84 mg 4 mg (N=76) (N=80) (N=75) (N=80) Lorazepam Use n (%) 52 (68.4) 50 (62.5) 55 (73.3) 61 (76.3)

Benztropine Use n (%) 2 (2.6) 2 (2.5) 7 (9.3) 1 (1.3)

Propranolol Use n (%) 2 (2.6) 0 2 (2.7) 2 (2.5) Source: Clinical reviewer generated table.

Efficacy Results – Primary Endpoint On the primary efficacy endpoint, the 42 mg lumateperone dose was statistically significantly superior to placebo (Table 58). The unadjusted two-sided p-value was 0.017, and the multiplicity adjusted p-value was 0.034. Adjusting appropriately for the sample size increase after the unblinded interim analysis, the multiplicity adjusted two-sided p-value was 0.04.

Table 58: Study 005: Primary Efficacy Results

Primary Efficacy Endpoint: PANSS Total Score

Study Treatment Group N Mean Baseline LS Mean Placebo- Score (SD) Change from subtracted Baseline (SE) Difference (95% CI)a 005 Lumateperone (42 mg)* 84 88.1 (11.0) -13.2 (1.7) -5.8 (-10.5, -1.1) Lumateperone (84 mg) 84 84.6 (11.6) -8.3 (1.7) -0.9 (-5.6, 3.8) Risperidone (4 mg)b 82 86.1 (12.2) -13.4 (1.7) -6.0 (-10.8, -1.3) Placebo 85 86.3 (13.1) -7.4 (1.7) --

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons a Difference (drug minus placebo) in LS mean change from baseline not adjusted for sample size increase after unblinded interim analysis. b Included for assay sensitivity, not included in multiple comparison procedure. *Dose statistically significantly superior to placebo. Source: 005 CSR, results confirmed by Statistical Reviewer

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The following figure illustrates the change from baseline in PANSS total score, by treatment group, at each visit until end of treatment. The least-squares means (LS Means) displayed in the figure below are the primary analysis model-based estimates. Figure 14. Primary Efficacy Endpoint (Change from Baseline in PANSS Total Score to Day 28) [Study 005, ITT set]

Source: Statistical Reviewer

Although mean treatment responses are important, the distribution of treatment responses can highlight extreme responders. Changes in PANSS score are shown graphically in the histogram below (Figure 15), with patients characterized in “bins” by their magnitude of improvement at the final study visit (i.e., week 4). Two additional bins are displayed: “Missing” at final visit and “No Change or Worsened.” For example, the greatest improvement (41 to 60 points on the PANSS) was reported in approximately 4% of subjects in the placebo and lumateperone 42-mg groups, no patients in the lumateperone 84-mg group, and 2% of patients in the risperidone group.

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Figure 15. Percent of Patients with Specified Magnitude of PANSS Total Score Improvement at the End of Week 4 [Study 005, ITT set]

Improvement 

Source: Statistical Reviewer

Interim Analysis The effect sizes observed for the 42-mg (effect size: 0.47) and 84 mg (effect size: 0.44) lumateperone doses were below the assumed 0.6 at the interim analysis (50% or roughly 30 patients per group had finished the 4-week treatment phase). The interim analysis statistician calculated the sample size required to achieve 90% power given the interim results (utilizing the effect size of 0.47). A sample size of 76 evaluable patients per arm (i.e., total sample size of 152 for the lumateperone 42 mg – placebo comparison) was needed. To account for early discontinuations, the target sample size was increased to 82 per arm for a total of 328 across the four arms.

Statistical reviewer note: The effect size assumed prior to the study start was larger than the one observed at the interim. The Applicant increased the sample size but did not adjust for this increase based on accumulated study data in the primary analysis. The appropriately adjusted results were provided after an information request by the FDA. The estimate of the mean treatment difference between the 42-mg dose and placebo remained unchanged at -5.8. The adjusted 95% confidence interval for the mean difference was (-10.8, -0.8) compared to the

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unadjusted confidence interval (-10.5, -1.1). The two-sided p-value increases from those originally reported were 0.017 to 0.020. The efficacy conclusion for the 42-mg lumateperone dose remained unchanged.

Furthermore, it is interesting to note that the effect size for the 84-mg dose estimated based on the data at the interim was close to the effect size for the 42-mg dose. For unknown reasons the PANSS data collected after the interim analysis for the 84-mg dose was similar to the PANSS data for the placebo group.

Demographic Subgroups Subgroup analyses for the primary efficacy endpoint (PANSS change from Baseline to Day 28) for the 42-mg lumateperone dose were conducted (Table 59 and Table 60).

Study 005 enrolled patients 18 to 55 years of age. A subgroup analysis with the conventional age threshold of 65 years is therefore not feasible. The statistical reviewer conducted subgroup analyses by sex and race using the primary analysis model (MMRM) with the triple interaction term (i.e., treatment by visit by subgroup) and necessary lower-level interaction terms (i.e., subgroup by treatment and subgroup by visit) added. The subgroup analysis by race excluded a small number of patients from races other than “Black or African American” and “White” because those subgroup results would have been uninterpretable because of small samples (i.e., less than 10 patients). Results for the subgroup of females and the subgroup of White patients should be interpreted cautiously given the small sizes of these subgroups.

Table 59: Study 005: Exploratory Subgroup Analysis by Sex Treatment Group (n) Efficacy Measure: Change from Baseline in PANSS Total Score to Day 28 Mean Baseline LS Mean Placebo-subtracted Score (SD) Change from Differencea (95% CI) Baseline (SE) Lumateperone (42 mg/day) Females (15) 83.3 (9.9) -19.8 (3.8) -12.0 (-22.0, -2.0) Males (61) 89.3 (11.0) -11.4 (1.8) -4.0 (-9.3, 1.2) Placebo Females (18) 89.7 (10.5) -7.8 (3.4) -- Males (62) 85.3 (13.7) -7.4 (1.9) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. Source: Statistical Reviewer

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Table 60: Study 005: Exploratory Subgroup Analysis by Race Treatment Group (n) Efficacy Measure: Change from Baseline in PANSS Total Score to Day 28 Mean Baseline LS Mean Placebo-subtracted Score (SD) Change from Differencea (95% CI) Baseline (SE) Lumateperone (42 mg/day) Black or African American (63) 88.2 (11.2) -13.6 (1.8) -3.6 (-8.8, 1.7) White (12) 88.5 (10.2) -9.9 (4.6) -10.6 (-22.4, 1.2) Placebo Black or African American (61) 85.5 (12.1) -10.0 (1.9) -- White (16) 89.4 (17.1) 0.7 (3.9) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. Source: Statistical Reviewer

Data Quality and Integrity During site inspections conducted by the Office of Scientific Investigations (OSI), the Applicant stated that the database for Study 005 was unlocked approximately one month following database lock and unblinding of the study to correct some data discrepancies and then relocked one week later. The Applicant reported to OSI that the discrepancies prompting the database unlock included waist circumference recorded in inches rather than centimeters, an incorrect dose date, an incorrect birth year for a patient, and a suicide attempt year incorrectly recorded as 2007 instead of 2010.

Clinical reviewer comment: These corrections to the database are not anticipated to have an effect on the efficacy analysis or safety analysis for Study 005.

Efficacy Results – Secondary and other relevant endpoints

Results on secondary or exploratory endpoints are not relevant for discussion in this review. There was no prospective plan to control the Type-I error rate for the secondary endpoints. Therefore, all secondary endpoints were regarded as exploratory.

Dose/Dose Response Efficacy was demonstrated for lumateperone 42 mg but not for lumateperone 84 mg. The reason for the failure of the higher lumateperone dose is not clear. To some extent, the lack of a treatment effect for the higher dose undercuts the persuasiveness of efficacy for the lower

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dose. None of the other registration studies included an 84-mg treatment arm, so the data on the 84-mg dose are limited to this study.

Durability of Response Patients in the lumateperone 42-mg treatment arms showed both separation from placebo and a gradual improvement in PANSS total scores compared to baseline at Day 8, Day 16, Day 22, and Day 28 (end of treatment) (see Figure 14 above). Thus, the antipsychotic effect of the 42- mg dose appeared to continue throughout the duration of the trial.

Persistence of Effect This trial did not include investigation of persistence of effect after discontinuation of the drug.

Efficacy Results – Secondary or exploratory COA (PRO) endpoints

The trial did not employ secondary or exploratory PRO endpoints.

Additional Analyses Conducted on the Individual Trial

No additional analyses were conducted on this trial.

Study ITI-007-301 (Study 301; ClinicalTrials.gov Identifier NCT02282761)

Overview and Objectives Study Title: “A Randomized, Double-blind, Placebo-controlled, Multi-center Study to Assess the Antipsychotic Efficacy of ITI-007 in Patients with Schizophrenia”

Primary Objective: To determine whether lumateperone administered to subjects with acutely exacerbated schizophrenia demonstrated antipsychotic efficacy compared to placebo, as measured by change from baseline to Day 28 on the PANSS total score.

Secondary Objectives: To determine whether, compared to placebo, lumateperone administered to subjects with acutely exacerbated schizophrenia: • demonstrated therapeutic efficacy as assessed by change from baseline on the CGI-S; • demonstrated enhanced social function as measured by change from baseline on a PANSS-derived Prosocial Factor; • demonstrated enhanced social function as demonstrated by change from baseline on the PSP; • demonstrated efficacy as assessed by change from baseline on any of the individual PANSS subscales: Positive, Negative, and General Psychopathology; • demonstrated efficacy as assessed by change from baseline on the negative symptoms subscale of the PANSS in a subgroup of subjects with prominent negative symptoms at baseline (a score of 4 or higher on at least 3 negative subscale symptom items) and as assessed by change from baseline on a PANSS-derived Negative Symptom Factor in a

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subgroup of subjects with prominent negative symptoms at baseline (a score of 4 or higher on at least 3 Negative Symptom Factor items); • demonstrated an improvement in symptoms of depression as measured by the CDSS in a subgroup of subjects with comorbid depressive symptoms at baseline (CDSS total score > 6); • demonstrated an improvement in symptoms of psychosis as measured by the total PANSS and PANSS subscales in a subgroup of subjects with comorbid depressive symptoms at baseline (CDSS total score > 6).

Trial Design Study Design Overview: Please see Figure 16 for a schematic of the study design. Patients with an acute exacerbation of schizophrenia were randomized 1:1:1 to receive lumateperone 28 mg, lumateperone 42 mg, or placebo daily for four weeks. The study was conducted on an inpatient hospital unit.

Figure 16: Study 301: Design Schematic

Source: ITI-007-301 Clinical Study Report, Figure 9.1, page 21.

Trial Location: The study was conducted at twelve sites in the United States.

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Diagnostic Criteria: Eligible patients had a diagnosis of schizophrenia according to criteria in the DSM-5 and confirmed by the Structured Clinical Interview for DSM Disorders – Clinical Trial Version (SCID-CT). Eligibility of potential subjects was confirmed through a formal adjudication process in which screening data, including CGI-S, BPRS, SCID-CT, and DSM-5 diagnosis, were reviewed by a member of an independent EAC.

Key Inclusion Criteria: • Male or female, age 18-60 years. • Diagnosis of schizophrenia. • Acute exacerbation of psychosis where the following criteria are met: o BPRS score ≥ 40 at screening. o BPRS at screening included a minimum score ≥ 4 on at least two of the following four positive symptom items: . suspiciousness; . conceptual disorganization; . hallucinatory behavior; . unusual thought content. o CGI-S score ≥ 4 at screening and prior to randomization. o Baseline PANSS score ≥ 70. o Current exacerbated episode started within four weeks of screening. o Sufficient history and/or independent reporter (such as a family member, caregiver, outside practitioner) had to verify that the current state was an exacerbated state for the individual patient. • History of at least three months’ exposure to one or more antipsychotic therapies. • A prior response to antipsychotic therapy within the previous five years, where response was defined as a clinically significant decrease in delusions and/or hallucinations during an exacerbated episode. • BMI of 19 to 40 kg/m2 at screening. • Female patients had to be of non-childbearing potential or had to use effective methods of birth control from at least one month prior to randomization to the end-of-study visit.

Key Exclusion Criteria: • Female patients who were pregnant, breast-feeding, or had a positive urine pregnancy test at screening or on Day 1. • Concurrent dementia, delirium, mental retardation, epilepsy, drug-induced psychosis, history of significant brain trauma, history of prolonged loss of consciousness, or history of seizure disorder other than single seizure episode. • Diagnosis of schizoaffective disorder, schizophreniform disorder, , , bipolar disorder with psychotic features, or major depression with psychotic features. Symptoms of depression were allowed. • Patient was considered to be an imminent danger to themselves or others.

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• C-SSRS score ≥ 4 within 6 months prior to screening or any suicidal behavior in the two years prior to screening, as indicated by any “yes” answers on the suicidal behavior section of the C-SSRS. • Abnormal laboratory values or clinical findings on screening that were judged to be clinically significant. • Diagnosis of moderate or severe substance use disorder within the six months prior to screening, positive urine drug or alcohol test at screening, or evidence of acute intoxication or withdrawal at screening. • Prior history of neuroleptic malignant syndrome induced by any antipsychotic medication. • Any subject who had received clozapine, as verified by the clozapine patient registry. • Any subject who was unable to be safely discontinued from current antipsychotic therapy, mood stabilizers, lithium, anticholinergics, and antidepressant medications.

Prohibited Concurrent Medications: • Use of any antipsychotic medication within the screening period through Day 1. • Use of depot antipsychotic medication within 1.5 treatment cycles prior to Day -1 (baseline). • Use of any of the following agents: mianserin, mirtazapine, nefazodone, cyproheptadine, , or fluvoxamine within 30 days prior to Day -1. • Use of any strong or moderate cytochrome P450 isoenzyme 3A4 inhibitor or inducer within seven days prior to Day -1. • Medications other than lorazepam, such as zaleplon and zolpidem, to manage insomnia.

Allowable Concurrent Medications: • Lorazepam was allowed to help alleviate agitation or insomnia, not to be given within eight hours prior to PANSS, CGI-S, PSQI, or CDSS. • Benztropine was allowed for treatment of extrapyramidal adverse effects, not to be given within eight hours of SAS, BARS, or AIMS. • Propranolol was allowed for treatment of akathisia, not to be given within eight hours of SAS, BARS, or AIMS.

Study Treatments: Starting on the first day of screening, all antipsychotic and other psychotropic medications were stopped, with tapering conducted as per investigator clinical judgment.

Lumateperone and placebo were administered in capsule form. Placebo capsules were given along with drug capsules to maintain study blinding. Study treatments were administered once daily in the morning.

Lumateperone doses of 28 mg and 42 mg once daily were selected for evaluation. The 42-mg dose had demonstrated antipsychotic efficacy in Study ITI-007-005 and was found to be well- tolerated in that study. The Applicant reported that previous PET receptor occupancy studies 173 Version date: October 12, 2018

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had suggested that human striatal D2 receptor occupancy in the should not exceed 60% and should be targeted to around 40% for maximal therapeutic efficacy and to avoid EPS liability in patients with schizophrenia. Based on earlier PET data using lower doses of lumateperone in healthy volunteers, a lumateperone dose of 42 mg was projected to occupy approximately 50% of the striatal D2 receptors. A lumateperone dose of 28 mg demonstrated peak striatal D2 receptor occupancy of approximately 40% and an average striatal D2 receptor occupancy of 29%. Thus, the 28-mg and 42-mg doses of lumateperone were predicted to provide a level of D2 occupancy that would result in antipsychotic efficacy.

Assignment to Treatment: Patients were randomized 1:1:1 to lumateperone 28 mg, lumateperone 42 mg, or placebo daily. No dose titration was deemed necessary.

Procedures and Schedule: Please see Table 61. The total study duration was approximately seven weeks, including a screening period of two to seven days prior to Day 1, an inpatient treatment period of four weeks, an inpatient stabilization period of up to five days during which patients were stabilized on standard antipsychotic medication, and an outpatient safety follow- up approximately two weeks after the end of the treatment period.

Table 61: Study 301: Schedule of Assessments Screen Baseline Study Treatment Period End of End of Event Stabilization Study -7 to -2 a -1 1 8 15 22 28 33 b Day 42 ± 2

Visit Number 1 2 3 4 5 6 7 8 9 Informed consent, Medical History X Admission to Inpatient Unit X Inclusion/Exclusion Criteria Review X X Screening Adjudication X Form(s)/Recordings, SCID-CT, c BPRS, Hepatitis/HIV Modified Physical Exam X X Urine Drug and Alcohol Screen d X X Urine pregnancy Test X X X X Clinical Laboratories e X X X X X 12-Lead ECG f X X X X X X Vital Signs g X X X X X X X Randomization X Study Drug Dosing X X X X X h PK Sample Collection X X X X i j i Protein biomarkers , genetic testing X X k k,l PANSS, Central CGI-S X X X X X Site-based CGI-S l X X X X X X X PSP, CDSS X X m m m SAS, BARS , AIMS X X X X

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C-SSRS X X X X X X X Adverse events, n Concomitant Meds X X X X X X X X X Restart Standard X Antipsychotics o

a) Upon signing of the ICF, patients are to be admitted to the inpatient unit, if they are not inpatient already. b) The End of Stabilization period is up to 5 days. c) These assessments are to be recorded and submitted to an independent psychiatrist or clinical (or panel of psychiatrists and/or clinical ) for review. d) The Urine Drug and Alcohol screen will also be performed upon patient’s return to the inpatient unit from the day pass. e) Clinical Laboratory samples are to be taken after an overnight fast of at least 10 hours. f) ECGs are to be triplicate 10 second epochs with 5 min between recordings. One triplicate ECG will be performed during Screening and one triplicate ECG will be performed on Day 33. On Days 1, 8, and 28, triplicate ECGs will be taken pre-dose (trough, before breakfast) and at 3-4 h post-dose (peak, before lunch). An additional triplicate ECG will be performed on Day 28 at 6-7 h post-dose. Triplicate ECGs on Day -1 are to be performed at the same time of day planned for Day 28: once before breakfast (approximately 7:00 am corresponding to the same time of day for the trough measure), again before lunch (approximately 11:00 am – noon, corresponding to the same time of day for the 3-4 h post-dose peak measure), and again at approximately 2:00-3:00 pm corresponding to the same time of day of the 6-7 h post-dose measure. In all cases ECGs are conducted before other assessments scheduled in the same time window; for example, when ECG, vital signs and blood sample collection for PK measures are scheduled for the same time window, ECG measures should be conducted first, followed by vital signs and then blood sample collection. g) Respiratory rate, oral temperature, and 3-positional blood pressure and pulse (after at least 10 minutes lying down, after approximately 1 minute sitting, immediately upon standing, and after approximately 3 minutes standing) will be taken at least once at all scheduled visits. On Days 1, 8, 15, and 28 vitals will be taken pre- dose (trough) and 3-4 h post-dose (peak). Additionally, vital signs will be assessed on Days -1 and 28 at 6-7 h post-dose. Vital signs are always taken after conducting the ECGs, as applicable, and prior to any other assessments scheduled in the same time window. Height, weight and waist circumference should be collected during screening. Weight and waist circumference should be collected again on Day -1 for baseline and again on Day 28. h) Blood samples for PK collection are to be collected prior to dosing (trough) and then 3-4 h after dosing (peak) on Days 1, 8, and 28, again at 6-7 h post-dose only on Day 28, and then once on Day 33. Samples are collected after ECGs and vital signs. i) Sample for protein biomarkers on Day 1 has to be collected pre-dose. j) Blood sample is to be collected once for genetic testing, if the optional ICF addendum is signed. If the addendum is signed prior to Day 1 then the sample will be taken on Day 1. If it is signed after Day 1, then the sample will be taken on Day 28. It is not to be taken twice. k) PANSS and CGI-S are to be conducted by a remote central rater. Efforts should be made to schedule the remote interviews at approximately the same time of day of each visit. Due to potential limitations around scheduling of the remote rater, the PANSS may be conducted within a 1-day window provided for this assessment. PANSS and CGI scores at Baseline Visit are reviewed for inclusion of subject (subject will be included with the baseline PANSS score of 70 or higher and baseline CGI-S score of 4 or higher). l) CGI-S is conducted by a qualified site rater at screening (in addition to the CGI-S conducted by the remote central rater) at baseline through Day 28. Site-based CGI-S is conducted by qualified site rater; during the treatment period, the site rater will interview the subject and review baseline and current PANSS and CGI-S scores from the remote centralized rater prior to rating the site-based CGI-S for the visit. m) On Days 8, 15, 22, and 28, the SAS, BARS, and AIMS assessments are to be conducted 3-6 hours after the administration of study treatment. n) The recording of adverse events is to start immediately after the ICF is signed and continue through the End of

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Study, Visit 9. o) On Day 28, after all study assessments have been completed, or on Day 29 patients are to be started on standard antipsychotic medication as prescribed by the Investigator. Source: ITI-007-301 Clinical Study Protocol, Version 2.1, Table 4, page 47-49.

Study Endpoints (see Section 7.3 for descriptions of study endpoints)

Primary efficacy endpoint: • mean change in total PANSS score from baseline to the end of treatment (Week 4)

Key secondary efficacy endpoint: • CGI-S: change from baseline to Day 42.

Secondary efficacy endpoints: • PANSS Positive subscale • PANSS Negative subscale • PANSS General Psychopathology subscale • PANSS Prosocial Factor Score • PANSS five factors (Marder and Gaag) • PSPCDSS • PSP • CDSS

Safety assessments: • reported and observed AEs • physical examination • body weight and waist circumference • vital signs • 12-lead ECG • clinical laboratory values • SAS • BARS • AIMS • C-SSRS

Statistical Analysis Plan The SAP is dated 07/20/2015. Database lock occurred on 08/17/2015.

Primary Efficacy Analysis Set The ITT set contains all randomized subjects who received at least one dose of study medication, and had data recorded for at least one valid baseline and at least one valid post- baseline PANSS measurement (Study 301 SAP page 13).

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Primary Analysis Model The treatment effect on the primary efficacy endpoint, change from baseline to Day 28 in PANSS total score, was evaluated using a MMRM model. The model includes the PANSS change from baseline as response variable and study visit, baseline PANSS total score, baseline PANSS total score-by-study visit interaction, treatment (lumateperone 28 mg, lumateperone 42 mg, placebo), and treatment-by-study visit interaction. An unstructured covariance matrix was used to model the correlation among repeated measures within subject.

Sample Size Determination The Applicant, using the information obtained from Study 005, lowered its assumption about the expected effect size from 0.6 (Study 005) to 0.4 in this study. The Applicant planned to randomize approximately 440 subjects in a 1:1:1 ratio in Study 301. Assuming a 10% early discontinuation rate (prior first post-dose efficacy assessment), a sample size of 132 evaluable patients per arm was planned (corresponding to 90% power to detect a 6-point difference at two-sided alpha=0.05 and a standard deviation of 15).

Multiple Comparisons A mixture-based gatekeeping procedure was pre-specified to adjust for multiplicity due to testing two doses and two efficacy endpoints. This method proposed by Dmitrienko et al is a valid approach for controlling the familywise error rate (Dmitrienko, Kordzakhia et al. 2016).

Missing Data/Sensitivity Analyses A pattern-mixture model using a placebo-based multiple imputation method was pre-specified in the SAP to explore the impact of a different assumption regarding missing data. The primary analysis (MMRM) assumes Missing At Random (MAR). The placebo-based multiple imputation sensitivity analysis considered a Missing Not At Random (MNAR) mechanism for the missing data, where it was assumed that outcomes of subjects who discontinued early from the lumateperone arms would follow a trajectory similar to the placebo arm, taking into account observed values prior to discontinuation (Study 301 SAP page 27).

Protocol Amendments Original protocol date: September 12, 2014

Amendment 2.1: May 27, 2016 This amendment, incorporating Amendments #1 and #2 (dated October 23, 2014), included the following changes: • Addition of a visit at Day 22. Assessments at Day 22 to include the PANSS, CGI-S, SAS, BARS, and AIMS. • Clarified that washout of prior psychotropic medications (including antipsychotics) was to occur during the Screening Period, and that any tapering schedules during the Screening Period needed to be reviewed and approved by the medical monitor. • Added a list of the metabolites of lumateperone that would be evaluated in the PK

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samples: IC200161, IC200131, and IC200565.

Study ITI-007-301 Results

Compliance with Good Clinical Practices Section 5.2, page 13 of the Clinical Study Report states: “The procedures set out in the study protocol, pertaining to the conduct, evaluation, and documentation of this study, were designed to ensure that the Applicant and Investigator abided by the principles of the Good Clinical Practice (GCP) guidelines and the ethical principles laid down in the current revision of the Declaration of Helsinki. The study was also carried out in keeping with local legal and regulatory requirements in the United States (US).”

Financial Disclosure No disclosable financial interests or arrangements were reported for any of the investigators participating in this study. See Section 14.2, Financial Disclosures, for details.

Patient Disposition A total of 630 patients were screened for the study, of which 450 were randomized, with 150 patients assigned to each treatment group. One patient in the placebo group discontinued the study because of an AE prior to receiving any study medication. Reasons for discontinuation of study drug and for discontinuing from the study are summarized in Table 62. Patients may have discontinued from the study without discontinuing from study drug if the patient left the study after completing the study treatment. Discontinuations related to AEs are discussed in more detail in Section 8.2.

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Table 62: Study 301: Disposition of Randomized Patients Lumateperone Lumateperone Placebo 28 mg 42 mg (N=150) (N=150) (N=150) Disposition n (%) n (%) n (%) Completed the Treatment Period 123 (82.0) 131 (87.3) 112 (74.7) Discontinued Study Drug 27 (18.0) 19 (12.7) 37 (24.7) Adverse Event 4 (2.7) 2 (1.3) 1 (0.7) AE associated with worsening of 0 1 (0.7) 1 (0.7) schizophrenia AE not associated with worsening of 4 (2.7) 1 (0.7) 0 schizophrenia Lack of efficacy 11 (7.3) 6 (4.0) 17 (11.3) Physician decision 0 0 2 (1.3) Patient withdrew consent 11 (7.3) 11 (7.3) 17 (11.3) Personal or family reasons 6 (4.0) 8 (5.3) 5 (3.3) Refused to provide a reason and 3 (2.0) 2 (1.3) 4 (2.7) refused all end of study procedures Self-reported adverse event 1 (0.7) 0 1 (0.7) Self-reported lack of efficacy 1 (0.7) 1 (0.7) 7 (4.7) Other 1 (0.7) 0 0

Completed the Study 120 (80.0) 128 (85.3) 111 (74.0) Discontinued from Study 30 (20.0) 22 (14.7) 39 (26.0) Adverse Event 6 (4.0) 2 (1.3) 1 (0.7) AE associated with worsening of 0 1 (0.7) 1 (0.7) schizophrenia AE not associated with worsening of 6 (4.0) 1 (0.7) 0 schizophrenia Death 0 0 1 (0.7) Lack of efficacy 11 (7.3) 6 (4.0) 17 (11.3) Lost to follow-up 2 (1.3) 2 (1.3) 1 (0.7) Physician decision 0 0 2 (1.3) Patient withdrew consent 8 (5.3) 10 (6.7) 16 (10.7) Personal or family reasons 5 (3.3) 8 (5.3) 4 (2.7) Refused to provide a reason and 3 (2.0) 0 5 (3.3) refused all end of study procedures Self-reported adverse event 0 2 (1.3) 7 (4.7) Self-reported lack of efficacy 0 2 (1.3) 7 (4.7) Other 3 (2.0) 2 (1.3) 1 (0.7) Source: based on Study ITI-007-301 Clinical Study Report, Table 10.1, page 62.

Clinical reviewer comments: The frequency of study drug discontinuations related to lack of efficacy was higher in the 28-mg treatment arm than in the 42-mg treatment arm. This suggests lower efficacy of the 28-mg dose compared to the 42-mg dose, which is confirmed by the efficacy analysis later in this section.

The frequency of discontinuations of study drug related to adverse events was higher in the 28- mg treatment arm than in the 42-mg treatment arm. The frequency of study drug

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discontinuations and study discontinuations related to AEs not related to worsening of schizophrenia was also higher in the 28-mg arm than in the 42-mg arm. This suggests that the lower dose may have been less tolerable for patients, but the reason for this is not clear. Given the small numbers, the difference could simply represent play of chance.

The frequency of study drug discontinuations and study discontinuations related to lack of efficacy, physician discontinuation, and patient withdrawal of consent were all higher in the placebo arm than in the 28-mg or 42-mg arm, supporting the finding of a difference between lumateperone and placebo in antipsychotic efficacy.

Protocol Violations/Deviations The most common protocol deviation was incorrect concomitant use of lorazepam, benztropine, or propranolol. The patient who met exclusion criteria but was randomized had a treatment-emergent AE of seizure and was later found to have pre-existing risk factors for seizure. Major protocol deviations are presented in Table 63.

Table 63: Study 301: Major Protocol Deviations, Intent-to-Treat Population Lumateperone Lumateperone Placebo 28 mg 42 mg (N=146) (N=148) (N=141) Deviation n (%) n (%) n (%) Patients with at least one major 26 (17.8) 28 (18.9) 34 (24.1) deviation Exclusion criteria met but subject 1 (0.7) 0 0 randomized and received treatment Patient had a positive drug screen for 2 (1.4) 0 1 (0.7) substance of abuse during the treatment period Prohibited Medication 23 (15.8) 28 (18.9) 33 (23.4) Patient received lorazepam, 23 (15.8) 28 (18.9) 32 (22.7) benztropine, or propranolol outside of protocol guidelines Patient received psychotropic 0 0 1 (0.7) medications other than lorazepam, benztropine, or propranolol Source: Study ITI-007-301 Clinical Study Report, Table 10.2, page 64.

Site inspections by OSI revealed that Site #106 was not able to provide full information on the total dose and times of administration of as-needed doses of lorazepam for 28 of 31 enrolled patients. This made it difficult to establish an accurate count of the number of protocol deviations related to use of lorazepam as a concomitant medication. The administration of

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lorazepam close to the time of a PANSS assessment could potentially have had an effect on the scoring of the primary efficacy endpoint.

Clinical reviewer comment: The numbers presented by the Applicant in the Clinical Study Report suggest that the percentage of patients who received prohibited medications outside of protocol guidelines was similar in the two lumateperone treatment groups and was higher in the placebo group than in either lumateperone treatment group. However, based on the results of the OSI inspection, these numbers may not be accurate. The Division of Biometrics performed sensitivity analyses demonstrating that removing Site #106 from the efficacy analysis did not adversely affect the study results.

Table of Demographic Characteristics Table 64 presents the demographics of the safety population. The majority of patients in all treatment groups were males. The mean age was 42.4. The majority of patients in each treatment group were African American or of African descent. Demographic characteristics were comparable across the three treatment groups.

Clinical reviewer comment: The age and race distribution for this study was similar to that in Study 005, with the exception of a small number of patients of Asian descent included in this study. Of note, only 5% of subjects (21) were Caucasian females.

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Table 64: Study 301: Demographic Characteristics, Safety Population Lumateperone Lumateperone Placebo 28 mg 42 mg (N=150) (N=150) (N=149) n (%) n (%) n (%) Gender, n (%) Male 113 (75.3) 110 (73.3) 123 (82.6) Female 37 (24.7) 40 (26.7) 26 (17.4)

Age (years) Mean (SD) 43.5 (10.1) 42.4 (10.3) 41.4 (10.3) Median 44.0 44.0 41.0 Min, Max 23, 60 20, 60 19, 60

Age (years), n (%) ≤ 40 56 (37.3) 62 (41.3) 71 (47.7) > 40 94 (62.7) 88 (58.7) 78 (52.3)

Race, n (%) White 42 (28.0) 33 (22.0) 42 (28.2) Black / African American / 94 (62.7) 108 (72.0) 96 (64.4) African Descent Asian 6 (4.0) 1 (0.7) 1 (0.7) American Indian / Alaska Native 0 0 1 (0.7) Native Hawaiian / Other Pacific 1 (0.7) 1 (0.7) 0 Islander Other 6 (4.0) 4 (2.7) 5 (3.4) Multiple 1 (0.7) 3 (2.0) 4 (2.7)

Ethnicity, n (%) Hispanic or Latino 16 (10.7) 13 (8.7) 14 (9.4) Not Hispanic or Latino 133 (88.7) 137 (91.3) 135 (90.6) Unknown 1 (0.7) 0 0

BMI (kg/m2) Mean (SD) 97.4 (13.1) 97.8 (14.9) 96.9 (14.7) Median 97.3 96.1 96.4 Min, Max 65.0, 130.8 70.0, 138.0 68.5, 190.0 Source: ITI-007-301 Clinical Study Report, page 67, Table 11.2.Other Baseline Characteristics (e.g., disease characteristics, important concomitant drugs) The most commonly used prior medication was lorazepam. Other commonly used prior medications were quetiapine, risperidone, haloperidol, , benztropine, olanzapine, aripiprazole, diphenhydramine, , zolpidem, and valproic acid. Prior medication use was comparable across treatment groups.

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The mean time since first diagnosis of schizophrenia, mean baseline BPRS scores, PANSS total scores, PANSS subscores, percentage of patients with symptoms of depression (defined as CDSS total score >6), CDSS scores, PSP scores, and CGI-S scores were similar across treatment groups. Table 65 presents baseline clinical characteristics for patients in the ITT population.

Clinical reviewer comment: The study population’s mean BPRS score of 53.5 and mean PANSS total score of 90 are comparable to the scores of the study population for Study 005 and similarly reflect a clinical state of acute exacerbation of schizophrenia symptoms for which a prescription of antipsychotic medication would be appropriate.

Table 65: Study 301: Baseline Clinical Characteristics, ITT Population Lumateperone Lumateperone Placebo 28 mg 42 mg (N=146) (N=148) (N=141) Time since First Diagnosis of Schizophrenia (Years) Mean (SD) 17.0 (10.6) 16.5 (10.4) 17.4 (10.6) Symptoms of Depression, n (%) Yes 8 (5.5) 7 (4.7) 9 (6.4) No 138 (94.5) 141 (95.3) 132 (93.6) BPRS Total Score Mean (SD) 53.3 (7.2) 53.7 (7.5) 53.9 (7.6) PANSS Total Score Mean (SD) 89.3 (10.2) 90.1 (9.5) 89.8 (10.3) PANSS Positive Subscale Score Mean (SD) 25.8 (3.9) 26.0 (3.5) 25.8 (3.9) PANSS Negative Subscale Score Mean (SD) 20.4 (4.2) 20.6 (3.8) 21.0 (4.4) PANSS General Psychopathology Subscale Score Mean (SD) 43.1 (6.0) 43.5 (6.1) 43.2 (6.3) CGI-S Score Mean (SD) 4.7 (0.6) 4.8 (0.5) 4.8 (0.6) PSP Total Score Mean (SD) 48.2 (12.2) 47.8 (11.9) 47.7 (12.4) CDSS Total Score Mean (SD) 3.8 (2.9) 4.0 (3.4) 3.9 (3.2) Source: Clinical reviewer generated from ITI-007-301 Clinical Study Report, Appendix of Tables, Tables 14.1.3.4 and 14.1.3.8.

Treatment Compliance, Concomitant Medications, and Rescue Medication Use For the ITT population, the reported mean treatment compliance rate was 100% and was similar across treatment groups. Treatment compliance was evaluated by reviewing PK data in an ongoing, blinded manner. If a patient assigned to receive lumateperone was shown to have

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blood levels below the limit of quantitation, indicating likely noncompliance with study medication, the Applicant could have requested an investigation by an unblinded third party to determine whether the subject should be discontinued from the study. No patients were discontinued from the study because of non-compliance with study drug.

Efficacy Results – Primary Endpoint

With respect to primary efficacy endpoint, the effect of 42 mg lumateperone was statistically significantly superior to placebo (Table 66; unadjusted two-sided p-value=0.022; multiplicity adjusted two-sided p-value=0.045).

The estimated effect size of 0.3 (corresponding to a 4 point mean difference in PANSS total score change from baseline to Day 28) is smaller than assumed at the outset of Study 301 (0.4 or target of 6 point mean difference) and smaller than at the outset of Study 005 (0.6 or target of 10.5 point mean difference). The time course for the primary efficacy measure is presented in Figure 17 and a histogram displaying the percentages of patients experiencing specified magnitudes of improvement is shown in Figure 18.

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Table 66: Study 301: Primary Efficacy Results

Primary Efficacy Endpoint: PANSS Total Score

Study Treatment Group N Mean Baseline LS Mean Placebo- Score (SD) Change from subtracted Baseline (SE) Difference (95% CI)a 301 Lumateperone (28 mg) 150 89.5 (10.5) -12.9 (1.3) -2.6 (-6.2, 1.1) Lumateperone (42 mg)* 150 90.0 (9.6) -14.5 (1.3) -4.2 (-7.8, -0.6) Placebo 150 89.0 (10.3) -10.3 (1.3) --

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons a Difference (drug minus placebo) in LS mean change from baseline. *Dose statistically significantly superior to placebo. Source: 301 CSR, results confirmed by Statistical Reviewer Figure 17. Primary Efficacy Endpoint (Change from Baseline in PANSS Total Score to Day 28) [Study 301, ITT set]

Source: Statistical Reviewer

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Figure 18. Percent of Patients with Specified Magnitude of PANSS Total Score Improvement at the End of Week 4 [Study 301, ITT set]

Improvement 

Source: Statistical Reviewer

Sensitivity Analyses The point estimate of the treatment difference and 95% confidence interval obtained from the pattern-mixture model (PPM) for the 42-mg lumateperone dose versus placebo are close to the estimates obtained from the MMRM primary analysis (PPM: -3.9 (-7.4, -0.4) versus MMRM: -4.2 (-7.8, -0.6)). The primary endpoint efficacy results appear robust to possible deviations from the Missing at Random assumption used for the primary analysis.

Observed PANSS trajectories (spaghetti plots of individual patient primary efficacy profiles) for completers and for early dropouts by discontinuation reason are included in the statistical appendices to this review.

Demographic Subgroups Subgroup analyses for the primary efficacy endpoint (PANSS change from Baseline to Day 28) for the 42-mg lumateperone dose were conducted (see Table 67 and Table 68).

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Study 301 enrolled patients 18 to 60 years of age. A subgroup analysis with the conventional age threshold of 65 years is therefore not feasible. The statistical reviewer conducted subgroup analyses by sex and race using the primary analysis model (MMRM) with the triple interaction term (i.e., treatment by visit by subgroup) and necessary lower level interaction terms (i.e., subgroup by treatment and subgroup by visit) added. The subgroup analysis by race excluded a small number of patients from races other than “Black or African American” and “White” because results would not have been representative due to the small sample size (i.e., less than 10 patients in study). The results appear consistent between males and females and the two race subgroups investigated.

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Table 67: Study 301: Exploratory Subgroup Analysis by Sex Study Treatment Group (n) Efficacy Measure: Change from Baseline in PANSS Number Total Score to Day 28 Mean Baseline LS Mean Change Placebo- Score (SD) from Baseline subtracted

(SE) Differencea (95% CI) Lumateperone (42 mg/day) Females (35) 90.6 (9.6) -15.2 (2.4) -5.0 (-12.6, 2.6) Study Males (108) 90.0 (9.6) -14.2 (1.5) -3.9 (-8.0, 0.2) 301 Placebo Females (21) 88.8 (8.9) -10.2 (3.0) -- Males (115) 90.1 (11.4) -10.3 (1.5) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. Source: Statistical Reviewer

Table 68: Study 301: Exploratory Subgroup Analysis by Race Study Treatment Group (n) Efficacy Measure: Change from Baseline in PANSS Number Total Score to Day 28 Mean Baseline LS Mean Change Placebo- Score (SD) from Baseline subtracted

(SE) Differencea (95% CI) Lumateperone (42 mg/day) Black or African American (107) 90.3 (9.5) -15.9 (1.5) -4.6 (-8.9, -0.3) Study White (32) 89.4 (9.3) -12.0 (2.6) -3.1 (-10.3, 4.1) 301 Placebo Black or African American (92) 89.7 (11.6) -11.3 (1.6) -- White (38) 91.3 (10.1) -8.9 (2.5) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. Source: Statistical Reviewer

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Data Quality and Integrity Issues related to the recording of times and total doses of administration of as-needed lorazepam are discussed in Section 8.1.4 under Protocol Violations/Deviations.

Efficacy Results – Secondary and other relevant endpoints The point estimate of the difference in change from baseline in the CGI-S score at Day 28 (analyzed via MMRM) for the 42 mg lumateperone dose versus placebo is -0.3 (95% CI: -0.5, - 0.1) with an unadjusted p-value of 0.003 (multiplicity adjusted p-value=0.045). Note, that the CGI-S results were not replicated in other studies in this program.

Dose/Dose Response Efficacy was demonstrated for lumateperone 42 mg but not for lumateperone 28 mg. None of the other registration studies included a 28-mg treatment arm; therefore, the data on the 28- mg dose are limited to this study.

Durability of Response

As in Study 005, patients in the lumateperone 42-mg treatment arm showed both separation from placebo and a gradual improvement in PANSS total scores compared to baseline at Day 8, Day 16, Day 22, and Day 28 (end of treatment) (see Figure 17 above). Thus, the antipsychotic effect of the 42-mg dose appeared to continue throughout the duration of the trial.

Persistence of Effect

This trial did not include investigation of persistence of effect after discontinuation of the drug.

Efficacy Results – Secondary or exploratory COA (PRO) endpoints The trial did not employ secondary or exploratory PRO endpoints.

Additional Analyses Conducted on the Individual Trial No additional analyses were conducted on this trial.

Study ITI-007-302 (Study 302: ClinicalTrials.gov Identifier NCT02469155)

Overview and Objectives Study Title: “A Randomized, Double-blind, Placebo- and Active-Controlled, Multi-center Study to Assess the Antipsychotic Efficacy of ITI-007 After 6 Weeks of Treatment in Patients with Schizophrenia”

Primary Objective: To determine whether lumateperone administered to subjects with acutely exacerbated schizophrenia demonstrated antipsychotic efficacy compared to placebo, as measured by change from baseline to Day 42 on the PANSS total score.

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Secondary Objectives: To determine whether, compared to placebo, lumateperone administered to subjects with acutely exacerbated schizophrenia: • demonstrated therapeutic efficacy as assessed by change from baseline on the CGI-S severity scale (key secondary objective); • demonstrated enhanced social function as measured by change from baseline on a PANSS-derived Social Factor; • demonstrated enhanced social function as demonstrated by change from baseline on the PSP scale; • demonstrated efficacy as assessed by change from baseline on any of the individual PANSS subscales: Positive, Negative, and General Psychopathology; • demonstrated efficacy as assessed by change from baseline on the negative symptoms subscale of the PANSS in a subgroup of subjects with prominent negative symptoms at baseline (a score of 4 or higher on at least 3 negative subscale symptom items) and as assessed by change from baseline on a PANSS-derived Negative Symptom Factor in a subgroup of subjects with prominent negative symptoms at baseline (a score of 4 or higher on at least 3 Negative Symptom Factor items); • demonstrated an improvement in symptoms of depression as measured by the CDSS in a subgroup of subjects with comorbid depressive symptoms at baseline (CDSS total score > 6); • demonstrated an improvement in symptoms of psychosis as measured by the total PANSS and PANSS subscales in a subgroup of subjects with comorbid depressive symptoms at baseline (CDSS total score > 6); • demonstrated improved quality of life as measured by change from baseline on the SWN-S scale.

Safety Objectives: to determine whether lumateperone: • demonstrated superiority to risperidone with respect to certain safety measures, including but not limited to blood levels of prolactin, fasting glucose, total cholesterol, triglycerides, and insulin, in addition to relative risk for akathisia as a treatment- emergent adverse event (TEAE); • was safe and well-tolerated.

Trial Design Study Design Overview: Patients with an acute exacerbation of schizophrenia were randomized 1:1:1:1 to receive lumateperone 14 mg, lumateperone 42 mg, risperidone 4 mg, or placebo daily for six weeks (Figure 19). The study was conducted on an inpatient hospital unit.

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Figure 19: Study 302: Design Schematic

Source: ITI-007-302 Clinical Study Report, Figure 9.1, page 21.

Trial Location: The study was conducted at thirteen sites in the United States.

Diagnostic Criteria: Eligible patients had a diagnosis of schizophrenia according to DSM-5 criteria and confirmed by the SCID-CT. Eligibility of potential subjects was confirmed through a formal adjudication process in which screening data, including CGI-S, BPRS, SCID-CT, and DSM-5 diagnosis, were reviewed by a member of an independent EAC.

Key Inclusion Criteria: • Male or female, age 18-60 years. • Diagnosis of schizophrenia. • Acute exacerbation of psychosis where the following criteria are met: o BPRS score ≥ 40 at screening. o BPRS at screening included a minimum score ≥ 4 on at least two of the following four positive symptom items: . suspiciousness; . conceptual disorganization; . hallucinatory behavior;

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. unusual thought content. o CGI-S score ≥ 4 at screening and prior to randomization. o Baseline PANSS score ≥ 70. o Current exacerbated episode started within four weeks of screening. o Sufficient history and/or independent reporter (such as a family member, caregiver, outside practitioner) must have verified that the patient’s current state was an exacerbated state for the individual patient. • History of at least three months exposure to one or more antipsychotic therapies. • A prior response to antipsychotic therapy within the previous five years, where response was defined as a clinically significant decrease in delusions and/or hallucinations during an exacerbated episode. • BMI of 19 to 40 kg/m2 at screening. • Female patients had to be of non-childbearing potential or must use effective methods of birth control from at least one month prior to randomization to the end-of-study visit.

Key Exclusion Criteria: • Female patients who are pregnant, breast-feeding, or have a positive urine pregnancy test at screening or on Day 1. • Concurrent dementia, delirium, mental retardation, epilepsy, drug-induced psychosis, history of significant brain trauma, history of prolonged loss of consciousness, or history of seizure disorder other than single seizure episode. • Diagnosis of schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, bipolar disorder with psychotic features, or major depression with psychotic features. Symptoms of depression are allowed. • Patient was considered to be an imminent danger to themselves or others. • C-SSRS score ≥ 4 within 6 months prior to screening or any suicidal behavior in the last two years prior to screening, as indicated by any “yes” answers on the suicidal behavior section of the C-SSRS. • Abnormal laboratory values or clinical findings on screening that are judged to be clinically significant. • Diagnosis of moderate or severe substance use disorder within the six months prior to screening, positive urine drug or alcohol test at screening, or evidence of acute intoxication or withdrawal at screening. • Any subject who had received clozapine, as verified by the clozapine patient registry. • Prior history of neuroleptic malignant syndrome induced by any antipsychotic medication. • Any subject who was unable to be safely discontinued from current antipsychotic therapy, mood stabilizers, lithium, anticholinergics, and antidepressant medications.

Prohibited Concurrent Medications: • Use of any antipsychotic medication within the screening period through Day -1.

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• Use of depot antipsychotic medication within 1.5 treatment cycles prior to Day -1 (baseline). • Use of any of the following agents: mianserin, mirtazapine, nefazodone, cyproheptadine, pimavanserin, or fluvoxamine within approximately five half-lives prior to Day -1. • Use of any strong or moderate cytochrome P450 isoenzyme 3A4 inhibitor or inducer within seven days prior to Day -1. • Medications other than lorazepam, such as zaleplon and zolpidem, to manage insomnia.

Allowable Concurrent Medications: • Lorazepam was allowed to help alleviate agitation or insomnia, not to be given within eight hours prior to PANSS, CGI-S, PSP, or CDSS. • Benztropine was allowed for treatment of extrapyramidal adverse effects, not to be given within eight hours of SAS, BARS, or AIMS. • Propranolol was allowed for treatment of akathisia, not to be given within eight hours of SAS, BARS, or AIMS.

Study Treatments: Starting on the first day of screening, all antipsychotic and other psychotropic medications were stopped, with tapering as per investigator’s clinical judgment.

Lumateperone, risperidone, and placebo were administered in capsule form. Placebo capsules were given along with drug capsules to maintain study blinding. Study treatments were administered once daily in the morning.

As in Study ITI-007-005, risperidone was selected as an active control. lumateperone doses of 14 mg and 42 mg once daily were selected for evaluation in the current study. The 42-mg dose had demonstrated antipsychotic efficacy in Study ITI-007-005 and was found to be well tolerated in that study. Study ITI-007-301, which evaluated the 28-mg and 42-mg doses of ITI- 007, had not been completed at the time of initiation of Study ITI-007-302. For this study, 14 mg was selected to evaluate a dose of lumateperone lower than 42 mg.

Assignment to Treatment: Patients were randomized 1:1:1:1 to the four treatment groups. As a one-day dose titration, patients in the risperidone group received risperidone 2 mg on Day 1, and 4 mg daily thereafter. No dose titration was deemed necessary for either lumateperone treatment group.

Procedures and Schedule: Please see Table 69 below. Total study duration was approximately nine weeks, including a screening period of two to seven days prior to Day 1, an inpatient treatment period of six weeks, an inpatient stabilization period of up to five days during which patients were stabilized on standard antipsychotic medication, and an outpatient safety follow- up approximately one week after the end of the stabilization period.

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Table 69: Study 302: Schedule of Assessments Screen Baseline Study Treatment Period End of End Event Stabilization of Study a c -7 to -2 -1 1 8 15 22 28 42/ 47 Day 54 b ET ± 2

Visit Number 1 2 3 4 5 6 7 8 9 10

Informed consent, medical X h istory, admission to inpatient unit Inclusion/Exclusion X X Criteria Review d SCID-CT, BPRS X Screening Adjudication X d Form(s) and Recordings Modified Physical Exam X X Hepatitis/HIV Testing X Urine Drug and Alcohol X X e Screen Urine pregnancy Test X X X X f Clinical Laboratories X X X X X g 12-Lead ECG X X X X X X X h Vital Signs X X X X X X X X X Randomization X Study Drug Dosing X X X X X X i PK Sample Collection X X X X X Samples for protein X X X j biomarkers Sample for genetic X X k k testing l l,m PANSS , Central CGI-S X X X X X X m Site-based CGI-S X X X X X X X X PSP, SWN-S X X CDSS X X X n SAS , BARS, AIMS X X X X X X C-SSRS X X X X X X X X X Concomitant medication X X X X X X X X X X o Adverse events X X X X X X X X X X

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Restart Standard X p Antipsychotics a) Upon signing of the ICF, patients are to be admitted to the inpatient unit, if they are not inpatient already. However, patients may have initial screening procedures conducted outpatient after informed consent is signed as long as they are admitted inpatient at the end of the first screening day to stay inpatient for the duration of the screening and treatment periods. b) Day 42 procedures to be performed at the Early Term (ET) visit. c) The End of Stabilization period is up to 5 days. d) These assessments are to be recorded and submitted to an independent psychiatrist or clinical psychologist (or panel of psychiatrists and/or clinical psychologists) for review. e) The Urine Drug and Alcohol screen will also be performed upon patient’s return to the inpatient unit from the day pass. f) Clinical Laboratory samples are to be taken after an overnight fast of at least 10 hours as early in the Screening Period as feasible, but not necessarily on Day -7. g) ECGs are to be triplicate 10 second epochs with 5 min between recordings. One triplicate ECG will be performed during Screening and one triplicate ECG will be performed on Day 47. On Days 1, 8, 28 and 42, triplicate ECGs will be taken pre-dose (trough, before breakfast) and at 3-4 h post-dose (peak, before lunch). An additional triplicate ECG will be performed on Day 42 at 6-7 h post-dose. Triplicate ECGs on Day -1 are to be performed at the same time of day planned for Day 42: once before breakfast (approximately 7:00 am corresponding to the same time of day for the trough measure), again before lunch (approximately 11:00 am – noon, corresponding to the same time of day for the 3-4 h post-dose peak measure), and again approximately 2:00-3:00 pm corresponding to the same time of day of the 6-7 h post-dose measure. In all cases ECGs are conducted before other assessments scheduled in the same time window; for example, when ECG, vital signs and blood sample collection for PK measures are scheduled for the same time window, ECG measures should be conducted first, followed by vital signs and then blood sample collection. h) Respiratory rate, oral temperature, and 3-positional blood pressure and pulse (after at least 10 minutes lying down, after approximately 1 minute sitting, immediately upon standing, and after approximately 3 minutes standing), body weight and waist circumference will be taken at least once at all scheduled visits through Day 47. On Days 1, 8, 15, 22, 28, and 42 vitals will be taken pre-dose (trough) and 3-4 h post-dose (peak). Additionally, vital signs will be assessed on Days -1 and 42 at 6-7 h post- dose. Vital signs are always taken after conducting the ECGs, as applicable, and prior to any other assessments scheduled in the same time window. Height should be collected during screening only. Weight and waist circumference should be collected at screening and again on Day -1 for baseline and at every scheduled visit through Day 47, but only once per visit, with the pre-dose (trough) vital signs measures. i) Blood samples for PK collection are to be collected prior to dosing (trough) and then 3-4 h after dosing (peak) on Days 1, 8, 28 and 42. On Day 42 blood sample for PK will be collected again at 6-7 h post-dose. Single blood sample for PK will be collected on Day 47. Samples are collected after ECGs and vital signs. j) Samples for protein biomarkers on Day 1 has be collected pre-dose and at the time clinical labs are collected to avoid additional venipuncture. Additional samples for protein biomarkers are collected on Days 8 and 42 at the time PK samples 3-4 hours post-dose are collected. k) Blood sample is to be collected once for genetic testing, if the optional ICF addendum is signed. If the addendum is signed prior to Day 1 then the sample will be taken on Day 1. If it signed after Day 1, then the sample will be taken on Day 42. It is not to be taken twice. l) PANSS and CGI-S are to be conducted by a remote central rater. Efforts should be made to schedule the remote interviews at approximately the same time of day for each visit. Due to potential limitations around scheduling of the remote rater, the PANSS may be conducted within a 1-day window provided for this assessment (see Section 6.2). PANSS and CGI scores at Baseline Visit are reviewed for inclusion of subject (subject will be included with the baseline PANSS score of 70 or higher and baseline CGI-S score of 4 or higher). m) CGI-S is conducted by a qualified site rater at screening (in addition to the CGI-S conducted by the remote central rater) at baseline through Day 42. Site-based CGI-S is conducted by qualified site rater; during the

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treatment period, the site rater will interview the subject and review baseline and current PANSS and CGI-S scores from the remote centralized rater prior to rating the site-based CGI-S for the visit. n) On Days 8, 15, 22, 28 and 42, the SAS, BARS, and AIMS assessments are to be conducted 3-6 hours after the administration of study treatment o) The recording of adverse events is to start immediately after the ICF is signed and continue through until End- of-Study, Visit 9. p) On Day 42, after all study assessments have been completed, or on Day 43 patients are to be started on standard antipsychotic medication as prescribed by the Investigator. Source: ITI-007-302, Clinical Study Protocol Version 1.1, Table 4, page 163-166.

Study Endpoints (see Section 7.3 for descriptions of study endpoints) Primary efficacy endpoint: • mean change in total PANSS score from baseline to end of treatment (Week 6)

Key secondary efficacy endpoint: • CGI-S: change from baseline to Day 42.

Secondary efficacy endpoints: • PANSS Positive subscale • PANSS Negative subscale • PANSS General Psychopathology subscale • PANSS Prosocial Factor Score • PANSS five factors (Marder and Gaag) • PSPSWN-S • PSP • SWN-S • CDSS

Safety assessments: • reported and observed AEs • physical examination • body weight and waist circumference • vital signs • 12-lead ECG • clinical laboratory values • SAS • BARS • AIMS • C-SSRS

Statistical Analysis Plan The Statistical Analysis Plan is dated 05/10/2016 and superseded the statistical methods section

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of the protocol.

Primary Efficacy Analysis Set The ITT set was defined as containing all randomized subjects who received at least one dose of study medication, and had data recorded for at least one valid baseline and at least one valid post-baseline PANSS measurement.

Primary Analysis model The treatment effect on the primary efficacy endpoint, change from baseline to Day 42 in PANSS total score, was evaluated using an MMRM model. The model included the change from baseline at each pre-specified timepoint as the response variable and study visit, baseline PANSS total score, baseline PANSS total score-by-study visit interaction, treatment (lumateperone 14 mg, lumateperone 42 mg, risperidone 4 mg, and placebo) and treatment-by- study visit interaction. An unstructured covariance matrix was used to model the correlation among repeated measurements within subject.

Sample Size Originally, the overall planned sample size (i.e., 587 randomized subjects) was based on the interim results of Study 301 (observed effect size of 0.4). Once the final results for Study 301 including the smaller effect size for the 42 mg lumateperone dose (observed effect size of 0.3) were available, the Applicant decided to increase the overall sample size to 680.

Statistical reviewer note: Increasing the sample size while Study 302 was ongoing is permissible without any adjustments to the analysis because the decision is based on external data and not on accumulating data from Study 302.

Multiple Comparisons A fixed sequence testing strategy was pre-specified (primary endpoint for 42 mg lumateperone versus placebo followed by key secondary endpoint 42 mg lumateperone versus placebo followed by primary endpoint for 14 mg lumateperone versus placebo and lastly key secondary endpoint for 14 mg lumateperone versus placebo).

Missing Data/Sensitivity Analysis A placebo-based multiple imputation sensitivity analysis assuming a Missing Not At Random (MNAR) missingness mechanism was pre-specified to evaluate the impact of deviations of the Missing At Random assumption in the primary analysis.

Protocol Amendments Original protocol date: April 6, 2015

Protocol Clarifications: January 11, 2016 The Applicant provided a letter describing the following protocol clarifications: • The target sample size will be increased from 587 to approximately 680 randomized

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subjects in order to maintain appropriate statistical power, based on the effect size observed for the lumateperone 42-mg dose on the primary efficacy endpoint in Study ITI-007-301. Study ITI-007-302 will remain blinded. • ITI-007-302 pharmacokinetic samples will be analyzed with a newly validated method which assays lumateperone and metabolites IC200565, IC200131, IC200161 (as in Study ITI-007-301), as well as two additional metabolites, IC201308 and IC201309. There will be no change in the schedule of pharmacokinetic sample collections.

Study ITI-007-302 Results

Compliance with Good Clinical Practices

Section 5.2, page 13 of the Clinical Study Report states: “The procedures set out in this study protocol, pertaining to the conduct, evaluation, and documentation of this study, were designed to ensure that the Applicant and Investigator abided by the principles of the Good Clinical Practice (GCP) guidelines and the ethical principles laid down in the current revision of the Declaration of Helsinki. The study was also carried out in keeping with local legal and regulatory requirements in the United States (US).”

Financial Disclosure No disclosable financial interests or arrangements were reported for any of the investigators participating in this study. See Section 14.2, Financial Disclosures, for details.

Patient Disposition A total of 976 patients were screened, of whom 696 were randomized, with 174 patients assigned to each of the four treatment groups. Reasons for discontinuation of study drug and for discontinuing from the study are summarized in Table 70. Patients may have discontinued from the study without discontinuing from study drug if the patient left the study after completing the study treatment. Study drug discontinuations related to lack of efficacy were highest in the lumateperone 14-mg arm. Study discontinuations related to lack of efficacy were highest in the placebo arm. Discontinuations related to adverse events are discussed in more detail in Section 8.2.4.

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Table 70: Study 302: Disposition of Randomized Patients Lumateperone Lumateperone Risperidone Placebo 14 mg 42 mg 4 mg (N=174) (N=174) (N=174) (N=174) Disposition n (%) n (%) n (%) n (%) Completed the Treatment Period 118 (67.8) 130 (74.7) 109 (62.6) 137 (78.7) Discontinued Study Drug 56 (32.2) 44 (25.3) 64 (36.8) 37 (21.3) Adverse Event 6 (3.4) 0 19 (5.7) 1 (0.6) AE associated with worsening of 2 (1.1) 0 0 0 schizophrenia AE not associated with 4 (2.3) 0 10 (5.7) 1 (0.6) worsening of schizophrenia Lack of efficacy 13 (7.5) 11 (6.3) 8 (4.6) 12 (6.9) Protocol violation 0 1 (0.6) 1 (0.6) 0 Physician decision 0 0 1 (0.6) 1 (0.6) Patient withdrew consent 34 (19.5) 27 (15.5) 37 (21.3) 20 (11.5) Personal or family reasons 22 18 26 15 Refused to provide a reason and 8 (4.6) 6 (3.4) 7 (4.0) 4 (2.3) refused all end of study procedures Self-reported adverse event 1 (0.6) 0 1 (0.6) 0 Self-reported lack of efficacy 3 (1.7) 3 (1.7) 3 (1.7) 1 (0.6) Other 3 (1.7) 5 (2.9) 7 (4.0) 3 (1.7)

Completed the Study 113 (64.9) 128 (73.6) 105 (60.3) 133 (76.4) Discontinued from Study 61 (35.1) 46 (26.4) 69 (39.7) 41 (23.6) Adverse Event 6 (3.4) 0 10 (5.7) 1 (0.6) AE associated with worsening of 2 (1.1) 0 0 0 schizophrenia AE not associated with 4 (2.3) 0 10 (5.7) 1 (0.6) worsening of schizophrenia Lack of efficacy 13 (7.5) 10 (5.7) 8 (4.6) 19 (5.7) Lost to follow-up 5 (2.9) 2 (1.1) 2 (1.1) 7 (4.0) Protocol violation 0 1 (0.6) 1 (0.6) 0 Physician decision 0 0 0 1 (0.6) Patient withdrew consent 34 (19.5) 30 (17.2) 37 (21.3) 20 (11.5) Personal or family reasons 21 (12.1) 21 (12.1) 25 (14.4) 15 (8.6) Refused to provide a reason and 9 (5.2) 7 (4.0) 8 (4.6) 3 (1.7) refused all end of study procedures Self-reported adverse event 1 (0.6) 0 2 (1.1) 0 Self-reported lack of efficacy 3 (1.7) 2 (1.1) 2 (1.1) 2 (1.1) Other 3 (1.7) 3 (1.7) 10 (5.7) 2 (1.1) Source: based on Study ITI-007-302 Clinical Study Report, Table 10.1, page 65.

Protocol Violations/Deviations The most common protocol deviations were positive drug screen and incorrect concomitant use of lorazepam, benztropine, or propranolol. Major protocol deviations are described in Table 71.

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Table 71: Study 302: Major Protocol Deviations, Intent-to-Treat Population Lumateperone Lumateperone Risperidone Placebo 14 mg 42 mg 4 mg (N=166) (N=162) (N=157) (N=169) Deviation n (%) n (%) n (%) n (%) Patients with at least one 11 (6.6) 4 (2.5) 9 (5.7) 7 (4.1) major deviation Informed consent: site 0 0 0 1 (0.6) collected DNA sample when patient did not consent for collection Exclusion criteria met but 0 0 1 (0.6) 0 subject randomized and received treatment Inclusion criteria not met but 0 0 1 (0.6) 0 subject randomized and received treatment Incorrect treatment: patient 2 (1.2) 1 (0.6) 0 0 treated with a different medication than randomized Patient had a positive drug 7 (4.2) 2 (1.2) 4 (2.5) 1 (0.6) screen for substance of abuse during the treatment period Prohibited Medication Patient received lorazepam, 2 (1.2) 0 2 (1.3) 5 (3.0) benztropine, or propranolol outside of protocol guidelines Patient received 0 1 (0.6) 2 (1.3) 1 (0.6) psychotropic medications other than lorazepam, benztropine, or propranolol Source: ITI-007-302 Clinical Study Report, Table 10.2, page 69.

Clinical reviewer comment: The percentage of patients who received prohibited medications outside of protocol guidelines was similar across the treatment groups. The use of prohibited medications is not anticipated to significantly affect the efficacy analysis.

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Table of Demographic Characteristics Table 72 presents the demographics of the safety population. The majority of patients in all treatment groups were males. The mean age was 42.6. The majority of patients in each treatment group were African American or of African descent. Demographic characteristics were comparable across the three treatment groups. The age and race distributions for this study were similar to those in Study 005 and Study 301.

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Table 72: Study 302: Demographic Characteristics, Safety Population Lumateperone Lumateperone Risperidone Placebo 14 mg 42 mg 4 mg (N=172) (N=172) (N=173) (N=178) n (%) n (%) n (%) n (%) Gender, n (%) Male 125 (72.7) 123 (71.5) 132 (76.3) 132 (74.2) Female 47 (27.3) 49 (28.5) 41 (23.7) 46 (25.8)

Age (years) Mean (SD) 42.7 (10.0) 41.9 (9.9) 42.4 (10.8) 43.5 (9.9) Median 43.5 42.5 44.0 46.0 Min, Max 20, 60 23, 60 18, 60 18, 60

Age (years), n (%) ≤ 40 65 (37.8) 77 (44.8) 75 (43.4) 65 (36.5) > 40 107 (62.2) 95 (55.2) 98 (56.6) 113 (63.5)

Race, n (%) White 26 (15.1) 30 (17.4) 40 (23.1) 35 (19.7) Black / African American / 140 (81.4) 140 (81.4) 123 (71.1) 133 (74.7) African Descent Asian 2 (1.2) 0 2 (1.2) 3 (1.7) American Indian / Alaska 1 (0.6) 0 2 (1.2) 0 Native Native Hawaiian / Other 0 0 0 0 Pacific Islander Other 2 (1.2) 2 (1.2) 4 (2.3) 7 (3.9) Multiple 1 (0.6) 0 2 (1.2) 0

Ethnicity, n (%) Hispanic or Latino 11 (6.4) 14 (8.1) 22 (12.7) 27 (15.2) Not Hispanic or Latino 161 (93.6) 158 (91.9) 151 (87.3) 151 (84.8)

BMI (kg/m2) Mean (SD) 94.3 (14.6) 96.1 (15.9) 98.6 (16.2) 94.1 (14.3) Median 92.9 94.9 98.5 92.0 Min, Max 68.9, 166.0 62.0, 143.0 53.8, 140.0 60.0, 136.0 Source: ITI-007-302 Clinical Study Report, page 73, Table 11.2.

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Other Baseline Characteristics (e.g., disease characteristics, important concomitant drugs) Please see Table 73 below. The most commonly used prior medication was lorazepam. Other commonly used prior medications were risperidone, quetiapine, haloperidol, aripiprazole, olanzapine, trazodone, benztropine, , and sertraline. Prior medication use was comparable across treatment groups.

The mean time since first diagnosis of schizophrenia, mean baseline BPRS scores, PANSS total scores, PANSS subscores, percentage of patients with symptoms of depression, CDSS scores, PSP scores, and CGI-S scores were similar across treatment groups. Table 73 presents baseline clinical characteristics for patients in the ITT population.

Clinical reviewer comment: The study population’s mean BPRS score of 55 and mean PANSS total score of 90 are comparable to the scores of the study populations for Study 005 and Study 301, and similarly reflect a clinical state of acute exacerbation of schizophrenia symptoms for which prescription of antipsychotic medication would be appropriate.

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Table 73: Study 302: Baseline Clinical Characteristics, ITT Population Lumateperone Lumateperone Risperidone Placebo 14 mg 42 mg 4 mg (N=166) (N=162) (N=157) (N=169) Time since First Diagnosis of Schizophrenia (Years) Mean (SD) 18.9 (11.0) 16.8 (10.5) 18.2 (10.4) 17.5 (10.4) Symptoms of Depression, n (%) Yes 8 (4.8) 5 (3.1) 9 (5.7) 7 (4.1) No 158 (95.2) 157 (96.9) 148 (94.3) 162 (95.9) BPRS Total Score Mean (SD) 54.6 (6.6) 55.7 (7.3) 54.9 (7.7) 54.3 (7.3) PANSS Total Score Mean (SD) 88.5 (10.1) 90.4 (10.2) 89.7 (9.6) 90.2 (9.8) PANSS Positive Subscale Score Mean (SD) 25.4 (3.8) 25.4 (3.6) 25.5 (3.7) 25.9 (3.9) PANSS Negative Subscale Score Mean (SD) 20.5 (4.1) 21.8 (4.2) 21.3 (3.8) 20.9 (3.5) PANSS General Psychopathology Subscale Score Mean (SD) 42.7 (5.8) 43.2 (6.1) 42.9 (5.7) 43.4 (6.0) CGI-S Score Mean (SD) 4.6 (0.5) 4.8 (0.5) 4.7 (0.5) 4.8 (0.6) PSP Total Score Mean (SD) 46.4 (13.2) 44.2 (12.3) 46.0 (12.5) 45.9 (12.7) CDSS Total Score Mean (SD) 3.9 (3.4) 4.3 (3.4) 4.0 (3.6) 4.2 (3.6) Source: Clinical reviewer generated from ITI-007-302 Clinical Study Report, Appendix of Tables, Tables 14.1.3.4 and 14.1.3.8.

Treatment Compliance, Concomitant Medications, and Rescue Medication Use For the ITT population, the reported mean treatment compliance rate was ≥98.9% for all treatment groups. Treatment compliance was evaluated by reviewing PK data in an ongoing, blinded manner. If a patient assigned to receive lumateperone was shown to have blood levels below the limit of quantitation, indicating likely noncompliance with study medication, then the Applicant could have requested an investigation by an unblinded third party to determine whether the subject should be discontinued from the study. No patients were discontinued from the study because of non-compliance with study drug.

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Efficacy Results – Primary Endpoint

The changes from baseline were not statistically significant for either lumateperone dose compared to placebo (Table 74). The time course of results on primary efficacy measure and a histogram presenting the percentages of patients experiencing specified magnitudes of improvement are in Figure 20 and Figure 21, respectively.

Table 74: Study 302: Primary Efficacy Results

Primary Efficacy Endpoint: PANSS Total Score

Study Treatment Group N Mean Baseline LS Mean Placebo- Score (SD) Change from subtracted Baseline (SE) Difference (95% CI)a 302 Lumateperone (14 mg) 174 88.5 (10.1) -15.0 (1.3) 0.1 (-3.4, 3.5) Lumateperone (42 mg) 174 90.4 (10.2) -14.6 (1.2) 0.5 (-2.9, 3.8) Risperidone (4 mg)b 174 89.7 (9.6) -20.5 (1.3) -5.4 (-8.9, -1.9) Placebo 174 90.2 (9.8) -15.1 (1.2) --

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons a Difference (drug minus placebo) in LS mean change from baseline to Day 42. b Included for assay sensitivity, not included in multiple comparison procedure. *Doses statistically significantly superior to placebo. Source: 302 CSR, results confirmed by Statistical Reviewer

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Figure 20. Primary Efficacy Endpoint (Change from Baseline in PANSS Total Score to Day 42) [Study 302, ITT set]

Source: Statistical Reviewer

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Figure 21. Percent of Patients with Specified Magnitude of PANSS Total Score Change at the End of Week 6 [Study 302, ITT set]

Improvement →

Source: Statistical Reviewer

Study 302 provides no evidence of efficacy for lumateperone 42 mg, and the lack of a treatment effect is concerning. There were discussions with the Applicant with respect to classification of the study as “negative” or “failed.” In essence, the question is whether the study demonstrates assay sensitivity. A positive finding for risperidone (vs. placebo) would demonstrate assay sensitivity, such the study would be deemed “negative” with respect to lumateperone. Conversely, if the effect of risperidone were statistically indistinguishable from placebo, the study would lack assay sensitivity and be deemed a “failed” study – a study incapable of detecting the treatment effect of even an effective drug.

The distinction between “negative” and “failed” would not change the reality that Study 302 is not supportive of efficacy; however, classifying the study as “failed” rather than “negative” could lessen its negative weight in the overall consideration of whether the application provides substantial evidence of lumateperone’s effectiveness.

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imputation without added shift) are consistent with the results of the primary analysis, showing a nominally significant difference between the risperidone and placebo groups (but not between the lumateperone and placebo groups).

In response to the Division’s concerns about the primary efficacy results of Study 302 (i.e., lumateperone 42 mg arm did not separate from placebo, whereas the risperidone 4 mg arm did), the Applicant conducted numerous post-hoc sensitivity analyses. The Applicant made the case that the primary efficacy analysis (i.e., MMRM with Missing at Random assumption) was not well-suited to account properly for the higher discontinuation rate in the risperidone arm (37%) compared to the placebo arm (21%) or the 42 mg lumateperone arm (25%). The Applicant’s post-hoc sensitivity analyses were conducted under varying Missing Not At Random assumptions (e.g., a responder analysis treating all patients without a Day 42 assessment as non-responders and several variants of multiple imputation with a shift added (akin to tipping point analysis)). Based on those analyses the Applicant states that “all active treatments, including risperidone, very likely have no efficacy versus placebo” in Study 302 (Response to Mid-Cycle Communication Issues 2 – Statistics (Serial 52, 05/31/2019, p. 49)).

The statistical reviewer conducted an additional sensitivity analysis (Wilcoxon rank sum test) to test whether a non-parametric analysis ranking the PANSS change from baseline to Day 42 scores and assigning the worst change value observed to patients with missing PANSS scores at Day 42 would reject the hypothesis of no difference in the effects of the two treatments (i.e., placebo and risperidone). This hypothesis could not be rejected (two-sided p-value=0.4). In other words, under the assumption that assigning the worst observed PANSS change score to the missing PANSS change scores at Day 42 is reasonable, one would not be able to reject the hypothesis that the PANSS change scores for the placebo and risperidone subjects are originating from the same distribution. This analysis aligns with the Applicant’s assertion about viewing Study 302 as “failed” study.

Irrespective of whether the risperadone results are deemed to be negative or nominally positive, the lack of an effect for both doses of lumateperone is concerning. For controlled superiority studies that do not find a statistically significant result, typical concerns hypothesized to explain the absence of a treatment effect(s) include the possibility that the enrolled patients did not have the disease, e.g., “professional patients,” or that symptoms were exaggerated (by patients or investigators) to gain study entry, as well as the possibility that patients weren’t taking their study medications. Given that the study was conducted exclusively in the inpatient setting under close observation, wholly in the US, and with excellent documentation of compliance based on blood monitoring (PK samples), the negative results of Study 302 are more difficult to ignore. Moreover, Study 302 was the largest of the three studies, and it was also the longest study.

The Applicant has pointed out that the placebo response in Study 302 was larger than in Studies 301 and 005, although the positive trend with risperidone (superior to placebo) undercuts this argument. (Moreover, the dose of risperadone used, 4 mg, is at the lower end of the range of

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doses recommended for the treatment of schizophrenia [target dose = 4 to 8 mg].) Perhaps unfavorable randomization (important, yet unknown baseline factors could have favored the placebo group) or play of chance explains the absence of lumateperone’s treatment effect in this study, but this is speculative. Our only source of reassurance is the fact that a number of drugs, approved for the treatment of schizophrenia and thought to be effective, have similarly failed in adequate and well-controlled studies.

Data Quality and Integrity No issues related to data quality or integrity were identified during review of the results of this study.

Efficacy Results – Secondary and other relevant endpoints With failure on the primary endpoint, results on secondary or exploratory endpoints are not relevant for discussion.

Dose/Dose Response Efficacy was not demonstrated for either lumateperone 14 mg or lumateperone 42 mg, so the study does not provide any information about dose-response.

Durability of Response Efficacy was not demonstrated for either lumateperone 14 mg or lumateperone 42 mg. The total PANSS scores improved over time for both treatment arms, but neither separated from placebo.

Persistence of Effect

This trial did not include investigation of persistence of effect after discontinuation of the drug.

Efficacy Results – Secondary or exploratory COA (PRO) endpoints The trial did not employ secondary or exploratory PRO endpoints.

Additional Analyses Conducted on the Individual Trial No additional analyses were conducted on this trial.

Assessment of Efficacy across Trials

All three studies examined the change from baseline in PANSS total score as the primary endpoint, a well-established metric for demonstrating the effectiveness of antipsychotics for the treatment of schizophrenia.

All three studies were conducted exclusively in inpatient settings in the US, and all subjects were adults.

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Assessment of efficacy across the three placebo-controlled trials is complicated mostly by the fact that the three studies examined different lumateperone doses. All three studies examined the 42-mg dose of lumateperone: only Study 005 had a lumateperone 84-mg treatment arm; only Study 301 had a lumateperone 28-mg treatment arm; and only Study 302 had a lumateperone 14-mg treatment arm. Studies 005 and 302 included a risperidone 4-mg treatment arm, whereas Study 301 did not include an active comparator.

Aside from differences in the treatments examined, the principal difference between studies was their length (4 weeks for Studies 005 and 301; 6 weeks for Study 302). Nevertheless, for Study 302, assessments were obtained at Week 4, and the Week 4 results (no treatment effect) were similar to those obtained at Week 6, helping to enable a cross-study comparison.

Table 75 provides for a summary of the primary efficacy endpoint results across Studies 005, 301, and 302.

Table 75: Difference in Least Squares Means for Primary Efficacy Endpoints (Placebo-subtracted Change in PANSS Total Score) for the Three Controlled Studies Study Lumateperone dose (mg/d) Risperidone (n randomized) (95% Confidence Interval [CI]) (mg/d) 14 28 42 84 4 Study 005 -5.8 -0.9 -6.0 (n=335) (-10.5, -1.1) p=0.040 p=NS Study 301 -2.6 -4.2 (n=450) (-6.2, 1.1) (-7.8, -0.6) p=NS p=0.045 Study 302 +0.1 +0.5 -5.4 (n=696) p=NS p=NS Source: Clinical Study Reports (CSRs); results confirmed by statistical reviewer; p-values for Studies 005 and 301 are adjusted for multiplicity, 95% CIs are not adjusted for multiplicity, NS = not statistically significant at 0.05 level

The Applicant pointed out that, across the three studies, the point estimates of the primary efficacy endpoint have similar trajectories over time for the 42-mg lumateperone arm across the three studies. The Applicant believes that differences in treatment effects are caused by differences in the placebo response across studies. We acknowledge that the placebo response appears to be more robust in Study 302, but it is not clear why this was the case and note that risperidone 4 mg/day still appeared to separate from placebo in that study.

The Applicant pointed out that, across the three studies, the point estimates of the mean PANSS total scores for the 42-mg lumateperone groups have similar trajectories over time. The Applicant believes that differences in treatment effects are caused by differences in the placebo response across studies (Figure 22). We acknowledge that the placebo response

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appears to be more robust in Study 302; but it is not clear why this was the case, and, importantly, risperidone 4 mg/day still appeared to separate from placebo in that study.

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Figure 22. PANSS Total Score LS Mean Change from Baseline (42 mg Lumateperone vs. Placebo) by Study [ITT set]

Source: Statistical Reviewer

Secondary and Other Endpoints There were no results on secondary or exploratory endpoints across trials that were relevant for discussion in this review.

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Subpopulations As described previously, the composition of the study population was skewed in each of the three studies, with a predominance of male patients and patients of African descent. Exploratory subpopulation analyses conducted by the statistical reviewer for the three placebo- controlled trials are described in Sections 8.1.2, 8.1.4, and 8.1.7. Because of the small numbers of female patients and patients of other races, it was not possible to draw conclusions related to efficacy analyses across subpopulations.

Additional Efficacy Considerations

The reasons for lack of efficacy of the 84-mg dose of lumateperone in Study 005 remain unclear. We typically expect higher doses of an antipsychotic medication to be associated with both higher adverse event rates (which was observed for lumateperone 84 mg) and either higher or at least equivalent efficacy to that seen in lower doses. Because of the low bioavailability of the drug, patients taking the same oral dose of the drug may not have the same level of drug exposure.

It is possible that some patients taking the 84-mg dose of lumateperone experienced improvement in some PANSS items but worsening in other items, resulting in a net effect of a lack of change in the total PANSS score compared to baseline. Table 76 displays the items in each of the PANSS subscales for which patients in the 84-mg treatment group showed improvement, and Table 77 displays the items for which patients in the same treatment group showed worsening. Both tables show the mean change from baseline on individual PANSS items for each of the three PANSS subscales. Within each subscale, items are sorted in descending order based on the size of magnitude of the mean change from baseline. We note that the number of items for which patients in the 84-mg group showed improvement was higher for each of the PANSS subscales (Positive=6, Negative=4, General Psychopathology=14) than the number of items for which this group showed worsening (Positive=1, Negative=3, General Psychopathology=2). The number of items with a magnitude of change above 0.5 (a cutoff selected arbitrarily) was also higher for the subset of items showing improvement than for the subset of items showing worsening (eight vs. two). It is not clear why the total PANSS score showed a lack of separation from placebo. Further analysis could potentially suggest whether comparison of the total PANSS score to placebo might have been dominated by the differences in magnitude of change from placebo in a small number of PANSS items for which the lumateperone 84-mg group showed a worsening compared to baseline.

Table 76: Study 005: Questions from PANSS Showing Improvement from Baseline, Lumateperone 84-mg Treatment Group (N=81) Subscale Question Topic Mean SD Positive P3 Hallucinatory Behavior -0.83 1.38 P6 Suspiciousness/Persecution -0.75 1.09 P5 Grandiosity -0.62 1.51

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P1 Delusions -0.60 1.17 P4 Excitement -0.16 1.42 P2 Conceptual Disorganization -0.05 1.42

Negative N4 Passive/Apathetic Social Withdrawal -0.44 1.27 N2 Emotional Withdrawal -0.40 1.19 N5 Difficulty in Abstract Thinking -0.28 1.23 N7 Stereotyped Thinking -0.14 1.61

General G2 Anxiety -1.07 1.73 Psychopathology G16 Active Social Avoidance -0.74 1.35 G4 Tension -0.78 1.64 G6 Depression -0.52 1.37 G3 Guilt Feelings -0.41 1.37 G9 Unusual Thought Content -0.31 1.17 G1 Somatic Concern -0.27 1.42 G5 Mannerisms and Posturing -0.19 1.35 G10 Disorientation -0.16 1.11 G12 Lack of Judgment and Insight -0.15 1.38 G7 Motor Retardation -0.15 1.11 G13 Disturbance of Volition -0.09 1.35 G8 Uncooperativeness -0.05 1.36 G14 Poor Impulse Control -0.05 1.24

Source: Clinical reviewer generated table. Items in bold showed a magnitude of improvement greater than 0.5 (arbitrary cutoff).

Table 77: Study 005: Questions from PANSS Showing Worsening from Baseline, Lumateperone 84-mg Treatment Group (N=81) Subscale Question Topic Mean SD Positive P7 Hostility 0.04 1.54

Negative N6 Lack of Spontaneity and Flow of 0.93 1.50 Conversation N3 Poor Rapport 0.74 1.41 N1 Blunted Affect 0.25 1.50

General G11 Poor Attention 0.35 1.50 Psychopathology G15 Preoccupation 0.02 1.52

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Source: Clinical reviewer generated table. Items in bold showed a magnitude of worsening greater than 0.5 (arbitrary cutoff).

Integrated Assessment of Effectiveness

The three placebo-controlled trials all evaluated the change in mean total PANSS score from baseline to the end of treatment as the primary efficacy endpoint. Lumateperone 42 mg demonstrated a statistically significant difference from placebo on the primary efficacy endpoint in Study 005 and Study 301, but not in Study 302. The other doses of lumateperone tested in the three studies, both lower and higher (14 mg, 28 mg, and 84 mg), did not separate from placebo in the studies in which they were tested.

Studies 005 and 302 included an active comparator arm, allowing the assessment of assay sensitivity. In Study 005, both risperidone 4 mg and lumateperone 42 mg separated from placebo. In Study 302, which enrolled a larger study population and had a longer duration than the other two placebo-controlled studies, risperidone 4 mg separated from placebo, but lumateperone 42 mg did not. The reason why lumateperone 42 mg failed to demonstrate efficacy in Study 302 was not clear during the review of study findings. The Applicant has proposed a higher than expected response in the placebo group as a possible reason for the failure of lumateperone 42 mg to separate from placebo, but this would not explain why risperidone 4 mg was able to separate from placebo. (Moreover, as noted above, the dose of risperadone used, 4 mg, is at the lower end of the range of doses recommended for the treatment of schizophrenia.) The Applicant also proposed that the primary efficacy analysis model in Study 302 was not suited for the higher discontinuation rate in the risperidone arm (37%, as compared to 21% for placebo and 25% for lumateperone 42 mg), and that risperidone would have not appeared to be superior to placebo with more appropriate assumptions in the analysis model. We consider the Applicant’s proposed reasons for the negative results to be reasonable hypotheses, but at the conclusion of the review do not fully understand the why the efficacy findings for lumateperone 42 mg in Study 302 were discordant with the other studies.

Overall, despite the failure of lumateperone 42 mg in Study 302, the demonstration of efficacy for lumateperone 42 mg in two placebo-controlled studies provides the substantial evidence of effectiveness necessary for approval.

It is also important to consider the clinical meaningfulness of statistically significant efficacy findings for a drug. Although the mean placebo-subtracted effects of lumateperone 42 mg ranged from -4 to -6 on the PANSS total score across the studies (mean baseline scores: 85 to 90), response distribution histograms illustrate that a greater percentage of patients receiving lumateperone 42 mg than placebo experienced large improvements on the PANSS (i.e., >30 points). Thus, the benefit of lumateperone is expected to be clinically meaningful for a substantial proportion of patients who receive the treatment.

Because efficacy has not been demonstrated for the 14-mg, 28-mg, or 84-mg doses of lumateperone, the product label will include only lumateperone 42 mg as an approved dose of

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the drug.

Review of Safety

Safety Review Approach

The safety review was focused on analyzing data from the three placebo-controlled trials and the one-year, uncontrolled safety trial (see Table 51). Whether the safety analyses are based on specific studies or pooled data is described in the text. In addition to safety analyses that would be conducted for the evaluation of any new molecular entity NDA, the clinical safety review focused on assessing the database for any signals suggestive of toxicities observed in nonclinical studies.

Review of the Safety Database

Overall Exposure At the time of submission of the application (December 10, 2018), a total of 1949 subjects had received at least one dose of lumateperone, including 1724 patients with schizophrenia, 24 subjects with hepatic impairment, 24 subjects with renal impairment, 19 subjects with insomnia, 5 geriatric subjects with dementia, and 153 healthy volunteers. A total of 811 patients with schizophrenia were treated with lumateperone in the three placebo-controlled clinical trials. A total of 904 patients with schizophrenia had been treated with lumateperone in the one-year open-label study, with 301 patients completing the initial six-week phase of the study and 603 patients in the ongoing one-year phase of the study.

At the time of submission of the 120-Day Safety Update (January 25, 2019), a total of 315 patients in the open-label study had received at least six months of study medication and 107 patients had received at least one year of study medication. The safety population was defined as subjects who received at least one dose of lumateperone, and subjects were analyzed according to the actual treatment received (regardless of randomization).

The primary Applicant-defined pool used for pooled safety analyses was the Phase 2 and 3 Efficacy Study pool, containing the controlled Studies 005, 301, and 302. Subjects received treatment for 4 weeks in Studies 005 and 301 and for 6 weeks in Study 302. Please refer to Table 78 below for tabulation of the number of patients and demographics in this pool by treatment arm.

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Table 78: Safety Population, All Randomized, Double-blind, Placebo-controlled Trials (Studies 005, 301, and 302) Subjects >40 Age Sex Race Treatment Group n= years of age mean (SD) (M/F %) (Black/White %) (%) Lumateperone 14 mg 172 42.7 (10.0) 62.2 72.7/27.3 81.4/15.1 Lumateperone 28 mg 150 43.5 (10.1) 62.7 75.3/24.7 62.7/28.0 Lumateperone 42 mg 406 41.3 (10.2) 54.4 73.6/26.4 78.3/18.7 Lumateperone 84 mg 83 41.1 (8.9) 56.6 86.7/13.3 74.7/19.3 Lumateperone (all doses combined) 811 42.0 (10.0) 57.8 75.1/24.9 75.7/19.7 Placebo 412 42.1 (10.1) 57.3 77.7/22.3 71.4/22.8 Risperidone 255 41.9 (10.3) 56.5 80.4/19.6 73.3/22.0 (active comparator) Source: Reviewer-created with data from Applicant-submitted ISS Table 1.2.1

Adequacy of the safety database Per the ICH E1 Guideline, the safety database should include at least 1500 subjects with short- term exposure to the investigational drug, 300 to 600 subjects with exposure for at least six months, and 100 subjects with exposure for at least a year. The Applicant’s safety database meets the numbers recommended in the ICH E1 Guideline for subject exposures to the study drug.

Adequacy of Applicant’s Clinical Safety Assessments

Issues Regarding Data Integrity and Submission Quality The Applicant provided original Case Report Forms for all deaths, serious adverse events, and adverse events leading to discontinuation. It appears that adverse events were coded appropriately, based on review of the AE data files for each of the pivotal trials. The organizational structure of the submitted data allowed for adequate review of the safety data. Although there were some deficiencies noted by inspectors for several study sites (see Section 4.1), there were no issues with data integrity or submission quality that had a significant effect on the safety review.

Categorization of Adverse Events AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 17.1 to classify events by primary system organ class and preferred term (PT). The Applicant defined a TEAE as an adverse event that started or worsened on or after the first day of study drug.

In addition to reviewing adverse events by PT and system organ class, the clinical reviewer used custom MedDRA queries to identify adverse event signals based on grouping preferred terms that describe related clinical concepts (discussed further in Section 8.2.4)

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according to schedules presented in review of Studies 005, 301, and 302 (Sections 8.1.1, 8.1.3, and 8.1.5, respectively). For each continuous laboratory parameter, the baseline, actual value, and change from baseline at last on-treatment assessment were summarized using descriptive statistics. For hematology and chemistry parameters, mean changes from baseline to minimum and maximum post-baseline values (outlier analysis) were also summarized. Markedly abnormal laboratory values were identified using criteria specified in the Statistical Analysis Plan. The Applicant’s schedule of laboratory assessments was acceptable.

Safety Results

Deaths Study 005: no deaths occurred.

Study 301: one death, two weeks after last dose of study drug (placebo). The patient was found dead in a hotel room. No autopsy information was available, and the cause of death is unknown.

Study 302: one death four days after last dose of study drug (risperidone 4 mg). The patient was hospitalized following an episode of recreational drug use and died the day after admission. Autopsy information was not included in the clinical study report. The cause of death is believed to be recreational drug use.

Study 303: one death two weeks after last dose of study drug (lumateperone 42 mg). The patient was reported to have died in his sleep. No autopsy was information available, and the cause of death is unknown.

Clinical reviewer comment: The deaths in Study 301 and Study 302 did not involve patients in the lumateperone treatment arms. The death in Study 303 occurred two weeks after the last dose of study drug and is unlikely to have been related to lumateperone administration.

Serious Adverse Events

Serious adverse events in Studies 005, 301, 302, and 303 are discussed below.

Study 005: Treatment-emergent serious adverse events (SAEs) were reported for two patients in this study: worsening psychotic symptoms for one patient in the risperidone 4 mg group and worsening psychotic symptoms for one patient in the placebo group.

Study 301: Treatment-emergent SAEs were reported for two patients in this study. The first patient, who was randomized to the lumateperone 28 mg group, experienced a single convulsive episode on Study Day 8. The patient had risk factors for seizures prior to study entry, including a previous history of loss of consciousness (which the patient was told may have been a seizure) and a family history of seizures. This historical information was not obtained at the

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time of screening and the patient’s randomization into the study was documented as a protocol violation. The second patient was on placebo and had an exacerbation of asthma.

Study 302: One patient experienced a treatment-emergent SAE of agitation secondary to worsening psychosis on Day 22 of the study. The patient had been randomized to lumateperone 42 mg daily. During this episode of agitation, the patient withdrew consent to continue participation in the study, reporting lack of efficacy of the study medication. The patient was evaluated by the crisis center and transferred to a community hospital for admission. The study medication was discontinued.

Study 303: An interim analysis submitted by the Applicant at the 1-year point in the long-term uncontrolled study indicated that, of 603 patients in the safety population, 24 patients experienced treatment-emergent SAEs. Table 79 lists the treatment-emergent SAEs recorded for patients in Study 303.

Table 79: Listing of treatment-emergent SAEs in Study 303 (all patients receiving lumateperone 42 mg)

Subject ID(b) (6) Preferred Term Start Date (Study Day) Non-cardiac chest 18 Psychotic disorder 59 Psychotic disorder 172 Deep vein thrombosis 226 Suicidal ideation 258 Overdose 18 Schizophrenia 185 Schizophrenia 14 Psychotic disorder 22 97 Alcohol poisoning; Schizophrenia 26 Anemia 219 Pericarditis; Lumbar vertebral fracture; Concussion; 213 Rib fracture; Radius fracture Schizophrenia 18 Hypoesthesia 34 Psychotic disorder 13 Suicidal ideation 47 Tooth abscess 166 Schizophrenia 8 Sinus node dysfunction 22 Delirium 5 Psychotic disorder 19

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(b) (6) Acute pancreatitis; Acute respiratory distress 50 syndrome Cerebrovascular accident 57 Dizziness 329 Seizure 70 Acute respiratory failure 34 Pneumonia pneumococcal 19 Paranoia 37 Psychotic disorder 302 Osteoarthritis 37 Schizophrenia 35 Schizophrenia 57 Source: Reviewer-created from Applicant-submitted Study ITI-007-303 Interim Analysis 3, Table 14.3.2.2.2

The following SAEs were reviewed because of their possible clinical significance, but they do not appear to have been related to study drug:

(b) (6) • Patient , a 39-year-old African American male, was diagnosed with pericarditis, as well as multiple rib fractures and a concussion, following a motor vehicle accident.

(b) (6) • Patient , a 60-year-old Caucasian male, was noted to have sinus bradycardia on screening. He was hospitalized on Study Day 21 after a fall. He was diagnosed with sick sinus syndrome, had a pacemaker inserted, and was discharged from the study.

(b) (6) • Patient , a 29-year-old African American male, presented to an outpatient recovery center on Study Day 30 after reported ingestion of an unknown illicit substance, fell asleep, and could not be awakened. He remained obtunded after receiving intravenous , and urine drug screen was negative. He was hospitalized, diagnosed with acute respiratory failure, intubated, and placed on a ventilator. Chest X-ray showed pneumonia, but blood cultures were negative. By the sixth day of admission, the patient had shown enough improvement to be discharged from the hospital with an oxygen tank. The cause of the patient’s acute respiratory failure was not definitively determined, but was felt to be related to the substance the patient had taken prior to presentation at the recovery center.

(b) (6) • Patient , a 57-year-old African American male, was diagnosed with left leg deep vein thrombophlebitis three weeks after he became immobile following a leg injury.

(b) (6) • Patient , a 58-year-old African American female who had a history of chronic pancreatitis and alcohol abuse, was hospitalized for acute pancreatitis and acute respiratory distress syndrome, both of which improved after placement of a pancreatic drain.

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Three patients had SAEs of suicidal ideation or self-injurious behavior.

(b) (6) • Patient , a 51-year-old Caucasian male who had a previous history of depression and alcohol abuse, was hospitalized after he walked into a liquor store and stated that he wanted to kill himself by running into traffic. He had consumed more than a pint of alcohol prior to this incident. The patient was discharged from the study. The patient’s history of depression and alcohol abuse may have been contributing factors to this incident.

(b) (6) • Patient , a 27-year-old Caucasian female, had a psychiatric hospital admission after stating that she would rather be dead than deal with the abdominal pain she had. No cause for abdominal pain was identified. The patient improved after receiving intramuscular haloperidol and lorazepam, and was discharged from the hospital after three days. The patient continued in the study after discharge. The improvement in symptoms after administration of supplemental antipsychotic medication suggests that the patient’s suicidal ideation may have been related to her underlying psychotic illness.

(b) (6) • Patient a 47-year-old Caucasian female who had a previous history of depression, was hospitalized after she impulsively took her remaining 11 lumateperone tablets after an argument with her partner. She denied suicidal ideation and denied any intent to die, and stated that she took the overdose out of anger with her partner. She had no medical sequelae following the overdose. She was discharged from the study.

Because the nonclinical studies described neuropathological changes in animal species following long-term exposure to lumateperone, we reviewed the treatment-related SAEs related to the neurological system in detail.

Patient (b) (6) : Cerebrovascular Accident

The patient is a 52-year-old African American male who received the first dose of lumateperone (b) (6) (b) (6) (b) on . The last dose of study drug was on . On February (6) , the patient was hospitalized for a stroke. The patient’s sister reported that the patient had an apparent seizure prior to the stroke. Intermittent tonic movements of the right upper extremity and right lower extremity were noted after admission. CT scan of the head showed a (b) (6) right middle cerebral artery infarct. The patient underwent a right hemicraniotomy on to relieve increased intracranial pressure. During the hospitalization he was started on (b) (6) . On , the patient was discharged from the hospital to a rehabilitation facility. The Investigator assessed the stroke as unlikely to be related to the study drug. Previous medical records noted a possible history of seizure disorder. The patient denied any history of alcohol abuse, but a urine drug screen at the investigational site on February 13, 2018 was positive for alcohol. On the day of admission for the stroke, the patient’s serum alcohol level was 218 mg/dL.

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Patient(b) (6) : Delirium

The patient is a 71-year-old African American male who was hospitalized for a sudden onset of delirium four days after the first dose of study drug. He had become increasingly confused, not oriented to time, dressing inappropriately, and making statements that did not make . Urinalysis showed high leukocyte esterase, bacteria, and white blood cells too numerous to count. He was diagnosed with a urinary tract infection. His mental status improved after treatment with antibiotics.

Patient (b) (6) : Dizziness

The patient is a 63-year-old African American female who received the first dose of study drug (b) (6) (b) (6) on . She first experienced dizziness on August 12, 2018. On , she went to the emergency room with complaints of dizziness, loss of appetite, changes in her voice, memory impairment, and visual hallucinations. She was admitted to rule out stroke. At admission, all of the patient’s symptoms were resolved. She appeared to be responding to internal stimuli, but did not appear to be in the midst of an acute psychotic decompensation. Neurological and cardiac examinations did not support a diagnosis of stroke. She was discharged from the hospital after two days. She resumed participation in the study after discharge.

Patient 618024: Hypoesthesia

The patient is a 44-year-old African American female who received the first dose of study (b) (6) (b) (6) medication on . On , the patient experienced facial numbness, perioral numbness, and left shoulder numbness. Neurological and cardiac examinations did not reveal a cause for the numbness. The patient was discharged from the (b) (6) hospital on , and was later discharged from the study. The onset of numbness could raise some concern because of the nonclinical studies indicating signs of peripheral neuropathy in animal species. However, the neurological signs appeared in animal studies after long-term drug exposure, and the patient had received study drug for approximately four weeks. In the 4- to 6-week placebo-controlled trials, the rate of hypoesthesia as an adverse event was 0.2% for patients receiving any dose of lumateperone and 0.5% for patients treated with placebo. A rate that is lower than that for placebo in the short-term studies offers some reassurance that occurrence of this adverse event early in the course of treatment with lumateperone does not have a high degree of clinical significance.

Patient (b) (6) : Possible Seizure Episode

The patient is a 51-year-old African American male, living at a residential housing facility, who (b) (6) (b) (6) received the first dose of investigational drug on . On , the patient woke up his roommate and said that he was having a seizure. The roommate did not witness the seizure. The patient was taken to the emergency room and underwent a

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neurological evaluation, which was negative. The patient reported having a seizure episode in 2005. No seizure activity was witnessed in the emergency room. The event was recorded as a “possible seizure episode” based on the patient’s report. The investigator assessed the incident as unlikely to be related to the study drug. The fact that the patient was fully alert while reporting to the roommate that he was having a seizure, the absence of any seizure activity that could be witnessed by others at the residential facility or by emergency room staff, and the negative neurological assessment all reduce the likelihood that the incident was a true seizure.

Clinical reviewer comment: In the absence of a concurrent control group, these serious adverse events are difficult to interpret; however, to the extent they can be interpreted in the absence of a control group, there is no pattern evident to suggest causality. For a number of these events, such as pneumonia, osteoarthritis, and tooth abscess, there is no reasonably plausible mechanism through which lumateperone appears to be causative. For many of the SAEs, pre- existing or concurrent medical illnesses seem more likely to be causative than lumateperone. The SAEs of psychotic disorder, paranoia, and schizophrenia may have occurred in patients for whom lumateperone was not adequately treating their underlying mental illness. In addition, episodes of exacerbation of psychotic symptoms occur fairly commonly in patients with schizophrenia and could reasonably be expected in the course of observing a population of patients with schizophrenia for a year.

Dropouts and/or Discontinuations Due to Adverse Effects Study 005: Table 80 shows the number of discontinuations of study drug related to treatment- emergent adverse events or lack of efficacy. The adverse events resulting in discontinuations for the patients receiving lumateperone 42 mg were dry mouth and worsening of schizophrenia. The adverse events resulting in discontinuation for the patients receiving lumateperone 84 mg were worsening of schizophrenia and blurred vision. The adverse events resulting in discontinuations for the patients receiving risperidone 4 mg were akathisia in two patients, blood creatine phosphokinase increased in one patient, and anxiety and restlessness in one patient.

Table 80: Study 005: Discontinuations of Study Drug Due to Treatment-Emergent Adverse Event or Lack of Efficacy

Lumateperone Lumateperone Risperidone Placebo 42 mg 84 mg 4 mg (N=84) (N=84) (N=82) (N=85) n (%) n (%) n (%) n (%) Adverse Event 2 (2.4) 2 (2.4) 4 (4.9) 0 Lack of Efficacy 0 1 (1.2) 3 (3.7) 8 (9.4) Source: Reviewer-created

Study 301: Table 81 shows the number of study drug discontinuations related to treatment- emergent adverse events or lack of efficacy. The adverse events resulting in study drug

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discontinuations for the patients receiving lumateperone 28 mg were headache (n=2) and seizure (n=1). The adverse event resulting in discontinuation for the patient receiving lumateperone 42 mg was orthostatic hypotension. The adverse event resulting in discontinuations for the patient receiving placebo was worsening of schizophrenia.

Table 81: Study 301: Discontinuations of Study Drug Due to Treatment-Emergent Adverse Event or Lack of Efficacy Lumateperone Lumateperone Placebo 28 mg 42 mg (N=150) (N=150) (N=150) n (%) n (%) n (%) Adverse Event 3 (2.0) 1 (0.7) 1 (0.7) Lack of Efficacy 11 (7.3) 6 (4.0) 17 (11.3) Source: Reviewer-created

Study 302: Table 82 shows the number of discontinuations of study drug related to treatment- emergent adverse events or lack of efficacy. The adverse events resulting in study drug discontinuations for the patients receiving lumateperone 14 mg were elevated liver function tests (n=2), headache, worsening psychosis, and physical assault. The adverse event resulting in discontinuation for the patients receiving risperidone 4 mg were elevated liver function tests, QT prolongation on ECG, headache, akathisia, dizziness, dystonia, nausea, salivary hypersecretion, axillary pain, and diabetes mellitus. The adverse event resulting in discontinuations for the patient receiving placebo was rhabdomyolysis. There were no discontinuations of study drug related to treatment-emergent adverse events in the lumateperone 42 mg treatment group.

Table 82: Study 302: Discontinuations of Study Drug Associated with Treatment-Emergent Adverse Event or Lack of Efficacy Lumateperone Lumateperone Risperidone Placebo 14 mg 42 mg 4 mg (N=174) (N=174) (N=174) (N=174) n (%) n (%) n (%) n (%) Adverse Event 5 (2.9) 0 10 (5.8) 1 (0.6) Lack of Efficacy 13 (7.5) 11 (6.3) 8 (4.6) 12 (6.9) Source: Reviewer-created

Study 303: An interim analysis submitted by the Applicant at the 1-year point in the long-term study indicated that, of 603 patients in the safety population, 84 patients (13.9%) discontinued study medication because of one or more TEAEs. The TEAEs most commonly resulting in discontinuation of study medication were consistent with worsening of schizophrenia (preferred terms: schizophrenia, psychotic disorder, mania); 32 patients (5.3%) discontinued study medication as a result of one of these adverse events. Other TEAEs resulting in study discontinuation for more than one patient were anxiety, insomnia, suicidal ideation, headache,

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somnolence, dizziness, extrapyramidal disorder, , nausea, vomiting, alcohol poisoning, and fatigue.

Summary of Discontinuation Analyses: We did not identify any clinically meaningful pattern in the treatment-emergent adverse events that resulted in discontinuation of lumateperone in Studies 005, 301, and 302. We note that the frequency of discontinuations for lack of efficacy was higher for the 14 mg and 28 mg doses of lumateperone than for the 42 mg dose, and that the frequency of discontinuations for lack of efficacy in Study 302 was higher for lumateperone 14 mg than for placebo. In all three placebo-controlled studies, the discontinuations due to lack of efficacy were higher in the placebo group than in the lumateperone 42-mg group, which is consistent with the drug having a treatment benefit. In Study 303, the treatment-emergent adverse events leading to discontinuation of open-label lumateperone of highest frequency were consistent with worsening of schizophrenia. It is not uncommon for patients with schizophrenia to experience illness exacerbations over a 1-year period, and it is also possible that many of these patients were not fully adherent to the study medication.

Significant Adverse Events Please refer to Table 83 for a presentation of treatment-emergent adverse events of laboratory finding abnormalities from the three placebo-controlled studies. This tabulation suggests that lumateperone may cause elevations in creatine phosphokinase and hepatic transaminases in some subjects. These elevations did not appear to have any meaningful clinical relevance in the studies, but this information is important to convey in product labeling to inform clinicians that lumateperone has the potential to increase levels of these enzymes. Analysis of laboratory data is discussed in more detail later in this section, and provides a more precise assessment of lumateperone’s potential to cause laboratory abnormalities.

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Table 83: Laboratory Finding Treatment-Emergent Adverse Events Occurring in ≥2 Subjects Receiving Lumateperone in Studies 005, 301, and 302 Placebo LUM 14 mg LUM 28 mg LUM 42 mg LUM 84 mg (N=412) (N=172) (N=150) (N=406) (N=83) Preferred Term n= (%) n= (%) n= (%) n= (%) n= (%) Blood creatine phosphokinase 3 (0.7) 4 (2.3) 3 (2.0) 17 (4.2) 2 (2.4) increased Alanine aminotransferase 2 (0.5) 3 (1.7) 2 (1.3) 7 (1.7) 2 (2.4) increased Aspartate aminotransferase 1 (0.2) 2 (1.2) 1 (0.7) 4 (1.0) 1 (1.2) increased Gamma-glutamyltransferase 2 (0.5) 2 (1.2) 0 4 (1.0) 0 increased Glycosylated hemoglobin 2 (0.5) 1 (0.6) 0 3 (0.7) 0 increased Low density lipoprotein increased 1 (0.2) 1 (0.6) 0 2 (0.5) 0 Blood glucose increased 2 (0.5) 0 1 (0.7) 1 (0.2) 0 Hepatic enzyme increased 0 0 0 2 (0.5) 0 Source: Reviewer created from data in Applicant-submitted ISS, Table 2.2.1.1; LUM = lumateperone

The occurrence of TEAEs that were rated as “severe” was relatively low in Studies 005, 301, and 302. In subjects receiving lumateperone 42 mg, n=4 (1.0%) experienced severe TEAEs, which included dry mouth, paranoid , orthostatic hypotension, and blood creatine phosphokinase increased. In subjects receiving placebo, n=1 (0.2%) experienced a severe TEAE, which was pruritus. No severe TEAEs occurred in more than one subject receiving lumateperone.

Treatment Emergent Adverse Events and Adverse Reactions Table 84, Table 85, and Table 86 display the frequency of TEAE related groupings occurring in at least 2% of patients treated with lumateperone 42 mg and more frequently than in patients treated with placebo in Studies 005, 301, and 302, respectively. The tables present the frequencies of TEAEs for each treatment arm individually, and one column in each table presents the frequency for TEAEs occurring in the combined group of all patients treated with lumateperone. The tables are sorted in descending order of frequency of TEAEs based on the 42 mg lumateperone treatment group.

The frequencies presented are for queries that used customized groupings of preferred terms from the MedDRA, referred to hereafter as “custom MedDRA queries.” Each query consists of one or more related MedDRA terms. Each query is run on the adverse event database to identify adverse events coded with any of the MedDRA terms included in the query. If a patient has multiple adverse events coded to different MedDRA terms that are all part of the same custom MedDRA query, that patient is counted just once in the query result. This approach allows for a meaningful assessment of the frequency of symptoms that have been coded differently in the adverse event database but may represent a similar clinical concept. A listing

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of MedDRA terms included in each of the customized MedDRA queries used in this analysis is presented in the Appendix in Section 14.6.

Table 84: Study 005: Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients Treated with Lumateperone and More Frequently than in Patients Treated with Placebo, Safety Population

Placebo 42 mg 84 mg 42 & 84 Risperidone Custom MedDRA Query (N=85) (N=84) (N=83) (N=167) (N=82) (%) (%) (%) (%) (%) Headache 12.9 20.2 18.1 19.2 8.5 Somnolence, fatigue, sedation 14.1 17.9 33.7 25.7 22.0 CPK increased 1.2 8.3 3.6 6.0 12.2 Abnormal GOT, GPT, GGTP, liver function tests 1.2 8.3 2.4 5.4 3.7 Nausea, vomiting 2.4 8.3 13.3 10.8 6.1 Abdominal pain, distension, bloating, spasm, IBS, megacolon 5.9 7.1 7.2 7.2 4.9 Infection, all 4.7 7.1 4.8 6.0 4.9 Fall, dizziness, balance disorder 1.2 6.0 9.6 7.8 2.4 Dry mouth, dry lips, thirst 2.4 4.8 9.6 7.2 6.1 Allergic reaction, hypersensitivity 0.0 3.6 2.4 3.0 1.2 Dermatitis 1.2 3.6 0.0 1.8 1.2 Abscess, boil, furuncle 1.2 2.4 1.2 1.8 0.0 Anxiety, nervousness, panic attacks 0.0 2.4 0.0 1.2 1.2 Arrhythmia 1.2 2.4 4.8 3.6 11.0 Skin irritation 0.0 2.4 0.0 1.2 1.2 Tachycardia 1.2 2.4 4.8 3.6 11.0 URI, cold, rhinitis, upper respiratory tract infection, flu-like illness 1.2 2.4 1.2 1.8 3.7 Source: Reviewer-created

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Table 85: Study 301: Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients Treated with Lumateperone and More Frequently than in Patients Treated with Placebo, Safety Population

Placebo 28 mg 42 mg 28 & 42 Custom MedDRA Query (N=149) (N=150) (N=150) (N=300) (%) (%) (%) (%) Somnolence, fatigue, sedation 12.1 25.3 33.3 29.3 Headache 15.4 18.0 20.7 19.3 Nausea, vomiting 10.7 7.3 12.7 10.0 Abdominal pain, distension, bloating, spasm, IBS, megacolon 10.1 8.7 12.0 10.3 EPS, potential EPS, tardive dyskinesia, akathisia 8.1 6.0 10.0 8.0 Constipation 2.7 4.0 8.0 6.0 Dry mouth, dry lips, thirst 4.7 6.0 8.0 7.0 Fall, dizziness, balance disorder 4.0 6.7 7.3 7.0 Restlessness, agitation, hyperkinesia, akathisia 4.7 3.3 7.3 5.3 Akathisia, restlessness 4.7 3.3 6.7 5.0 CPK increased 0.7 2.7 6.7 4.7 Back pain 2.7 3.3 4.7 4.0 Anorexia, decreased appetite 0.7 2.0 4.0 3.0 URI, cold, rhinitis, upper respiratory tract infection, flu-like illness 3.4 6.0 4.0 5.0 Diarrhea, colitis, enteritis, proctitis, gastroenteritis, c- diff 2.0 5.3 3.3 4.3 Abnormal GOT, GPT, GGTP, liver function tests 2.0 2.0 3.3 2.7 Flatulence 0.7 2.7 2.7 2.7 , eruption, dermatitis 0.7 0.7 2.7 1.7 Arthralgia, arthritis, arthrosis 0.0 2.0 2.0 2.0 Cough 0.7 0.7 2.0 1.3 Toothache 0.7 4.0 2.0 3.0 UTI 0.7 1.3 2.0 1.7 Source: Reviewer-created

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Table 86: Study 302: Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients Treated with Lumateperone and More Frequently than in Patients Treated with Placebo, Safety Population

Custom MedDRA Query Placebo 14 mg 42 mg 14 & 42 Risperidone (N=174) (N=174) (N=174) (N=348) (N=173) (%) (%) (%) (%) (%) Somnolence, fatigue, sedation 9.8 17.2 23.6 20.4 26.0 Headache 17.2 9.2 21.3 15.2 20.8 Infection, all 12.1 9.2 13.2 11.2 10.4 Nausea, vomiting 5.2 5.2 10.3 7.8 11.0 EPS, potential EPS, tardive dyskinesia, akathisia 6.9 4.0 8.6 6.3 10.4 Insomnia, sleep disturbance, abnormal 1.7 5.2 6.9 6.0 5.2 URI, cold, rhinitis, upper respiratory tract infection, flu-like illness 5.7 4.6 6.3 5.5 4.6 CPK increased 2.3 3.4 5.2 4.3 2.3 Dry mouth, dry lips, thirst 0.0 2.9 5.2 4.0 4.0 Fall, dizziness, balance disorder 2.3 3.4 5.2 4.3 4.6 Diarrhea, colitis, enteritis, proctitis, gastroenteritis, c-diff 3.4 1.7 4.0 2.9 1.7 Insomnia 1.7 4.0 3.4 3.7 1.7 Reflux, GERD 1.1 0.6 3.4 2.0 0.6 UTI 2.9 1.7 3.4 2.6 2.3 Infection, fungal 0.6 1.7 2.9 2.3 0.0 Cramps, muscle spasm 1.1 0.6 2.3 1.4 0.6 Neck pain 1.7 0.0 2.3 1.1 0.6 Oropharyngeal pain 1.1 2.9 2.3 2.6 1.7 Source: Reviewer-created

Summary of TEAEs: The TEAEs across all 3 studies are summarized in Table 87.

Based on these analyses, treatment-emergent adverse events that will be listed in Section 6 of the Package Insert include CPK increased, dry mouth, fatigue, somnolence/sedation, dizziness, transaminases increased, nausea, vomiting, and decreased appetite (the latter is not in Table 85 because it is a single preferred term that was not included in a query).

TEAEs of elevated liver enzymes were noted in Study 005 and Study 301. Laboratory findings related to these TEAEs are discussed in the following section and in Section 8.2.8, where lab results for the long-term, open-label study are discussed.

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Table 87: Studies 005, 301, and 302: Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients Treated with Lumateperone 42 mg and More Frequently than in Patients Treated with Placebo, Safety Population

Lumaterperone Placebo all drug Risp RR 14 mg 28 mg 42 mg n 172 150 406 412 728 255 CPK increased 2.3% 2% 4.4% 1% 3.5% 4.3% 4.4 Dry mouth 2.3% 6% 5.9% 2.2% 5.5% 4.7% 2.7 Fatigue 0% 5.3% 3% 1.2% 2.8% 1.2% 2.5 Somnolence, fatigue, sedation 17.4% 25.3% 25.6% 10.7% 24.7% 24.3% 2.4 Fall, dizziness, balance disorder 3.5% 5.3% 5.9% 2.7% 5.7% 3.5% 2.2 Dizziness 4.1% 6.7% 5.4% 2.7% 6.2% 3.5% 2.0 Transaminases increased 2.3% 2% 3% 1.5% 2.6% 3.5% 2.0 Nausea 4.1% 4.7% 9.4% 4.9% 7.4% 7.5% 1.9 Nausea, vomiting 4.7% 7.3% 10.1% 5.8% 8.8% 9.4% 1.7 Vomiting 0.6% 3.3% 2.7% 1.9% 2.6% 3.1% 1.4 Headache 9.3% 16% 20.2% 14.3% 16.9% 16.9% 1.4

Laboratory Findings and Metabolic Effects For the three placebo-controlled studies, we performed exploratory analysis of variance (ANOVA) tests to assess for change from baseline in the mean values for the following parameters: glucose, hemoglobin A1c, insulin, total cholesterol, high-density lipoproteins, low- density lipoproteins, triglycerides, prolactin, alanine aminotransferase, aspartate aminotransferase, creatine kinase, and body weight. These laboratory assessments (and body weight) were selected to explore the metabolic safety profile of lumateperone. For each parameter, analyses were performed only for patients having both baseline and end-of- treatment values, with no imputation of missing values. In cases where the ANOVA analysis indicated a notable difference among treatment groups, we identified the treatment groups with the highest magnitude of difference from each other. The analyses are based on data submitted by the Applicant for the three individual studies and not the dataset that pools the three studies together.

Labs from Study 005 with Notable Differences Among Treatment Groups

Note that for Study 005, hemoglobin A1c values were measured only at baseline and not at the end of treatment; therefore, data on mean change from baseline are not available.

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Table 88: Study 005: Total Cholesterol, Mean Change from Baseline to End of Treatment

Placebo Lumateperone Lumateperone Risperidone 42 mg 84 mg 4 mg N 65 67 69 67 Mean Change, mmol/L 0.05 -0.04 -0.06 0.26 SD 0.63 0.72 0.62 0.63 SE 0.08 0.09 0.08 0.08 95% CI [-0.10, 0.21] [-0.22, 0.13] [-0.21, 0.08] [0.10, 0.41] Source: Reviewer-created

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 84 mg group.

Table 89: Study 005: Glucose, Mean Change from Baseline to End of Treatment Placebo Lumateperone Lumateperone Risperidone 42 mg 84 mg 4 mg N 65 67 69 67 Mean Change, mmol/L 0.11 0.02 0.15 0.54 SD 1.02 1.01 0.71 1.19 SE 0.13 0.12 0.09 0.15 95% CI [-0.13, 0.36] [-0.22, 0.27] [-0.01, 0.32] [0.25, 0.83] Source: Reviewer-created

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 42 mg group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 42 mg group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 42 mg group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 42 mg group.

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Table 90: Study 005: Prolactin, Mean Change from Baseline to End of Treatment

Placebo Lumateperone Lumateperone Risperidone 42 mg 84 mg 4 mg N 64 67 67 67 Mean Change, mcIU/mL -23.4 6.12 -59.3 689.0 SD 299.0 186.0 180.0 901.0 SE 37.4 22.8 22.1 110.0 95% CI [-97.3, 50.4] [-38.9, 51.2] [-103, -15.6] [472, 907] Source: Reviewer-created

In comparisons between all pairs of treatment groups, the numerically highest magnitudes of differences in mean change were between the risperidone 4 mg group and the lumateperone 84 mg group, the risperidone 4 mg group and the lumateperone 42 mg group, and the risperidone 4 mg group and the placebo group.

Table 91: Study 005: Triglycerides, Mean Change from Baseline to End of Treatment Placebo Lumateperone Lumateperone Risperidone 42 mg 84 mg 4 mg N 65 67 69 67 Mean Change, mmol/L 0.04 0.01 -0.18 0.18 SD 0.65 0.42 0.63 0.72 SE 0.08 0.05 0.08 0.09 95% CI [-0.12, 0.20] [-0.09, 0.11] [-0.33, -0.03] [0.01, 0.35] Source: Reviewer-created

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 84 mg group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 84 mg group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 84 mg group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 84 mg group.

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Table 92: Study 005: Body Weight, Mean Change from Baseline to End of Treatment Placebo Lumateperone Lumateperone Risperidone 42 mg 84 mg 4 mg N 67 69 69 68 Mean Change, kg 0.83 2.01 1.93 3.01 SD 3.46 3.10 3.35 3.69 SE 0.42 0.37 0.40 0.45 95% CI [-0.00, 1.67] [1.27, 2.75] [1.13, 2.73] [2.13, 3.90] Source: Reviewer-created

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the placebo group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the placebo group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the placebo group.

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the placebo group. Labs from Study 301 with Notable Differences Among Treatment Groups

Table 93: Study 301: Hemoglobin A1c. Mean Change from Baseline to End of Treatment Placebo Lumateperone Lumateperone 28 mg 42 mg N 124 137 141 Mean Change, % 0.04 0.10 0.00 SD 0.26 0.26 0.30 SE 0.02 0.02 0.03 95% CI [-0.00, 0.09] [0.06, 0.14] [-0.05, 0.05] Source: Reviewer-created

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the lumateperone 28 mg group and the lumateperone 42 mg group.

Labs from Study 302 with Notable Differences Among Treatment Groups

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Table 94: Study 302: Hemoglobin A1c. Mean Change from Baseline to End of Treatment Placebo Lumateperone Lumateperone Risperidone 14 mg 42 mg 4 mg N 161 137 144 137 Mean Change, % 0.15 0.18 0.09 0.27 SD 0.33 0.29 0.32 0.67 SE 0.03 0.02 0.03 0.06 95% CI [0.10, 0.20] [0.13, 0.23] [0.04, 0.14] [0.16, 0.38] Source: Reviewer-created

In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 42 mg group.

Table 95: Study 302: Prolactin, Mean Change from Baseline to End of Treatment Placebo Lumateperone Lumateperone Risperidone 14 mg 42 mg 4 mg N 160 139 147 138 Mean Change, mIU/mL -2.6 -15.8 -54.8 745 SD 150 180 231 839 SE 11.9 15.2 19.0 71.4 95% CI [-26.0, 20. 8] [-45.8, 14.2] [-92.2, -17.4] [605, 886] Source: Reviewer-created

In comparisons between all pairs of treatment groups, the numerically highest magnitudes of differences in mean change were between the risperidone 4 mg group and the lumateperone 42 mg group, the risperidone 4 mg group and the lumateperone 14 mg group, and the risperidone 4 mg group and the placebo group.

Table 96: Study 302: Triglycerides, Mean Change from Baseline to End of Treatment Placebo Lumateperone Lumateperone Risperidone 14 mg 42 mg 4 mg N 162 137 147 139 Mean Change, mmol/L 0.09 0.04 -0.07 0.26 SD 0.64 0.70 0.70 0.77 SE 0.05 0.06 0.06 0.07 95% CI [-0.01, 0.19] [-0.08, 0.16] [-0.18, 0.05] [0.13, 0.39] Source: Reviewer-created

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In comparisons between all pairs of treatment groups, the numerically highest magnitude of difference in mean change was between the risperidone 4 mg group and the lumateperone 42 mg group.

Summary of laboratory findings and metabolic effects: The review of metabolic laboratory studies and body weight measurements does not reveal a clear pattern of adverse metabolic effects for lumateperone. Most of the comparisons in the three studies showed no clear difference in mean changes from baseline among the treatment arms. When differences did occur, the highest magnitude of difference was between the risperidone 4 mg arm and one or more of the other treatment arms. Study 301 did show a mean change in hemoglobin A1c that was higher for lumateperone 28 mg than for lumateperone 42 mg. However, the mean change for the placebo group was intermediate between the mean change for the 28 mg group and the 42 mg group, so neither group was notably different from the placebo group. In addition to the above analyses, we inspected the Applicant’s analyses of shifts in change from normal to abnormal lab values for the three placebo-controlled studies and for the long-term study. These analyses did not reveal notable safety issues for lumateperone in comparison to risperidone (data not shown).

Vital Signs

For the three 4- to 6-week placebo-controlled studies, results for systolic blood pressure, diastolic blood pressure, pulse rate, and respiratory rate were reviewed to assess mean changes from baseline to end of treatment as well as the proportion of patients who had at least one post-baseline treatment-emergent markedly abnormal vital sign measurement, i.e.,

• Systolic blood pressure <95 mmHg and change from baseline ≤20 mmHg, or >140 mmHg and change from baseline ≥20 mmHg • Diastolic blood pressure <50 mmHg and change from baseline ≤10 mmHg, or >90 mmHg and change from baseline ≥10 mmHg • Pulse rate <50 bpm and change from baseline ≤15 bpm, or >100 bpm and change from baseline ≥15 bpm • Body weight percent change from baseline ≤7.0% or ≥7.0%

No pattern of clinically meaningful mean changes from baseline in laboratory values were identified (data not shown). The number and percentage of subjects with markedly abnormal vital sign values at any post-baseline measurement are presented in Table 97 for selected vital sign parameters that suggested a possible drug-related effect.

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Table 97: Subjects with Markedly Abnormal Post-Baseline Vital Sign Values, Studies 005, 301, and 302 Placebo LUM 14 mg LUM 28 mg LUM 42 mg LUM 84 Risperidone 4 mg (N=412) (N=172) (N=150) (N=406) mg (N=83) (N=255) n= (%) n= (%) n= (%) n= (%) n= (%) n= (%) Systolic blood pressure >140 mmHg and ≥20 mmHg increase 18 (4.4) 9 (5.2) 15 (10.0) 29 (7.1) 4 (4.8) 20 (7.8) from baseline Diastolic blood pressure >90 mmHg and ≥10 mmHg increase 31 (7.5) 19 (11.0) 14 (9.3) 39 (9.6) 11 (13.3) 27 (16.6) from baseline Pulse <50 bpm and change 0 0 0 4 (1.0) 2 (2.4) 1 (0.4) from baseline ≤-15 bpm Pulse >100 bpm and change 16 (3.9) 4 (2.3) 6 (4.0) 23 (5.7) 3 (2.4) 19 (7.5) from baseline ≥15 bpm Weight ≥7% decrease 7 (1.8) 0 1 (0.7) 4 (1.0) 1 (1.3) 6 (2.5) Weight ≥7% increase 35 (9.2) 26 (15.6) 6 (4.3) 35 (9.1) 12 (15.4) 52 (22.0) Source: Reviewer-created using data from Applicant-submitted ISS, Table 8-3

Clinical/Statistical reviewer comment: Although there were no trends suggestive of a lumateperone effect at the mean group level, assessment of the frequency of subjects with at least one post-baseline markedly abnormal value suggest that lumateperone may have the potential to increase blood pressure and affect pulse rate (increase or decrease) in a small proportion of subjects. The potential effects on vital sign parameters with lumateperone appeared less prominent than the active comparator risperidone.

Electrocardiograms

For the three 4- to 6-week placebo-controlled studies, review of ECG results did not reveal any clinically meaningful pattern of changes in heart rate, PR interval, RR interval, QT interval, or QRS duration. Patients treated with lumateperone 84 mg in Study 005 showed a lower mean change from baseline in RR interval and higher mean changes from baseline in QTcB and QTcF compared to placebo. However, the lumateperone 84-mg dose will not be approved for marketing because efficacy was not demonstrated for this dose.

QT The Applicant has completed a thorough QT study (Study ITI-007-017) to characterize the effects of lumateperone treatment on the QTc interval. In Study ITI-007-017, lumateperone was administered to patients with schizophrenia at the planned therapeutic dose (42 mg daily) and a supratherapeutic dose (126 mg daily), and the change in QTc interval was compared to subjects treated with the positive control drug moxifloxacin. Analysis by the FDA QT Interdisciplinary Review Team (QT-IRT) resulted in a calculated placebo-corrected change from baseline QTcF of 4.9 msec for the 42 mg dose and 15.8 msec for the 126 mg dose. QT-IRT suggested that the risk of QTc prolongation in the high-exposure scenarios for parent and metabolite, i.e. hepatic impairment or CYP3A4 inhibitor, should be described in the Warnings and Precautions section of the product label, with a requirement for ECG monitoring in those

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situations. However, the Division of Psychiatry is recommending that lumateperone should not be used in the context of hepatic impairment or concomitantly with CYP3A4 inhibitors. Because lumateperone will not be recommended for use in high-exposure scenarios, the product label will not include a warning for QTc prolongation. Data on the results of the thorough QT study will be included in the section of the product label.

Immunogenicity The Applicant did not submit immunogenicity data with this application.

Analysis of Submission-Specific Safety Issues

Extrapyramidal Symptoms (EPS)

EPS, which include symptoms such as akathisia, dystonia, and parkinsonism, are relatively common adverse reactions to antipsychotic drugs. The Applicant assessed EPS using measures including the BARS, the AIMS, and the SAS; please refer to Section 7.3 for additional information about these measures. There were no meaningful changes from baseline on the BARS, AIMS, or SAS scales in any treatment arm (placebo, lumateperone, or risperidone) in the three placebo-controlled Studies 005, 301, and 302 (data not shown). The Applicant also performed analyses on treatment-emergent adverse events in the narrow Extrapyramidal Symptoms standardized MedDRA query (SMQ), which includes preferred terms that are considered to be specific for EPS (Table 98). In addition to the narrow query, the Applicant performed analyses in the broad Extrapyramidal Symptoms SMQ, which includes a larger list of preferred terms that are considered to be sensitive but less specific for EPS (data not shown).

Table 98: Subjects with Treatment-Emergent Extrapyramidal Symptoms (Studies 005, 301, 302) Placebo LUM 14 mg LUM 28 mg LUM 42 mg LUM 84 Risperidone 4 mg (N=412) (N=172) (N=150) (N=406) mg (N=83) (N=255) n= (%) n= (%) n= (%) n= (%) n= (%) n= (%) Subjects with at least 1 TEAE within the Extrapyramidal 13 (3.2) 1 (0.6) 4 (2.7) 12 (3.0) 4 (4.8) 16 (6.3) Symptoms SMQ (narrow) Akathisia 12 (2.9) 1 (0.6) 2 (1.3) 8 (2.0) 2 (2.4) 12 (4.7) Dyskinesia 1 (0.2) 0 2 (1.3) 0 1 (1.2) 0 Dystonia 1 (0.2) 0 0 2 (0.5) 1 (1.2) 5 (2.0) Tardive Dyskinesia 0 0 0 2 (0.5) 0 0 Source: Reviewer-created using data from Applicant-submitted ISS, Table 2.9.1.1; LUM=lumateperone

In the 1-year uncontrolled Study 303, one patient (0.2%) was reported to experience treatment-emergent tardive dyskinesia in association with lumateperone 42 mg.

Clinical reviewer comment: Based on analyses of changes in measures designed to assess EPS and the frequency of TEAEs representing EPS, lumateperone did not appear to have a significant risk for causing EPS as compared to placebo. The active comparator risperidone, which is known to have EPS liability, was associated with a higher frequency of cases of akathisia and dystonia 237 Version date: October 12, 2018

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than placebo. There were two subjects receiving lumateperone 42 mg who were reported to have tardive dyskinesia in the 6-week Study 302. Tardive dyskinesia, by definition, is a late- emerging EPS that occurs in association with long-term antipsychotic treatment (estimated annual incidence with continuous exposure to an atypical antipsychotic: 5-6%; 5-year cumulative risk: 25% (Tarsy and Baldessarini 2006)). It would be highly unlikely for a new antipsychotic to cause tardive dyskinesia within the first 6 weeks of treatment. It is most likely that the tardive dyskinesia cases were withdrawal dyskinesias, which present as tardive dyskinesia on examination and can occur in patients who change antipsychotics or discontinue long-term antipsychotic treatment (Goel and Ondo 2017).

Analyses for Human Clinical Correlates of Toxicities Observed in Nonclinical Studies

Nonclinical studies revealed cardiomyopathy, neuropathy, and retinal degeneration in animal species (see Section 5), which are thought to be related to aniline metabolite exposure and accumulation of pigmented material in tissues.

Cardiomyopathy Data from the long-term study (Study 303) were reviewed to search for evidence for cardiomyopathy in humans. This review was complicated by the fact that symptoms of cardiomyopathy, such shortness of breath, , fatigue, chest discomfort, and dizziness, are not specific to cardiomyopathy and occur in a wide range of medical conditions. Symptoms of heart failure secondary to drug-induced cardiomyopathy are not easily distinguishable from symptoms of heart failure secondary to other medical causes. Furthermore, patients with schizophrenia have an increased risk for cardiovascular illness, including heart failure, compared to the general population, and this can make it difficult to ascertain whether the development of cardiomyopathy in patients with schizophrenia is drug-related.

A search of the adverse event database for the term “cardiomyopathy” yielded no results. Search of the physical exam database for patients who had normal cardiovascular examinations at baseline yielded three patients (0.5%) who had treatment-emergent abnormal cardiac findings on physical exam at later study visits. The findings were arrhythmia, bradycardia, and systolic ejection murmur. Because cardiomyopathy may present with breathing problems, a similar search of the physical exam database for patients who had normal pulmonary examinations at baseline was conducted. Ten patients (1.7%) were identified who had treatment-emergent abnormal lung findings on physical exam. The most frequent new findings were wheezing (six patients) and cough (three patients). Both the new heart findings and the new lung findings are nonspecific and cannot necessarily be attributed to cardiomyopathy.

Peripheral Neuropathy or Retinal Degeneration Data from the long-term study (Study 303) were reviewed to search for evidence of peripheral neuropathy or retinal degeneration.

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Notably, the documentation of neurological physical findings in Study 303 is based on neurological exams conducted at baseline, one month, and every ten weeks. The exams were conducted by study clinical staff as part of a general physical examination and did not include specialized neurological assessments for neuropathy such as nerve conduction studies.

A search of the adverse event database for the term “neuropathy” yielded one patient with onset of diabetic peripheral neuropathy several years prior to the patient’s entry into the study. A search of the physical exam database revealed eleven patients with treatment-emergent abnormal neurological exams. There was no discernable pattern in the types of abnormalities reported. We also searched the concomitant medications database for “neuropathy” or “peripheral neuropathy,” as the indication for new prescriptions initiated during the study. There were no new prescriptions for which either term appeared as the indication. We assessed specifically for new prescriptions for and , two medications commonly prescribed for patients with peripheral neuropathy. There were no new prescriptions for pregabalin. There were three new prescriptions for gabapentin, but the indications for these prescriptions were anxiety and mood stabilization.

In Study 303, ophthalmologic exams were conducted at baseline and every ten weeks. A search of the physical examination database revealed four subjects with treatment-emergent abnormal retinal exams, with retinal degeneration reported for one subject. The only visualization of the retina in the physical assessments conducted in the study was a funduscopic exam, although the ophthalmological examinations were not optimal for detecting retinal degeneration (e.g., Optical Coherence Tomography (OCT), best corrected distance visual acuity, and threshold visual field examinations would have been ideal).

Clinical reviewer comment: Review of adverse events, concomitant medication starts, and physical examination findings during 1-year of lumateperone exposure in Study 303 did not reveal any signals suggesting that humans experienced safety findings consistent with those seen in animal studies (i.e., cardiomyopathy, neuropathy, or retinal degeneration). A limitation of these analyses is that the safety assessments in Study 303 did not include special tests that would have been implemented for optimal detection of such safety findings. However, additional data provided by the Applicant provides reasonable assurance that the toxicities observed in the animal studies will not be relevant to humans, because humans are not expected to be exposed to quantifiable levels of aniline metabolites that are linked to non- human toxicities. Detailed analysis of these issues is presented in Section 5, Nonclinical Pharmacology/Toxicology.

Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability

COA analyses related to safety and tolerability were not performed in the course of this review.

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Safety Analyses by Demographic Subgroups

For each of the three placebo-controlled trials, the percentage of patients of African descent ranged from approximately 70% to 80%, and the percentage of male patients ranged from approximately 75% to 85%. The maximum age was 55 for Study 005 and 60 for Studies 301 and 302. None of the studies enrolled patients over the age of 65. Safety analyses according to demographic subgroups did not reveal any differences meaningful for presentation.

Specific Safety Studies/Clinical Trials

Study ITI-007-303: “An Open-Label, Multi-Center Trial to Assess the Safety and Effectiveness of ITI-007 in Patients with Schizophrenia”

The primary objective of this study is to determine the safety of lumateperone administered once daily for up to one year in patients with schizophrenia. In this study, patients with a diagnosis of schizophrenia and stable symptoms, as evidenced by the absence of any hospitalizations for a psychiatric illness for the previous three months, were treated with lumateperone 42 mg daily. This study was still ongoing at the time of this review. The Applicant submitted a 120-Day Safety Update on January 25, 2019. Safety analyses related to this study are based on the data submitted with this update. Please refer to Table 99 for the schedule of assessments for Study 303.

Table 99: Study 303: Schedule of Assessments BL/ BL a a V23 V24 Visit Screen V1 a Enroll V5 V6 V7 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 e V2 a /ET SFU V3 Up to 28 days within a a 8 15 25 50 75 100 125 150 175 200 225 250 275 300 325 350 368 382 Study Day Study Day -1 1 +/-2 +/-2 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 1

X

Informed Consent

Medical History (Including Current Schizophrenia X Diagnosis by DSM-5) and Demographics DupCheck X Inclusion / Exclusion Criteria X X Review Modified Physical Assessment X X X X X X X X (including Height b at Screening) Body Weight X X X X X X X X X X X X X X X X X X X X Drug and Alcohol X X X X X X X X X X X X X X X X X X X X Screen Urine Pregnancy X X X X X X X X X X X X X X X X X X X X Test

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Clinical b X X X X X X X X X X X X X X X Laboratories b PK Sample X X X X X X X X X X X X X X X X X X X Single 12-Lead b X X X X X X X X X X X X X X X X X X X X ECG b Vital Signs X X X X X X X X X X X X X X X X X X X X c Ophthalmic Exam X X X X X X PANSS X X X X X X CGI-S X X X X X X X X X X X X X X X X X X X X PSP X X X X X X CDSS X X X X X X WHO-5 X X X SAS X X X X X X X X X X X X X X X BARS X X X X X X X X X X X X X X X AIMS X X X X X X X X X X X X X X X C-SSRS X X X X X X X X X X X X X X X X X X X X Adverse Events X X X X X X X X X X X X X X X X X X X X X Concomitant X X X X X X X X X X X X X X X X X X X X X Medications Issue Treatment Card X X X X X X X X X X X X X X X Start Standard of Care Xd BL = Baseline; ET = Early Termination; SFU = Safety Follow Up. a) Inpatient, check-in and check-out procedures are not applicable for the current version of the protocol. For those patients participating on an outpatient basis, BL assessments can be completed on Day -1 or Day 1 before issuing of treatment card; for these patients Visit 2 and Visit 3 can be performed on the same date for the convenience of the patient or on two visits to reduce the burden of the number of assessments on a given day. Visit 4 (formerly corresponding to Day 4) and Visit 8 and 9 (formerly corresponding to Day 42 and Day 56) will not be used in the current version of the protocol, but numbering was kept so that numbering of subsequent visits will be consistent across protocol versions. b) A single 12-lead ECGs will be performed at each visit. Each ECG will be performed after patients have been supine for at least 10 minutes. An irregular ECG result can prompt a repeat measure at the same visit. ECG’s should be collected before vital signs assessments and vital signs assessments should be collected before any needle sticks for PK blood sample collection or clinical laboratory sample collection; clinical laboratory assessments will include hematology, serum chemistry and urinalysis; vital signs should be collected after at least 10 min supine with 3-positional vital signs measured only in response to an adverse event, including but not limited to dizziness or lightheadedness; height only needs to be collected at screening; clinical laboratory assessments should be collected after at least a 10-h fast when possible (especially for serum chemistry, though urine can be collected at any time during the study visit; if fasting labs are not possible during a visit including the screening visit, out of range values should be repeated under fasted conditions at the next visit or at an unscheduled visit at the discretion of the Investigator). c) Ophthalmic exam will allow for scheduling with specialist with a +/- 7 day window. d) Standard of care medication can be started following the last study procedure that has been completed. e) Early termination: for patients who discontinue the study early, efforts should be made to conduct all procedures scheduled for the last day of study treatment (V22/ET). Source: ITI-007-303 Clinical Study Protocol, Table 5-1, pages 40-42.

Changes in metabolic labs are known to be a safety risk of many atypical antipsychotic agents. In reviewing the adverse events from the three placebo-controlled trials of lumateperone, we noted that increase in creatine phosphokinase was reported at a rate higher than placebo and higher than 5%. For these reasons, we selected a collection of metabolic labs and enzymes for analysis in the long-term-exposure study. The labs selected for analysis were glucose, insulin, hemoglobin A1c, low-density lipoproteins (LDL), total cholesterol, triglycerides, creatine phosphokinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST),

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gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH).

Table 100 summarizes the changes in lab values for metabolic labs and enzymes for patients participating in Study 303. For each lab test, we present the number of patients (n) for whom we could retrieve both a baseline value and at least one post-treatment value. For this table, a high value is defined as any value higher than the upper limit of the normal range. We calculated the mean changes from baseline to the value at the last visit recorded for the patient, the mean changes from baseline to the maximal value recorded for the patient, and the percentages of patients with shifts from normal to high, from high to normal, and from high to high, with those three shifts assessed both from baseline to the last recorded visit and from baseline to the maximal recorded value.

Table 100: Study 303: Change in Lab Values Following Long-Term Exposure to Lumateperone TEST NORMAL UNITS N* MEAN % NORMAL % HIGH % HIGH MEAN % NORMAL % HIGH TO % HIGH TO RANGE CHANGE, TO HIGH, TO TO HIGH, CHANGE, TO HIGH, NORMAL, HIGH, BASELINE BASELINE NORMAL, BASELINE BASELINE BASELINE BASELINE BASELINE TO LAST TO LAST BASELINE TO LAST TO MAX TO MAX TO MAX TO MAX VISIT VISIT TO LAST VISIT VALUE VALUE VALUE VALUE VISIT

GLUC (3 33 - 6.38) mmol/L 580 0.22 9% 5% 3% 1.19 28% 1% 7%

INSULIN (18 0 - 173.0) pmol/L 594 23.12 13% 10% 11% 176.38 36% 3% 18%

HBA1C (4.0 - 6.0) % 553 0.02 5% 6% 12% 0.13 9% 3% 15%

HDL (1 04 - 1.55) mmol/L 595 0 8% 8% 19% 0.21 18% 2% 25%

LDL (1.3 - 4.14) mmol/L 593 -0.14 2% 4% 2% 0.42 7% 1% 4%

CHOL (3 24 - 5.18) mmol/L 595 -0.14 6% 12% 13% 0.48 21% 2% 23%

TRIG (0 51 - 2.26) mmol/L 595 0.01 6% 6% 6% 0.61 18% 3% 9%

CK (24 0 - 169.0) U/L 595 -2.25 12% 11% 34% 219.75 29% 2% 43%

ALT (10.0 - 33.0) U/L 595 0.88 4% 6% 5% 11.22 17% 3% 8%

AST (10.0 - 36.0) U/L 595 0.17 4% 3% 1% 12.55 16% 1% 3%

GGT (5.0 - 32.0) U/L 595 0.67 6% 6% 20% 11.71 15% 1% 25%

LDH (135.0 - 330.0) U/L 595 3.84 0% 0% 0% 37.68 3% 0% 0% *N = number of patients with both a baseline value and a last recorded value for this lab test. Source: generated by clinical reviewer.

The mean changes from baseline to last visit were small for all labs examined. For glucose, insulin, and CK, the percentage of patients with a shift from normal to high from baseline to the last visit is balanced by a similar percentage of patients with a shift from high to normal from baseline to the last visit. We noted that the mean change from baseline to the maximal recorded value were relatively high for insulin and CK. The percentage of patients with shifts from normal to high from baseline to the maximal recorded value were 31%, 36%, 20%, and 30% for glucose, insulin, total cholesterol, and CK. However, examination of the percentages of shifts in lab values from normal to high did not provide a clear picture of whether the shifts represented gradually rising values or transient elevations.

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presented in a series of figures below. To facilitate readability, we made decisions about which patients to include in each plot. Each plot is followed by text describing the criteria for selecting patients for that plot. We selected patients who had at least some abnormal lab values for the lab test being plotted, so the large number of patients with normal lab values for the duration of the study are omitted for clarity. The threshold for identifying abnormal lab values was a value above the upper limit of normal for glucose, insulin, hemoglobin A1c, HDL, cholesterol, triglycerides, and LDH, and a value three times the upper limit of normal for CPK, ALT, AST, and GGT. Because long gaps in time between study visits would make it difficult to follow patterns of change in lab values, we selected patients who attended at least 25% of the scheduled study visits and who had no consecutive gaps of more than ten visits between lab draws. Finally, we focused on patients who had at least one period of the lab value increasing over three to five consecutive study visits.

If a patient did not have a lab value recorded for a visit, the lab value for the previous visit was imputed for the missing visit. This allows each line plot to be a continuous line with no breaks. Horizontal line segments parallel to the x-axis typically represent missing lab values carried forward from a previous visit rather than labs that retained the same exact value over multiple visits. A line that stops prior to the last visit indicates that the patient either was discontinued from the study or had not completed an entire year of treatment at the time of submission of the 120-Day Safety Update. The plots were generated by the clinical reviewer using the Python programming language.

Conclusions:

Visual inspection of the plots did not reveal a pattern of continuously rising values for any of the lab tests analyzed. Periods of fairly consistently rising lab values did occur for hemoglobin A1c for three patients and for glucose, triglycerides, LDL, CK, AST, and GGT for one patient each. These periods of continuously rising lab values were uncommon and did not appear to reflect a clinically significant pattern. More commonly, elevations in metabolic labs and enzymes were transient. We hypothesize that the elevated values that did occur may be related to factors independent of the use of the study drug, such as concomitant medical illnesses, adjustments in concomitant medications, dietary changes, and changes in levels of physical activity.

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Figure 23: Study 303: Serum Glucose Results

Total number of patients with any lab values for this test: 580 Total number of patients plotted: 11

Criteria for patients to be selected for plotting: • at least one lab result above the upper limit of normal. • an increase in lab value for at least 5 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • one patient with consistently rising values through most of the study (purple plot) • one patient with a very high spike followed by a drop below the baseline level, which could represent acute illness or a treatment intervention for hyperglycemia (yellow plot) • most elevations were transient spikes followed by return to baseline values

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Figure 24: Study 303: Serum Insulin Results

Total number of patients with any lab values for this test: 594 Total number of patients plotted: 16

Criteria for patients to be selected for plotting: • at least one lab result above the upper limit of normal. • an increase in lab value for at least 5 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • one patient with a spike followed by return to baseline, and then a period of gradually rising values (blue plot) • one patient with a very high spike that eventually returned to baseline (brown plot) • one patient with a very high spike at end of the study; outcome is not known (uppermost gray plot) • most elevations were transient spikes followed by return to baseline values

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Figure 25: Study 303: Serum Hemoglobin A1c Results

Total number of patients with any lab values for this test: 553 Total number of patients plotted: 28

Criteria for patients to be selected for plotting: • at least one lab result above the upper limit of normal. • an increase in lab value for at least 3 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • three patients with values rising throughout the course of the study (blue, green, and uppermost gray plots) • among most patients with periods of increasing values, values showed little variability over the course of the study

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Figure 26: Study 303: Serum High-Density Lipoproteins

Total number of patients with any lab values for this test: 595 Total number of patients plotted: 14

Criteria for patients to be selected for plotting: • at least one lab result above the upper limit of normal. • an increase in lab value for at least 5 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • considerable variability among patients over time; no single characteristic pattern of change • note that the program that generates the plots focuses on abnormally high values, while for HDL decreasing values would be more of a potential concern. A slight trend towards decreasing values was seen for one patient (blue plot).

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Figure 27: Study 303: Serum Low-Density Lipoproteins

Total number of patients with any lab values for this test: 593 Total number of patients plotted: 18

Criteria for patients to be selected for plotting: • at least one lab result above the upper limit of normal. • an increase in lab value for at least 4 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • one patient with a trend primarily of increasing values (brown plot) • the patient with highest elevations gradually returned to values below baseline (uppermost gray plot) • most elevations were transient spikes followed by return to baseline values

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Figure 28: Study 303: Serum Total Cholesterol

Criteria for patients to be selected for plotting: • at least one lab result above the upper limit of normal. • an increase in lab value for at least 5 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • the patient with highest elevation eventually decreased to a level below baseline (purple plot) • the patient with lowest level at baseline eventually rose to one of the highest levels (lowermost gray plot) • no single characteristic pattern of change over time

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Figure 29: Study 303: Serum Triglycerides

Total number of patients with any lab values for this test: 595 Total number of patients plotted: 7

Criteria for patients to be selected for plotting: • at least one lab result above the upper limit of normal. • an increase in lab value for at least 5 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • one patient with fairly consistent rise in values over the course of the study (green plot) • very significant fluctuations over time for one patient (purple plot) • for most patients, periods of gradually rising and falling values, with a sinusoidal pattern for one patient (yellow plot)

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Figure 30: Study 303: Serum Creatine Phosphokinase

Total number of patients with any lab values for this test: 595 Total number of patients plotted: 9

Criteria for patients to be selected for plotting: • at least one lab result 3x the upper limit of normal. • an increase in lab value for at least 5 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • four patients with very high elevations compared to baseline (blue, orange, purple, yellow plots); one of these (blue plot) had mostly rising values over the course of the study • several patients for whom the last recorded value is an elevation above baseline; for these, the eventual outcome of the elevation is not known (pink, brown, and two gray plots)

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Figure 31: Study 303: Serum Alanine Aminotransferase

Total number of patients with any lab values for this test: 595 Total number of patients plotted: 6

Criteria for patients to be selected for plotting: • at least one lab result 3x the upper limit of normal. • an increase in lab value for at least 3 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • some patients with very high spikes that eventually returned to baseline levels (green, blue, orange plots) • some elevations with unknown outcomes (purple, brown, yellow plots)

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Figure 32: Study 303: Serum Aspartate Aminotransaminase

Total number of patients with any lab values for this test: 595 Total number of patients plotted: 3

Criteria for patients to be selected for plotting: • at least one lab result 3x the upper limit of normal. • an increase in lab value for at least 3 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • one patient with a very high value early in the study that returned to baseline, but rose again by the end of the study (blue plot) • one patient with values rising fairly consistently over the course of the study (purple plot)

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Figure 33: Study 303: Serum Gamma-Glutamyl Transferase

Total number of patients with any lab values for this test: 595 Total number of patients plotted: 11

Criteria for patients to be selected for plotting: • at least one lab result 3x the upper limit of normal. • an increase in lab value for at least 5 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • one patient with values gradually rising over the entire course of the study (uppermost gray plot) • one very high elevation with unknown outcome (second gray plot)

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Figure 34: Study 303: Serum Lactate Dehydrogenase

Total number of patients with any lab values for this test: 595 Total number of patients plotted: 8

Criteria for patients to be selected for plotting: • at least one lab result above the upper limit of normal. • an increase in lab value for at least 3 consecutive study visits. • attended at least 25% of scheduled study visits. • no consecutive gaps of more than 10 visits between lab draws.

Observations: • four patients with spikes at the same visit (yellow, green, brown, and orange plots); significance is not clear. Two patients returned to baseline levels (green and orange plots); for the other two, outcomes for the elevations are not known.

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Additional Safety Explorations

Human Carcinogenicity or Tumor Development The Applicant did not provide human carcinogenicity data with this application.

Human Reproduction and Pregnancy

The studies conducted in this clinical development program excluded patients who were pregnant or who were unwilling to agree to use of contraception during study participation. Postmarketing studies related to the use of lumateperone during pregnancy and lactation will be requested and are discussed in Section 13, Postmarketing Requirements and Commitments. Although aniline metabolites (linked to toxicities in nonclinical studies) were not present in (adult) humans at quantifiable levels, it is unknown whether infants exposed to lumateperone will exhibit comparable lumateperone metabolism and elimination pathways as adults. Therefore, until additional data is collected and reviewed, the label will specify that breastfeeding is not recommended during treatment with lumateperone.

Pediatrics and Assessment of Effects on Growth The studies conducted in this clinical development program excluded patients under the age of 18. Discussion of the Agreed Pediatric Study Plan is presented in Section 10, Pediatrics. Discussion of postmarketing requirements related to the use of lumateperone in adolescents is presented in Section 13, Postmarketing Requirements and Commitments.

Overdose, Drug Abuse Potential, Withdrawal, and Rebound The application was reviewed by the Controlled Substance Staff. Nonclinical abuse and dependence studies conducted by the Applicant did not reveal any abuse signals. Binding assays show that lumateperone and its metabolites have moderate to high affinities for several receptors (D1, 5-HT1A, 5-HT2A, and SERT) associated with abuse. The Applicant conducted functional assays with lumateperone to evaluate for agonist or antagonist activity of the drug at receptors known to be activated or blocked by drugs with abuse potential. Lumateperone did not produce agonist or antagonist activity associated with abuse-related effects. Activation of the 5-HT2A receptor is the primary underlying mechanism linked to the abuse-related effects of psychedelic drugs, which are full or partial agonists at this receptor. In contrast, lumateperone is a full antagonist at 5-HT2A receptors.

Abuse-related adverse events were not reported in the clinical trials. The adverse event data did not demonstrate any evidence of misuse, abuse, diversion, or dependence. There were no subjective central nervous system effects that might make the drug a target of abuse, such as mood elevation, stimulation, or hallucinogenic effects. The most frequent CNS-related adverse events were somnolence and sedation, which are commonly associated with other approved

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and unscheduled antipsychotic agents. Based on the absence of an abuse signal, Controlled Substance Staff recommends not including a section on drug abuse and dependence in the lumateperone label.

Expectations on Safety in the Postmarket Setting

The Division recommends postmarketing studies to assess the pharmacokinetics, safety, and efficacy of lumateperone in adolescents, the safety of lumateperone in pregnancy and lactation, the effect of UGT enzyme inhibitors on the pharmacokinetics of lumateperone, and inhibitor/inducer/substrate potential of lumateperone and its metabolites towards major transporters and cytochrome P450 isoenzymes. See Section 13, Postmarketing Requirements and Commitments. It is expected that use in the postmarket setting will include treatment of a broader range of patients than those enrolled in clinical trials (i.e., older patients and those with more medical comorbidities or concomitant medication use). In addition to assessing for safety findings in the broader general patient population, postmarketing pharmacovigilance will be important for assessing for adverse reactions too rare to be detected in the clinical development program.

Integrated Assessment of Safety

Review of lab data and adverse events from the three placebo-controlled trials of lumateperone suggest some safety advantages compared to risperidone (e.g., a lower propensity for metabolic changes and extrapyramidal symptoms) but many commonalities with other currently approved atypical antipsychotic agents. Common adverse reactions for lumateperone 42 mg included somnolence/sedation, nausea, dry mouth, dizziness, creatine phosphokinase increased, fatigue, vomiting, and hepatic enzymes increased. Although there were no group mean changes in vital sign parameters, lumateperone may increase blood pressure or affect pulse rate in a small proportion of subjects.

Consideration of the potential clinical implications of nonclinical findings was of particular importance in this NDA review. Specifically, the neuropathological findings and clinical signs of neurotoxicity observed in dogs after long-term exposure to lumateperone, as well as cardiomyopathy, retinal degeneration and peripheral neuropathy observed in the mouse and rat studies, raised concerns about whether similar toxicities might occur in humans after long- term exposure. The Applicant has provided nonclinical data suggesting that these toxicities are related to the formation of aniline metabolites and subsequent accumulation of pigmented material in lysosomes. Review of adverse events from the long-term, open-label human study did not reveal any pattern of new onset of cardiomyopathy, retinal degeneration, peripheral neuropathy, or other neurological changes in patients treated with lumateperone.

The Applicant hypothesizes that the aniline metabolites believed to be related to the animal toxicities are unlikely to accumulate in humans because humans metabolize lumateperone predominantly using an enzyme pathway (glucuronidation) that is different from the pathways predominantly used in the animal species. Additional clinical studies enrolling patients with at

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least six months of exposure to lumateperone 42 mg daily demonstrated that the aniline metabolites could not be detected in human circulation at the level of quantification at which the aniline metabolites were detected in the dog. We cannot completely rule out the presence of very low levels of aniline metabolites in humans treated with lumateperone (i.e., levels below the level of detection of available bioanalytical methods). However, the lack of quantifiable levels of aniline metabolites in humans treated with lumateperone, the plausible metabolic rationale by which anilines would accumulate in animal species but not in humans, and the absence of evidence from the long-term human studies of the pattern of aniline- related toxicities that occurred in the animal studies provide adequate support that the nonclinical safety findings are not relevant to humans.

Statistical Issues

The following features of Study 005 and its analysis cause some concern:

• The study was planned as a phase 2 study with a two-sided alpha level of 0.1 (versus the conventional level of 0.05 for an adequate and well-controlled study); FDA classified the study as “proof-of-concept” and provided comments to strengthen its design and analysis.

• The Applicant updated the primary analysis to the proposed repeated measures model but did not submit the SAP or the Interim Statistical Analysis Plan (ISAP) until the Clinical Study Report was submitted. Although both the SAP and ISAP were finalized prior to database lock, FDA had no opportunity to review them. The primary efficacy analysis did not account for the increase in sample size from 268 to 328 after the unblinded interim analysis. The issue was rectified by the Applicant in response to an FDA information request during the NDA review (the correctly adjusted p-value of 0.04 for comparison of the 42-mg lumateperone vs. placebo group is slightly larger than the originally reported value of 0.034).

• The conduct of the interim analysis caused a 9-month pause in enrollment, which might have contributed to the difference in efficacy between patients enrolled before vs. after the interim analysis for the 84-mg arm. Whereas the treatment effect in the 84-mg arm appeared similar to the treatment effect in the 42-mg arm for the pre-interim data, the 84- mg arm provided less improvement than the placebo arm on the PANSS for the post-interim data.

Conclusions and Recommendations

The Applicant has provided results of two placebo-controlled trials demonstrating the efficacy of lumateperone in the treatment of schizophrenia. The trials tested several doses of lumateperone, but the 42-mg dose was the only dose that demonstrated efficacy. A third placebo-controlled trial did not find lumateperone 42 mg to be superior to placebo. Nonclinical 258 Version date: October 12, 2018

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studies raised concerns about potential toxicities related to aniline metabolites, including neuropathological changes, cardiomyopathy, and retinal degeneration. However, further nonclinical and clinical studies provide evidence that these toxicities will not occur in humans. We recommend approval of lumateperone given orally at the dose of 42 mg daily for the treatment of schizophrenia.

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9 Advisory Committee Meeting and Other External Consultations

As described above in the Regulatory History, an Advisory Committee Meeting was originally scheduled for July 31, 2019. However, based on discussions with the Applicant at the Late Cycle Meeting about uncertainties in the review, the Division agreed that the Applicant could file a Major Amendment to the NDA application, documenting a plan to provide additional data and analyses to clarify the mechanisms of toxicities in the animal studies and support their hypothesis that similar toxicities following long-term exposure in humans would be unlikely. The Advisory Committee Meeting was cancelled, on the grounds that the Committee members would not have the full information necessary to support their positions, and the Major Amendment delayed the PDUFA goal date from September 27, 2019 to December 27, 2019.

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10 Pediatrics

The Applicant submitted an initial Pediatric Study Plan (iPSP) that had been previously agreed upon with the Division. The Applicant requested a Partial Waiver for ages 0 to 12 years because of the very low incidence of schizophrenia in this age range. Childhood-onset schizophrenia, before the age of 13, is very rare with an incidence of less than 0.04%. The Division concurs with the Applicant’s rationale and supports a waiver for this age group.

In the Agreed iPSP, the Division agreed with the Applicant’s plan to request deferral for pediatric studies (age 13 to 17 years) until safety and efficacy is established in adults. Now that the review of safety and efficacy in adults is complete, the Division recommends that the Applicant be required to evaluate the efficacy and safety of lumateperone in pediatric patients age 13 to 17 years. Details of the studies to be requested are presented in Section 13, Postmarketing Requirements and Commitments.

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11 Labeling Recommendations

Significant changes to the Prescribing Information submitted by the Applicant are presented below:

(b) (4) •

• Dose modifications for concomitant use with CYP3A4 inhibitors or for patients with hepatic impairment – There are no available strengths of lumateperone that would provide appropriate exposure for patients receiving a concomitant moderate or strong CYP3A4 (b) (4) inhibitor or who have moderate to severe impairment. the label will specify that use is not recommended in these circumstances.

• Revision to Section 8.2 – Lactation – The risk summary was revised to note that although aniline metabolites were not present in (adult) humans at quantifiable levels, it is unknown whether infants exposed to lumateperone will exhibit comparable lumateperone metabolism and elimination pathways as adults. Based on findings of toxicity in animal studies and the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment with lumateperone.

(b) (4) • Revisions to Section 12.1 – Mechanism of Action – Language stating

was removed. This language is not consistent with labels for other atypical antipsychotic drugs and draws a distinction between lumateperone and these other drugs that doesn’t exist. This language was revised to be consistent with other atypical (b) (4) antipsychotic drugs. In addition, language stating (b) (4) was removed. the in vitro functional activity data indicates lumateperone is an antagonist at both presynaptic and postsynaptic D2 receptors. Because it is not clear whether lumateperone is a partial agonist or antagonist at presynaptic D2 receptors this language was changed to indicate it is a postsynaptic D2 receptor antagonist only based on available data.

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• Revision to Section 12.2 – Pharmacodynamics – Extensive language detailing the pharmacodynamic effects of lumateperone were included in this section. For example, the (b) (4) Applicant stated that;

This language is not consistent with labels for other atypical antipsychotic drugs; however, many of the effects listed are not unique to lumateperone. This language was removed and this section was revised to be consistent (b) (4) with other atypical antipsychotic drugs

• Inclusion of nonclinical reproductive and developmental toxicity information for the reduced ketone human metabolite IC200131 – The nonclinical safety findings in pregnant rats administered metabolite IC200131 will be presented in Section 8.1 of the label.

• Inclusion of nonclinical toxicity information related to accumulation of pigmented material and associated toxicities – The nonclinical safety findings in dogs, rats, and mice will be presented in Section 13.2 of the label, along with discussion of review conclusions related to these toxicities.

(b) (4) • Revisions to Section 5.5 – Metabolic Changes –

(b) (4) Language was revised in this section

(b) (4) •

Other Prescription Drug Labeling: The proposed carton was reviewed by DMEPA; no changes were recommended.

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12 Risk Evaluation and Mitigation Strategies

There are 22 antipsychotics approved for the treatment of schizophrenia and most of these medicines are approved without a REMS, with the exception of Clozaril (clozapine), Zyprexa Relprevv (olanzapine), and Adasuve (), for which the risks are unique to those specific products and do not extend across the antipsychotic class. The review team considered whether a Risk Evaluation and Mitigation Strategy (REMS) should be required for evaluating and mitigating theoretical human risks related to the nonclinical toxicology findings of pigmented material accumulation (described in Section 5). The team concluded that if there was a reasonable possibility of human safety risks related to aniline metabolites, the overall benefit/risk determination would not support approval of lumateperone. During the course of the review, the Applicant provided additional data supporting the position that the nonclinical findings are not relevant to human use. Thus, there is no remaining safety issue that warrants consideration of a REMS, and a REMS has not been proposed or required for lumateperone. The review team determined that a REMS is not needed to ensure the benefits of lumateperone outweigh its risks.

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13 Postmarketing Requirements and Commitments

The following post-marketing requirements will be issued in accordance with the Pediatric Research Equity Act. Please refer to Section 10 (Pediatrics) for additional discussion.

• PMR #3760-1: Conduct an open-label, multiple oral dose study to demonstrate the safety, tolerability, and pharmacokinetics of lumateperone in patients ages 13 to 17 years diagnosed with schizophrenia. o Purpose: to characterize the pharmacokinetics of lumateperone and its metabolites and assess the safety and tolerability of lumateperone in adolescents. o Acceptable to assess post-approval following establishment of safety and efficacy in adults.

• PMR #3760-2: Conduct a randomized, double-blind, placebo-controlled study to assess the efficacy and safety of lumateperone for the treatment of schizophrenia in patients aged 13 to 17 years. o Purpose: to determine whether lumateperone is effective and safe for treatment of schizophrenia in adolescents. o Acceptable to assess post-approval following establishment of safety and efficacy in adults.

• PMR #3760-3: Conduct an open-label study to assess the long-term safety of lumateperone in patients aged 13 to 17 years diagnosed with schizophrenia. o Purpose: to assess the long-term safety of lumateperone for the treatment of schizophrenia in adolescents. o Acceptable to assess post-approval following establishment of safety and efficacy in adults.

The following post-marketing requirement will be issued in accordance with the FDA Amendments Act of 2007:

• PMR #3760-4: Perform a lactation study (milk only) in lactating women who have received therapeutic doses of lumateperone, using a validated assay to assess concentrations of lumateperone and its metabolites in breast milk. o Purpose: to provide data on the presence of lumateperone and its metabolites in human milk o Acceptable to assess post-marketing because only a small subpopulation (lactating females) is affected and it is only feasible to conduct the study post- approval.

The following post-marketing requirement will be issued to further characterize the PK of

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lumateperone and assess for potential clinical implications if UGT inhibitors are used concomitantly with lumateperone:

• PMR #3760-5: Conduct a clinical pharmacokinetic trial to evaluate if UGT enzyme inhibitors alter the PK of lumateperone and its metabolites (including metabolites IC201337 and IC201338) using fully validated assays and to determine appropriate dosing recommendations for CAPLYTA with regard to use of concomitant UGT enzyme inhibitors. o Purpose: to evaluate whether dosage adjustment for lumateperone is necessary when it is used concomitantly with UGT enzyme inhibitors. o Acceptable to assess post-marketing because the overall benefit/risk profile of the drug appears favorable; there are uncertainties about aspects of the drug’s safety profile in the specific subpopulation of patients who are prescribed co- medications that are UGT inhibitors.

The following post-marketing requirement will be issued to further characterize the drug interaction potential of lumateperone and its major metabolites with drug transporters and enzymes:

• PMR #3760-6: Conduct standard in vitro assays to determine:  Substrate potential of lumateperone for OATP1B1/1B3;  Inhibitor potential of lumateperone towards P-gp and BCRP;  Inhibitor potential of all major metabolites (IC200131, IC200161, IC200565, IC201308, IC201309, and IC200056-enol-glu), if not yet evaluated, towards: . transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, and MATE2K; . inhibitor/inducer potential towards major CYPs, except CYP3A (in vivo study with midazolam has been conducted).  Purpose: to further characterize the drug interaction potential of lumateperone and its major metabolites with drug transporters and enzymes.  Acceptable to assess post-marketing because the study is to further explore a theoretical concern that does not impact the approval determination.

The following post-marketing commitments will be requested:

• PMC #3760-7: Conduct a placebo-controlled randomized withdrawal maintenance study of lumateperone in patients with schizophrenia.  Purpose: to investigate the maintenance of efficacy over time for patients with schizophrenia who have been stabilized on lumateperone.  Acceptable to assess post-marketing because the benefit/risk profile of the drug appears favorable, but uncertainties about the long-term efficacy remain.

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• PMC #3760-8: Develop new strengths of 10.5 mg and 21 mg of lumateperone to meet the need for dose adjustment in patients with moderate to severe hepatic impairment or in patients who are taking concomitant strong or moderate CYP3A4 inhibitors.  Purpose: to develop appropriate new strengths for dosage adjustment when certain intrinsic/extrinsic factors are present that will impact lumateperone exposure.  Acceptable to develop post-approval because only small subpopulations are affected (e.g., patients with hepatic impairment or patients taking concomitant strong or moderate CYP3A4 inhibitors), and because initial labeling will state that use in those subpopulations should be avoided.

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14 Appendices

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Financial Disclosure

No disclosable financial interests/arrangements were reported for any of the investigators participating in the clinical studies.

Covered Clinical Study (Name and/or Number): ITI-007-001 ITI-007-002 ITI-007-003 ITI-007-004 ITI-007-005 ITI-007-006 ITI-007-008 ITI-007-009 ITI-007-010 ITI-007-011

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ITI-007-012 ITI-007-013 ITI-007-014 ITI-007-016 ITI-007-017 ITI-007-018 ITI-007-200 ITI-007-301 ITI-007-302 ITI-007-303

Was a list of clinical investigators provided: Yes No (Request list from Applicant) Total number of investigators identified: 178 Number of investigators who are Sponsor employees (including both full-time and part-time employees): 0

Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 0 If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: n/a Significant payments of other sorts: n/a Proprietary interest in the product tested held by investigator: n/a Significant equity interest held by investigator in Sponsor of covered study: n/a Is an attachment provided with details Yes No (Request details from of the disclosable financial Applicant) n/a interests/arrangements: Is a description of the steps taken to Yes No (Request information minimize potential bias provided: from Applicant) n/a Number of investigators with certification of due diligence (Form FDA 3454, box 3) 0 Is an attachment provided with the Yes No (Request explanation reason: from Applicant) n/a

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Nonclinical Pharmacology/Toxicology

Table 101. Incidence and Severity of Histopathology Findings Following Administration of Lumateperone to Rats for up to 6-Months Adrenal Glands Male Female Dose (mg/kg) 0 10.5 21 42 0 10.5 21 42 Hyperplasia 0 0 0 1 0 0 0 0 moderate - - - 1 - - - - Hypertrophy 0 1 0 6 0 0 0 0 minimal - 1 ------mild - - - 6 - - - - Pigmentation 0 10 10 15 0 10 10 15 minimal - 2 3 2 - 7 - - mild - 8 6 8 - 3 7 4 moderate - - 1 5 - - 3 11 Bone Marrow (Femur) Male Female Dose (mg/kg) 0 10.5 21 42 0 10.5 21 42 Number examined 15 10 10 15 15 10 10 15 Pigment laden macrophages 0 0 10 15 0 0 10 15 minimal - - 9 - - - 9 - mild - - 1 - - - 1 5 moderate - - - 15 - - - 10 Liver Male Female Dose (mg/kg) 0 10.5 21 42 0 10.5 21 42 Number examined 15 10 10 15 15 10 10 15 Degeneration 0 0 0 3 0 0 0 0 minimal - - - 1 - - - - mild - - - 2 - - - - Necrosis 0 0 0 5 0 0 2 3 minimal - - - 3 - - - - mild - - - 2 - - 1 3 moderate ------1 - Pigmentation 0 8 10 15 0 4 10 15 minimal - 8 3 - - 4 4 - mild - - 5 - - - 6 1 moderate - - 2 4 - - - 10 marked - - - 11 - - - 4 Proliferation 0 0 1 15 0 1 3 15 minimal - - 1 - - 1 2 2 mild - - - 1 - - 1 7 moderate - - - 12 - - - 6 marked - - - 2 - - - - Lungs Male Female Dose (mg/kg) 0 10.5 21 42 0 10.5 21 42 Number examined 15 10 10 15 15 10 10 15 Pigment laden macrophages 0 4 10 15 0 6 10 15 minimal - 4 - - - 5 - 1 mild - - 10 - - 1 4 2 moderate - - - 2 - - 6 11 marked - - - 13 - - - 1

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Hyperplasia 0 4 10 15 0 3 8 15 minimal - 4 10 - - 3 1 1 mild - - - 3 - - 7 4 moderate - - - 7 - - - 9 marked - - - 5 - - - 1 Mononuclear cell infiltrate 1 0 0 12 0 0 0 12 minimal 1 ------3 mild - - - 10 - - - 9 moderate - - - 2 - - - - Skeletal Muscle (Gastrocnemius) Male Female Dose (mg/kg) 0 15 30 60 0 15 30 60 Number examined 15 10 10 15 15 10 10 15 Degeneration/Necrosis 0 0 0 15 0 0 2 15 minimal - - - 2 - - 1 1 mild - - - 8 - - 1 7 moderate - - - 5 - - - 6 marked ------1 Pigmentation 0 0 0 15 0 0 2 15 minimal - - - 4 - - 2 7 mild - - - 11 - - - 8 Mononuclear cell infiltrate 0 0 0 15 0 0 3 15 minimal - - - 8 - - 2 7 mild - - - 7 - - 1 6 moderate ------2 Testes Male Dose (mg/kg) 0 15 30 60 Number examined 15 10 10 15 Aspermia 0 0 0 4 moderate - - - 1 marked - - - 3 Degeneration 1 0 0 7 minimal 1 - - 1 moderate - - - 2 marked - - - 2 Severe - - - 2 Hyperplasia 0 0 0 2 mild - - - 2 Mineralization 0 0 0 2 minimal - - - 1 mild - - - 1 In addition to the tissues listed in the table, accumulation of pigmented material was observed in parenchymal cells in the esophagus, intestine, larynx, mammary gland, pituitary gland, prostate gland, seminal vesicles, spleen, thyroid gland, tongue, and zymbal’s gland and in infiltrating macrophages in the cervix, kidney, lymph nodes, ovaries, thymus, uterus, and Peyer’s patches.

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Table 102. Incidence and Severity of Histopathology Findings Following Administration of Lumateperone to Dogs for 9-Months. Male Female Dose (mg/kg) 0 1.75 3.5 7 10.5 0 1.75 3.5 7 10.5 Number examined 3 4 4 4 4 4 4 4 4 4 Gall Bladder Pigmentation 0 4 4 4 4 0 4 4 4 4 Minimal - 2 ------Slight - 2 3 - - - 3 3 - - Moderate - - 1 4 - - 1 1 2 - Marked - - - - 4 - - - 2 3 Severe ------1 Liver Pigmentation 0 4 4 4 4 0 4 4 4 4 Minimal - 4 4 1 - - 4 3 1 1 Slight - - - 3 4 - - 1 3 2 Moderate ------1 Lungs Pigment Laden Macrophages 0 0 4 4 4 0 2 4 4 4 Minimal - - 4 4 4 - 2 4 3 4 Slight ------1 - Lymph nodes (Mandibular) Pigment Laden Macrophages 0 0 4 4 4 0 0 4 4 4 Minimal - - 3 - 1 - - 3 - - Slight - - 1 3 2 - - 1 3 3 Moderate - - - 1 1 - - - 1 1 Ovaries Pigment Laden Macrophages 0 0 2 4 2 Minimal - - 1 2 2 Slight - - 1 2 - Spleen Pigment Laden Macrophages 0 0 2 4 4 0 3 2 3 4 Minimal - - 2 4 4 - 3 2 3 4 Thyroid glands Pigment Laden Macrophages 0 0 2 4 4 0 3 2 3 4 Minimal - - 2 4 4 - - 2 4 4 Uterus Pigment Laden Macrophages 0 0 2 4 1 Minimal - - 2 3 1 Slight - - - 1 -

OCP Appendices (Technical documents supporting OCP recommendations)

19.4.1 Aniline Metabolites in Humans Aniline metabolites of lumateperone, IC201337 and IC201338, are deemed to be associated, at least in part, with the neuropathological changes observed in dogs. The neuropathological findings and clinical signs of neurotoxicity observed in dogs after long-term exposure to 275 Version date: October 12, 2018

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lumateperone raised concerns about whether similar neurotoxicities might occur in humans after long-term exposure. To date, the long-term human studies have not revealed any pattern of unexpected neurological adverse events emerging over time. However, it is unclear whether humans might develop the neuropathological changes, remain clinically asymptomatic for months or years, and then begin to show clinical signs of neurotoxicity at some point in the distant future. Because the neuropathologies cannot be assessed directly in humans without an autopsy, considerable efforts have been made to determine whether circulating levels of aniline metabolites can be detected in patients who have had long-term exposure to the dose of 42 mg lumateperone.

Comparison of Metabolism Between Species

Mass Balance Studies

Lumateperone is extensively metabolized in humans, dogs and rats. Following administration of 14C-labeled lumateperone, unchanged lumateperone represented less than 3% of the total radioactivity in plasma, and minimal intact compound was excreted in urine or feces. Based on the results shown in Table 103, the major route of radioactivity elimination is urine in humans (58%) and feces in dogs (46%) and rats (90%). The plasma radioactivity half-life is much longer in dogs (116 hours) than in humans (12 hours) and rats (20 hours), and the reason is unknown.

Glucuronidation seems to be a more prominent pathway in humans compared to dogs. As shown in Table 103, glucuronidated metabolites represent about 51% of the total radioactivity in the human plasma, but only 9% of total radioactivity in dogs.

Table 103: Mass Balance Study in Humans, Dogs and Rats Using 14C-Labeled Lumateperone Humans(n=6) Dogs (n=3) Rats (n=3) Dose 28 mg 3.5 mg/kg 7 mg/kg % Total recovery of radioactive dose 87.5 62.2 104 % Recovery of radioactive dose in feces 29.1 45.5 90.0 % Recovery of radioactive dose in urine 58.4 13.9 9.8 Plasma radioactive half-life (hour) 11.5 116 20 % of lumateperone in plasma (AUC0-24hr) 2.8 2.9 NA % of Glu-Metabolites in plasma (AUC0-24hr) 51 8.5 NA % of Glu-Metabolites in urine (0-24hr) 39 10 NA NA: not available; -Sources: human ITI-007-016; Dog: ICT/07; rats: ICT/01, ICT/04

In addition to glucuronidation, non-conjugation biotransformation of lumateperone, including reduction, dealkylation, and amidation, is also observed in Figure 35.

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Figure 35: Pathways to Formation of Lumateperone Major Unconjugated Metabolites

Note: M161 can be formed by demethylation from lumateperone; M308 can be formed by amidation from M161; M131 can be formed by AKR from lumateperone; M565 can be formed either by AKR from M161 or by demethylation from M131; M309 can be formed either by AKR from M308 or by amidation from M565. Lumateperone and its 5 metabolites (M161, M308, M131, M565, M309) can be further glucuronidated. Source: modified based on meeting minutes for March 28, 2017 meeting

Up to 5 unconjugated metabolites were monitored in the animal and human studies, and these were found to accumulate at different concentrations relative to the parent drug in each species. Specifically, the most abundant circulating moiety in humans is a tertiary down-stream metabolite, M309, which circulates at a level about 5.5-fold higher than the parent. In dogs, metabolite M161, a primary demethylation product, circulates at a level about 3.3-fold higher than the parent. In male rats, M308 is the most abundant moiety, circulating at a level about 6.1-fold higher than the parent. Although metabolite M565 was not detected at the dose of 3.5 mg/kg/day in rats, it was measurable at doses 10.5 mg/kg/day or greater. These data show that major metabolic pathways are qualitatively similar in humans, dogs, and rats, but quantitative differences exist, as relative levels of metabolites vary considerably across species.

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Figure 36: Relative Exposure of Unconjugated Metabolites to Lumateperone at Steady State

Source: human: 42 mg, study ITI-007-017; dog: 1.75 mg/kg/day, Study 11221; male rat: 3.5 mg//kg/day, Study 8328209

Aniline Metabolites

In addition to the major unconjugated metabolites, formation of two aniline metabolites IC201337 (M337) and IC201338 (M338), together with accompanying two-carbon fragments (Figure 37), is proposed by the Applicant. The Applicant claims that these two aniline metabolites cause the observed neurotoxicity in dogs and assert that they are not formed in humans.

Figure 37: Formation of Aniline Metabolites

Note: No studies were performed to elucidate explicitly the formation process of M337 and M338. It is postulated that the two aniline metabolites, M337 and M338, can be formed by 2-carbon scission from M131 (ketone reduction product of lumateperone) and demethylation metabolite of lumateperone, respectively. Red * is the 14C

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labeled carbon, which was cleaved off during M337 and M338 formation. Therefore, M337 and M338 could not be directly measured through radioactivity detection in the mass balance studies. Source: meeting minutes for March 28, 2017 meeting

Following daily oral administration of lumateperone at 1.75 mg/kg/day in dogs for 9 months, steady state exposure of aniline metabolite M337 was about 2-fold higher than the parent, and exposure to aniline metabolite M338 was similar to the parent. In rats, at a dose level of 3.5 mg/kg/day, M337 levels were low and no recorded results were available, and the exposure to M338 was about 0.07-fold that of the parent compound. Human data reported from the one- year open-label safety extension study (Study 303) show no quantifiable levels in patients treated with lumateperone 42 mg/day, with approximately 500, 300, and 100 subjects exposed through 1, 6, and 12 months, respectively. The aniline metabolites were below the LLOQ based on the analytical methods used.

Figure 38: Plasma Concentration Time Profile of M337 and M338 on Day 280 Following Daily Oral Administration of Lumateperone (1.75 or 3.5 mg/kg/day) in Dogs

M337 - 3.5mg/kg/day M338 - 3.5mg/kg/day 1.6 M337 - 1.75mg/kg/day 1.4 M338 - 1.75mg/kg/day 1.2 1.0 0.8 0.6 0.4

Plasma Conc (ng/mL) 0.2 0.0 pre-dose 0.25 0.5 1 4 8 24 Time (hour)

Two-Carbon Fragments – An Indicator of Possible Aniline Metabolites Formation

As shown in Figure 37, aniline metabolites are formed as a result of piperazine ring cleavage. Because the 14C label was placed on a carbon that was cleaved off during this process, aniline metabolites could not be directly measured through radioactivity detection in the mass balance studies. Instead, the two-carbon fragments carried the 14C-carbon, and they could be monitored through radioactivity detection. Assuming a 1:1 ratio between production of two- carbon fragments and aniline metabolites, the detection of two-carbon fragments in mass balance studies can be used as an indicator of aniline metabolite formation.

The two-carbon fragments have low molecular weight and are highly polar; as a result, they are eluted as an early peak, between 1.72 to 2.46 minutes in the chromatogram. They were assigned ‘R01’ in the radioactivity profiles of dog plasma.

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Figure 39: Dog Plasma Radiochromatogram

Source: Figure 4, ICT07 report

Though the Applicant states that no early elution peak has been identified in any of the human radioactivity profiles, an early eluting peak is observed in the plasma radiochromatogram from human mass balance study. This early eluting peak has a retention time of 2.44 minutes, which is very similar to what has been observed in dogs. In addition, a similar early elution peak with comparable retention time was also observed in the radiochromatograms from human urine and feces samples respectively (data not shown). Therefore, on the basis of these data, one cannot rule out the possibility that aniline metabolites are formed in humans as well.

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Figure 40: Human Plasma Radiochromatogram

Source: Figure 32, ICT03 report

Of note, the Agency has conducted (quantitative) structure-activity relationship ((Q)SAR) analyses for lumateperone and 7 unconjugated metabolites including M337 and M338. No conclusions can be drawn regarding associations between single metabolites and neurotoxicity on the basis of the available database. The observed multi-organ pigment accumulation and neuronal degeneration in animal studies, might be a collective effect of the lumateperone and/or its metabolites. For more details, refer to the pharmacology/toxicology section.

LC-MS/MS Evaluation of Aniline Metabolites in Humans

Several attempts have been made by the Applicant to measure the plasma levels of the aniline metabolites in humans. The first effort was to measure the aniline metabolite concentration s from plasma samples collected in the open-label long term safety Study ITI-007-303 (Study 303) in the original submission. Both aniline metabolites were found to be below LLOQ of 1.0 ng/mL. Unfavorably, because the time gap from lumateperone administration in the evening to blood sample collection the next day, there is a possibility that the early signals immediately following the lumateperone administration might be missed.

The second-round of try, made after Late-Cycle discussion, the Applicant reanalyzed the frozen plasma samples from the Thorough QT study ITI-007-017 (study completed in May 2018) and submitted in Major Amendment, where a series of intensive PK samples were collected on Day 5 following once daily administration with lumateperone. Unfortunately, it was identified that the stored samples were out of the long-term storage stability windows for IC201337 (94 days) and IC201338 (50 days) at -80˚C, originally established in the methods validation. Upon the

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Agency’s inquiry, the Applicant submitted data to support that the stability window can be extended to 171 days first in submission dated on Sep. 17, 2019 and then later to 567 days in submission dated Oct. 10, 2019. To ensure the validity of the newly-extended stability windows, (b) (6) an inspection/audit of the contracted bioanalytical site, was conducted by the FDA. The Agency identified no major issues to reject the stability data.

Per Agency’s request, the Applicant improved their bioanalytical assay sensitivity to 0.1 ng/mL for both aniline metabolites for analysis of the frozen TQT samples, with a caveat that the expanded range from 0.1 ng/mL to 1.0 ng/mL was not fully validated. Another limit of the bioanalytical run is that all calibration curves and QC samples were run in duplicates, rendering challenges in evaluating the assay performance. With the two constraints acknowledged, results from the TQT frozen samples showed that plasma level of both IC201337 and IC201338 were below 0.1 ng/mL for patients dosed to steady state with the therapeutic dose. However, peaks detected at the targeted retention times for the metabolites in the chromatograms were noticeable in some patients, suggesting that the aniline metabolites might be formed in some patients though in limited quantities.

The third round of efforts was made to measure the aniline metabolites in freshly-collected plasma samples from patients dosed to steady state in an ongoing clinical trial. Results from a total of number of 11 patients dosed at 42 mg lumateperone were submitted on Nov. 27, 2019, one month from the PDUFA Goal date Dec. 27, 2019. These patients have been treated with lumateperone 42 mg for duration ranging from 23 to 26 months in Study ITI-007-303. Unfortunately, the steady state of these patients has been disrupted by skipping of the evening dose, which is the way they have been taking lumateperone per study protocol instruction. Instead, the patients were dosed in the morning on the day of PK sample collection, after an overnight fast of at least 10 hours. Regardless of this disturbance in steady state condition, comparison of the parent and the other three major metabolites showed comparable levels from this study and the TQT study, suggesting at least for the parent and the measured major metabolites, skipping an evening dose and taking one the next morning does not seem to cause significant deviation from steady state measurements. The inherent PK characteristics of lumateperone (large PK variability with a coefficient of variation for exposure about 68-97% at steady state) might contribute to the finding of comparable circulation levels.

With all the points made above, results from the new PK analysis showed that the plasma circulation levels of the aniline metabolites IC201337 and IC201338 were below 0.1 ng/mL (LLOQ of partially validated bioanalytical methods), following administration of 42 mg lumateperone at different time points (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post- dose). Visual assessment of chromatograms from the PK samples yielded two patterns: in some patients, peaks associated with IC201337 or IC201338 were more noticeable, above the background noises but below the LLOQ (top panels of A and B in Figure below), while in others, no chromatographic peaks associated with IC201337 or IC201338 could be clearly identified above the background noise level (lower panels of A and B in Figure below).

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Figure 41: Representative Chromatograms For IC201337(A) And IC201338(B)

A: IC201337 (Retention Time: ~3.44min)

B: IC201338 (Retention Time: ~3.90min)

x-axis: time (min); y-axis: intensity (cps); cal11-1/2/3 are calibration standards at 0.1ng/mL; all others are study subjects Source: study report RIXA3

Conclusion Given the totality of data submitted, available evidence showed that at the therapeutic dose of 42 mg lumateperone, plasma levels of the two aniline metabolites (IC201337 and IC201338) in patients were below 0.1 ng/mL (LLOQ of the deployed bioanalytical methods). However, we cannot completely rule out the presence of lower levels of aniline metabolites in humans that are not quantifiable with available bioanalytical methods. Safety signals should be monitored by postmarketing pharmacovigilance.

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19.4.2 Population PK and/or PD Analyses The primary objectives of the study were: • To develop a population pharmacokinetic model that describes the single- and repeat- dose pharmacokinetics of IC200056 and two direct unconjugated metabolites following ITI-007 IV and oral administration in healthy subjects and patients with schizophrenia. • To estimate the population PK parameters (e.g., Clearance, Volume of Distribution) and the associated inter-subject variability and residual error. • The identification of significant covariates that could influence PK of IC200056 and direct unconjugated metabolites.

Data: Pharmacokinetic data from four different studies in healthy volunteers and subjects with schizophrenia (ITI-007-002, ITI-007-006, ITI-007-009 and ITI-007-016) were combined for the population pharmacokinetic modeling. Single and repeat oral doses of ITI-007 (up to 8 days of treatment) from 5 to 140 mg were included in the analysis together with a single 40 μg ITI-007 intravenous administration. Three different oral formulations were tested: solution, capsule and tablet. For the solid dose formulations, both fed and fasted conditions were evaluated. Summary information of data and demographics included in the analysis is shown in Table 104.

Model: The integrated PK model is shown in Figure 42.

Figure 42. Integrated PK model for parent drug (IC200056) and direct metabolites IC200131 and IC200161, including first pass effect description. Compartments numeration is indicated at their left bottom angle.

Source: Figure 2 on page 26 in pxl235821-report-body.pdf

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Table 104. Population demographics all together and stratified by study.

Source: Table 3 on page 34 in pxl235821.pdf

The estimates of pharmacokinetic parameters are provided in Table 105.

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Table 105. Final model (Model 3499) parameter estimates and precisions (root mean square errors percent, RSE%), together with parameter medians and confidence intervals (95%) obtained from bootstrap analysis.

Source: Table 4 on page 50 in pxl235821.pdf

Overall, the model was able to describe the data reasonably well. Based on covariate analysis, only creatinine clearance (CRCL) was found to modestly influence parent drug clearance. Other covariates tested include body weight, gender, subject type and race on IC200056 clearance. These findings are also supported by reviewer’s analyses.

Exposure-Response Analyses Exposure-response analyses conducted by the applicant showed that, for Studies ITI-007-005 and -301, the relationship between change from baseline in Total PANSS scores (last study visit Day 28) and IC200056 exposures follow a U-shape pattern.

19.4.3 Clinical PK and/or PD Assessments Review of individual study reports will be finalized in DARRTS separately.

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Statistical Appendices

Table 106: Discontinuation Reasons Study 005 Study Reason for Placebo Lumateperone dose (mg) Risperidone Discontinuation (mg) 14 28 42 84 4 005 # of patients 85 84 84 82 randomized Discontinued Study 19 17 14 15 Drug (22.4) (20.2) (16.7) (18.3) Adverse Event 0 2 (2.4) 0 3 (3.7) Lack of Efficacy 8 (9.4) 0 1 (1.2) 3 (3.7) Patient 6 9 9 8 Withdrew (7.1) (10.7) (10.7) (9.8) Consent Other 5 (5.9) 6 (7.2) 4 (4.8) 1 (1.2) Source: Compiled by Statistical reviewer based on Study 005 CSR

Table 107: Discontinuation Reasons Study 301 Study Reason for Placebo Lumateperone dose (mg) Risperidone Discontinuation (mg) 14 28 42 84 4 301 # of patients 150 150 150 randomized Discontinued 37 27 19 Treatment Period (24.8) (18.0) (12.7) Adverse Event 1 (0.7) 4 (2.7) 2 (1.3) Lack of Efficacy 17 11 6 (11.3) (7.3) (4.0) Patient 17 11 11 Withdrew (11.3) (7.3) (7.3) Consent Other 2 (1.3) 1 (0.7) 0 Source: Compiled by Statistical reviewer based on Study 301 CSR

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Table 108: Discontinuation Reasons Study 302 Study Reason for Placebo Lumateperone dose (mg) Risperidone Discontinuation (mg) 14 28 42 84 4 302 # of patients 174 174 174 174 randomized Discontinued 37 56 44 64 Treatment Period (21.3) (32.2) (25.3) (36.8) Adverse Event 1 (0.6) 6 0 10 (5.7) (3.4) Lack of Efficacy 12 13 11 8 (6.9) (7.5) (6.3) (4.6) Patient 20 34 27 37 Withdrew (11.5) (19.5) (15.5) (21.3) Consent Other 4 (2.3) 3 6 (3.5) 9 (5.2) (1.7) Source: Compiled by Statistical reviewer based on Study 302 CSR

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Figure 43: PANSS trajectories (observed) and dropout reasons (Study 301)

Source: Statistical Reviewer

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Figure 44: PANSS trajectories (observed) and dropout reasons (Study 301)

Source: Statistical Reviewer

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Figure 45: PANSS trajectories (observed) and dropout reasons (Study 302)

Source: Statistical Reviewer

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Figure 46: PANSS trajectories (observed) and dropout reasons (Study 302)

Source: Statistical Reviewer

MedDRA Terms Included in Custom MedDRA Queries Used for Analysis of Data on Treatment-Emergent Adverse Events

Custom MedDRA Individual MedDRA Terms Comprising Query Query Abdominal pain, Abdominal discomfort; Abdominal distension; Abdominal pain; distension, bloating, Abdominal pain lower; Abdominal pain upper; Abdominal rigidity; spasm, IBS, Abdominal tenderness; Acute abdomen; Constipation; Epiploic megacolon appendagitis; Gastrointestinal pain; Intestinal spasm; Irritable bowel syndrome; Megacolon; Stomach discomfort Abscess, boil, Staphylococcal abscess; Streptococcal abscess; Abscess bacterial; furuncle Abscess fungal; Abdominal abscess; Abdominal wall abscess; Abscess; Abscess drainage; Abscess intestinal; Abscess jaw; Abscess limb;

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Abscess neck; Abscess of eyelid; Abscess of salivary gland; Abscess oral; Abscess soft tissue; Anal abscess; Appendiceal abscess; Bartholin’s abscess; Brain abscess; Breast abscess; Catheter site abscess; Chest wall abscess; Colonic abscess; Douglas abscess; Extradural abscess; Eye abscess; Furuncle; Genital abscess; Gingival abscess; Groin abscess; Implant site abscess; Incision site abscess; Injection site abscess; Joint abscess; Liver abscess; Lung abscess; Lymph node abscess; Muscle abscess; Mycobacterium abscessus infection; Nasal abscess; Pancreatic abscess; Paraoesophageal abscess; Paraspinal abscess; Parotid abscess; Pelvic abscess; Penile abscess; Perianal abscess; Peridiverticular abscess; Perineal abscess; Perinephric abscess; Perirectal abscess; Peritoneal abscess; Peritonsillar abscess; Periumbilical abscess; Pharyngeal abscess; Postoperative abscess; Psoas abscess; Rectal abscess; Retroperitoneal abscess; Scrotal abscess; Splenic abscess; Stitch abscess; Subcutaneous abscess; Subdiaphragmatic abscess; Testicular abscess; Tongue abscess; Tooth abscess; Urinary bladder abscess; Vaginal abscess; Vulval abscess; Wound abscess; Stoma site abscess; Abscess of external auditory meatus; Abscess rupture; Abscess sweat gland; Abscess sterile; Administration site abscess; Administration site abscess sterile; Adrenal gland abscess; Fungal abscess central nervous system Akathisia, Akathisia; Restlessness restlessness Allergic reaction, Bronchopulmonary aspergillosis allergic; Allergic bronchitis; Allergic hypersensitivity oedema; Allergic pharyngitis; Allergic sinusitis; Allergic transfusion reaction; Allergy to vaccine; Alveolitis allergic; Anaphylactic reaction; Anaphylactic shock; Anaphylactic transfusion reaction; Anaphylactoid reaction; Angioedema; Angioneurotic oedema; Circumoral oedema; Conjunctivitis allergic; Contrast media allergy; Dermatitis allergic; Dermatitis atopic; ; Drug hypersensitivity; Drug rash with eosinophilia and systemic symptoms; Ear swelling; Face oedema; Fixed eruption; Fuchs syndrome; Hypersensitivity; Infusion related reaction; Laryngeal oedema; Laryngitis allergic; Laryngospasm; Multiple allergies; Oropharyngeal spasm; Photosensitivity allergic reaction; Swelling face; Swollen tongue; Tongue oedema; Urticaria; Urticaria cholinergic; Urticaria chronic; Urticaria generalized; Urticaria localized; Urticaria pigmentosa; Vasculitic rash; Blepharitis allergic; Injection site hypersensitivity; Device allergy; Epiglottic oedema; Lip swelling; Nephritis allergic; Palatal oedema; Pharyngeal oedema; Injection related reaction; Injection site atrophy; Injection site discomfort; Injection site hypertrophy; Injection site irritation;

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Injection site macule; Injection site necrosis; Injection site plaque; Injection site scab; Injection site scar; Injection site vesicles; Lip oedema Anorexia, decreased Anorexia; Decreased appetite appetite Anxiety, with anxiety; Adjustment disorder with mixed nervousness, panic anxiety and depressed mood; Anxiety; ; Anxiety attacks disorder due to a general medical condition; Anxiety postoperative; Cardiac ; Generalized anxiety disorder; Nervousness; ; ; Panic disorder with ; Panic reaction; Psychomotor hyperactivity; Anticipatory anxiety; Limited symptom panic attack; Performance ; Separation anxiety disorder; disorder; Animal ; Arachnophobia; Astraphobia; Autophobia; Dysmorphophobia; ; Fear of animals; Fear of closed spaces; Fear of crowded places; Fear of death; Fear of disease; Fear of eating; Fear of falling; Fear of injection; Fear of open spaces; Fear of pregnancy; Fear of weight gain; Haemophobia; Haphephobia; Hydrophobia; Immunization anxiety related reaction; Kinesiophobia; Mysophobia; Noctiphobia; Nocturnal fear; ; Ochlophobia; Osmophobia; Paruresis; Phagophobia; Pharmacophobia; Phobia of driving; Phobia of exams; Phobia of flying; Phobic avoidance; Phonophobia; Photaugiaphobia; Postpartum neurosis; Procedural anxiety; ; Social fear; Thanatophobia; Thermophobia Arrhythmia Atrial bigeminy; Supraventricular extrasystoles; Arrhythmia supraventricular; Atrial fibrillation; Atrial flutter; Atrial tachycardia; Sinus arrhythmia; Sinus bradycardia; Supraventricular tachyarrhythmia; Supraventricular tachycardia; pacemaker; Accelerated idioventricular rhythm; Arrhythmia; Bradyarrhythmia; Bradycardia; Cardiac flutter; Extrasystoles; Heart rate decreased; Heart rate increased; Heart rate irregular; Nodal arrhythmia; Nodal rhythm; Parasystole; Atrial parasystole; Paroxysmal arrhythmia; Rhythm idioventricular; Sick sinus syndrome; Sinus tachycardia; Tachyarrhythmia; Tachycardia; Tachycardia paroxysmal; Torsade de pointes; Ventricular arrhythmia; Ventricular bigeminy; Ventricular extrasystoles; Ventricular fibrillation; Ventricular flutter; Ventricular parasystole; Ventricular tachyarrhythmia; Ventricular tachycardia; Ventricular trigeminy; Rebound tachycardia; Reperfusion arrhythmia; Withdrawal arrhythmia; Arrhythmia neonatal; Bradycardia foetal; Foetal arrhythmia; Tachycardia foetal; Neonatal tachycardia; Bradycardia neonatal; Foetal heart rate deceleration abnormality; Baseline foetal heart rate variability disorder;

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Nonreassuring foetal heart rate pattern; Foetal heart rate acceleration abnormality; Sinusoidal foetal heart rate pattern; Foetal tachyarrhythmia Arthralgia, arthritis, Septic arthritis staphylococcal; Septic arthritis streptococcal; arthrosis Arthralgia; Arthritis; Arthritis reactive; Arthrofibrosis; Arthropathy; Crystal arthropathy; Facet joint syndrome; Localized osteoarthritis; Monoarthritis; Nodal osteoarthritis; Osteoarthritis; Polyarthritis; Reiters syndrome; Rheumatoid arthritis; Seronegative arthritis; Spinal osteoarthritis; Spondylosis Back pain Radiculitis lumbosacral; Sacral pain; Back pain Constipation Constipation; Infrequent bowel movements; Post procedural constipation Cough Allergic cough; Cough; Productive cough; Upper-airway cough syndrome CPK increased Blood creatine phosphokinase; Blood creatine phosphokinase abnormal; Blood creatine phosphokinase increased; Blood creatine phosphokinase mb abnormal; Blood creatine phosphokinase mb increased; Muscle enzyme increased Cramps, muscle Muscle cramp; Muscle spasms; Night cramps spasm Dermatitis Herpes dermatitis; Dermatitis infected; Catheter site dermatitis; Dermatitis bullous; Dermatitis contact; Dermatitis exfoliative; Dermatitis psoriasiform; Perivascular dermatitis; Solar dermatitis; Acarodermatitis; Angiodermatitis; Dermatitis; Dermatitis acneiform; Dermatitis allergic; Dermatitis atopic; Dermatitis diaper; Hand dermatitis; Implant site dermatitis; Neurodermatitis; Photodermatosis; Seborrhoeic dermatitis; Stasis dermatitis; Application site dermatitis; Administration site dermatitis Diarrhea, colitis, Campylobacter gastroenteritis; Campylobacter infection; enteritis, proctitis, Campylobacter intestinal infection; Clostridial infection; Clostridium gastroenteritis, c-diff colitis; Clostridium difficile colitis; Enterocolitis bacterial; Gastroenteritis aeromonas; Gastroenteritis bacterial; Gastroenteritis clostridial; Gastroenteritis escherichia coli; Gastroenteritis salmonella; Cytomegalovirus colitis; Enterocolitis viral; Gastroenteritis enteroviral; Gastroenteritis norovirus; Gastroenteritis norwalk virus; Gastroenteritis rotavirus; Gastroenteritis viral; Gastrointestinal viral infection; Viral diarrhea; Gastroenteritis adenovirus; Gastrointestinal candidiasis; Diarrhea infectious; Enteritis infectious; Enterocolitis hemorrhagic; Enterocolitis infectious; Gastroenteritis; Gastroenteritis cryptosporidial; Gastrointestinal infection; Parasitic infection intestinal; Pseudomembranous colitis; Amoebic ;

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Clostridium test positive; Colitis; Colitis erosive; Colitis ischaemic; Colitis microscopic; Colitis ulcerative; Colon dysplasia; Colonic obstruction; Crohn’s disease; Diarrhea; Diarrhea hemorrhagic; Dysentery; Enteritis; Enteritis necroticans; Enterocele; Enterocolitis; Gastrointestinal inflammation; Inflammatory bowel disease; Intestinal ; Intestinal perforation; Large intestinal ulcer; Large intestine perforation; Mechanical ileus; Necrotizing colitis; Post procedural diarrhea; Sigmoiditis; Colitis psychogenic; Acute hemorrhagic ulcerative colitis; Enterocolitis fungal Dry mouth, dry lips, Dry mouth; Thirst thirst EPS, potential EPS, Akathisia; Blepharospasm; ; Cogwheel rigidity; Drooling; tardive dyskinesia, Dyskinesia; Dystonia; Excessive eye blinking; Extrapyramidal disorder; akathisia Facial spasm; Grimacing; Muscle contractions involuntary; Muscle spasms; Muscle twitching; Musculoskeletal stiffness; Myoclonus; Nuchal rigidity; Oculogyric crisis; Oromandibular dystonia; Parkinsonian rest tremor; Parkinsonism; Protrusion tongue; Resting tremor; Restlessness; Tardive dyskinesia; Tongue ; Tongue spasm; Torticollis; Tremor Fall, dizziness, Fall; Gait disturbance; Progressive supranuclear palsy; Balance balance disorder disorder; Dizziness; Dizziness exertional; Dizziness postural; Procedural dizziness Flatulence Flatulence GOT, GPT, GGTP, Alanine aminotransferase; Alanine aminotransferase abnormal; LFTs Alanine aminotransferase increased; Aspartate aminotransferase; Aspartate aminotransferase abnormal; Aspartate aminotransferase increased; Drug-induced liver injury; Gamma-glutamyltransferase; Gamma-glutamyltransferase abnormal; Gamma-glutamyltransferase increased; Hepatic enzyme abnormal; Hepatic enzyme increased; Hepatic function abnormal; Hepatocellular injury; Hepatotoxicity; Hypertransaminasemia; Liver function test abnormal; Transaminases; Transaminases abnormal; Transaminases increased; Liver injury; Liver function test increased Headache Cluster headache; Complicated migraine; Exertional headache; Headache; Migraine; Migraine with aura; Migraine without aura; Post syndrome; Post procedural headache; Post- traumatic headache; Sinus headache; Tension headache; Vascular headache; Procedural headache; Medication overuse headache; Status migrainosus; Vestibular migraine Infection, all Bacterial sepsis; Citrobacter sepsis; Clostridium difficile sepsis; Enterobacter sepsis; Enterococcal sepsis; Escherichia sepsis; Klebsiella

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

sepsis; Listeria sepsis; Pneumococcal sepsis; Pseudomonal sepsis; Salmonella sepsis; Serratia sepsis; Staphylococcal sepsis; Streptococcal sepsis; Candida sepsis; Biliary sepsis; Device related sepsis; Neutropenic sepsis; Post procedural sepsis; Pulmonary sepsis; Sepsis; Sepsis syndrome; Septic ; Septic rash; Septic shock; Urosepsis; Wound sepsis; Atypical mycobacterial pneumonia; Pneumonia bacterial; Pneumonia chlamydial; Pneumonia hemophilus; Pneumonia klebsiella; Pneumonia legionella; Pneumonia moraxella; Pneumonia mycoplasmal; Pneumonia pneumococcal; Pneumonia pseudomonal; Pneumonia staphylococcal; Pneumonia streptococcal; Actinomycotic pulmonary infection; Acinetobacter bacteraemia; Acinetobacter infection; Arthritis bacterial; Atypical mycobacterial infection; Atypical mycobacterial lymphadenitis; Bacteraemia; Bacterial diarrhoea; Bacterial infection; Bacterial prostatitis; Bacterial pyelonephritis; Bacterial rhinitis; Bacteroides bacteraemia; Beta haemolytic streptococcal infection; Bronchitis bacterial; Bronchitis pneumococcal; Bullous impetigo; Bursitis infective staphylococcal; Campylobacter gastroenteritis; Campylobacter infection; Campylobacter intestinal infection; Cellulitis staphylococcal; Cellulitis streptococcal; Cervicitis streptococcal; Chlamydial infection; Citrobacter infection; Clostridial infection; Clostridium colitis; Clostridium difficile colitis; Clostridium difficile infection; Conjunctivitis bacterial; Cystitis bacterial; Cystitis escherichia; Cystitis klebsiella; Cystitis pseudomonal; Ecthyma; Endocarditis bacterial; Endocarditis enterococcal; Enterobacter bacteraemia; Enterobacter infection; Enterococcal bacteraemia; Enterococcal infection; Enterocolitis bacterial; Erythrasma; Escherichia bacteraemia; Escherichia infection; Escherichia pyelonephritis; Escherichia urinary tract infection; Eye infection bacterial; Eye infection staphylococcal; Gardnerella infection; Gastritis bacterial; Gastroenteritis aeromonas; Gastroenteritis bacterial; Gastroenteritis clostridial; Gastroenteritis escherichia coli; Gastroenteritis salmonella; Gastrointestinal bacterial infection; Genital infection bacterial; Genitourinary chlamydia infection; Gonorrhoea; Haemophilus infection; Helicobacter gastritis; Helicobacter infection; Klebsiella bacteraemia; Klebsiella infection; Laryngitis bacterial; Legionella infection; Lower respiratory tract infection bacterial; Lung infection pseudomonal; ; Meningitis listeria; Meningitis meningococcal; Meningitis pneumococcal; Meningitis streptococcal; Moraxella infection; Morganella infection; Murine typhus; bed infection bacterial; Neuroborreliosis; Oral bacterial infection; Overgrowth bacterial; Pasteurella infection; Peritonitis bacterial; Pertussis; Pharyngitis bacterial; Pharyngitis mycoplasmal; Pharyngitis streptococcal; Propionibacterium infection; Proteus infection;

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Pseudomonal bacteraemia; Pseudomonas bronchitis; Pseudomonas infection; Psittacosis; Pyoderma streptococcal; Q fever; Respiratory tract infection bacterial; Salmonellosis; Scrub typhus; Septic arthritis staphylococcal; Septic arthritis streptococcal; Serratia infection; Shigella infection; Sinusitis bacterial; Skin bacterial infection; Staphylococcal abscess; Staphylococcal bacteraemia; Staphylococcal infection; Staphylococcal osteomyelitis; Staphylococcal pharyngitis; Staphylococcal skin infection; Stenotrophomonas infection; Streptococcal abscess; Streptococcal bacteraemia; Streptococcal infection; Streptococcal urinary tract infection; Syphilis; Tonsillitis bacterial; Tonsillitis streptococcal; Toxic shock syndrome; ; Typhoid fever; Upper respiratory tract infection bacterial; Ureaplasma infection; Urethritis gonococcal; Urinary tract infection bacterial; Urinary tract infection enterococcal; Urinary tract infection pseudomonal; Urinary tract infection staphylococcal; Urogenital infection bacterial; Vaginitis bacterial; Vaginitis gardnerella; Vancomycin-resistant enterococcal infection; Vulvovaginitis gonococcal; Wound infection bacterial; Wound infection pseudomonas; Wound infection staphylococcal; Yersinia infection; Abscess bacterial; Bacterial tracheitis; Bacterial vaginosis; Mastitis bacterial; Otitis media bacterial; Peptic ulcer helicobacter; Sycosis barbae; Mycoplasma infection; Acid fast bacilli infection; Actinomycosis; Actinomycotic abdominal infection; Actinomycotic skin infection; Aeromonas infection; Alcaligenes infection; Ear infection bacterial; Pneumococcal bacteraemia; Endocarditis gonococcal; Endocarditis haemophilus; Endocarditis meningococcal; Endocarditis pseudomonal; Endocarditis staphylococcal; Endocarditis syphilitic; Meningococcal carditis; Myocarditis meningococcal; Myocarditis syphilitic; Pericarditis gonococcal; Pericarditis meningococcal; Pericarditis syphilitic; Streptococcal endocarditis; Syphilitic endocarditis of heart valve; Pneumonia herpes viral; Cytomegalovirus colitis; Cytomegalovirus infection; Cytomegalovirus test positive; Encephalitis herpes; Epstein-barr virus infection; Genital herpes; Herpes dermatitis; Herpes oesophagitis; Herpes ophthalmic; Herpes simplex; Herpes simplex meningoencephalitis; Herpes simplex ophthalmic; Herpes virus infection; Herpes zoster; Herpes zoster ophthalmic; Herpetic stomatitis; Keratitis herpetic; Meningitis herpes; Ophthalmic herpes simplex; Ophthalmic herpes zoster; Oral herpes; Kaposis varicelliform eruption; Herpes zoster oticus; Pneumonia cytomegaloviral; Pneumonia influenzal; Pneumonia viral; Acquired immunodeficiency syndrome; Adenoviral conjunctivitis; Adenovirus infection; Anorectal human papilloma virus infection; Avian influenza; Bronchitis acute viral; Bronchitis viral; Chikungunya virus infection;

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Conjunctivitis viral; Coxsackie viral infection; Croup infectious; Cytomegalovirus hepatitis; Dengue fever; Ear infection viral; Encephalitis viral; Enterocolitis viral; Enterovirus infection; Epidemic polyarthritis; Eye infection viral; Gastritis viral; Gastroenteritis enteroviral; Gastroenteritis norovirus; Gastroenteritis norwalk virus; Gastroenteritis rotavirus; Gastroenteritis viral; Gastrointestinal viral infection; H1n1 influenza; Hepatitis a; Hepatitis b; Hepatitis c; Hepatitis infectious; Hepatitis viral; Herpangina; HIV infection; Infectious mononucleosis; Influenza; Keratitis viral; Laryngitis viral; Lower respiratory tract infection viral; Meningitis aseptic; Molluscum contagiosum; Mononucleosis syndrome; Mumps; Oral viral infection; Otitis media viral; Papilloma viral infection; Parainfluenzae virus infection; Respiratory tract infection viral; Retroviral infection; Rhinovirus infection; Roseola; Rotavirus infection; Rubella; Tracheobronchitis viral; Varicella; Viraemia; Viral diarrhoea; Viral infection; Viral labyrinthitis; Viral myocarditis; Viral pericarditis; Viral pharyngitis; Viral rash; Viral rhinitis; Viral sinusitis; Viral tracheitis; Viral upper respiratory tract infection; West Nile viral infection; Cystitis viral; Tick-borne viral encephalitis; Urinary tract infection viral; Viral skin infection; Acute hepatitis b; Acute hepatitis c; Adenoviral haemorrhagic cystitis; Adenoviral hepatitis; Adenoviral upper respiratory infection; Gastroenteritis adenovirus; Endocarditis viral; Viral cardiomyopathy; Bronchopulmonary aspergillosis; Candida pneumonia; Pneumocystis jiroveci pneumonia; Pneumocystis jirovecii pneumonia; Pneumonia fungal; Pneumonia cryptococcal; Anal candidiasis; Anal fungal infection; Arthritis fungal; Aspergilloma; Aspergillosis; Axillary candidiasis; Balanitis candida; Bladder candidiasis; Body tinea; Bronchopulmonary aspergillosis allergic; Candida infection; Candidiasis; Candiduria; Cerebral toxoplasmosis; Coccidioidomycosis; Dermatophytosis; Ear infection fungal; Fungaemia; Fungal cystitis; Fungal infection; Fungal oesophagitis; Fungal rash; Fungal skin infection; Gastritis fungal; Gastrointestinal candidiasis; Gastrointestinal fungal infection; Genital candidiasis; Genital infection fungal; Intertrigo candida; Laryngitis fungal; Lower respiratory tract infection fungal; Mycetoma mycotic; Nail bed infection fungal; Nail tinea; Oesophageal candidiasis; Onychomycosis; Oral candidiasis; Oral fungal infection; Oropharyngeal candidiasis; Oropharyngitis fungal; Otitis externa fungal; Perianal fungal infection; Pulmonary mycosis; Respiratory moniliasis; Skin candida; Systemic candida; Systemic mycosis; Tinea capitis; Tinea cruris; Tinea faciei; Tinea infection; Tinea manuum; Tinea pedis; Tinea versicolour; Toxoplasmosis; Trichophyton infection; Trichophytosis; Upper respiratory fungal infection; Urinary tract infection fungal; Vaginal

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

candidiasis; Vaginal mycosis; Vulvovaginal candidiasis; Vulvovaginal mycotic infection; Wound infection fungal; Dermatophytosis of nail; Microsporidia infection; Abscess fungal; Acute pulmonary histoplasmosis; Sinusitis fungal; Endocarditis histoplasma; Fungal endocarditis; Myocarditis toxoplasmal; Diabetic gangrene; Gangrene; Gas gangrene; Loefflers syndrome; Atypical pneumonia; Bronchopneumonia; Lobar pneumonia; Organising pneumonia; Pneumonia; Pneumonia aspiration; Pneumonia necrotising; Pneumonia primary atypical; Post procedural pneumonia; Abdominal abscess; Abdominal infection; Abdominal wall abscess; Abdominal wall infection; Abscess; Abscess drainage; Abscess intestinal; Abscess jaw; Abscess limb; Abscess neck; Abscess of eyelid; Abscess of salivary gland; Abscess oral; Abscess soft tissue; Acute diverticulitis; Acute sinusitis; Acute tonsillitis; Adenoiditis; American ; Amoebiasis; Anal abscess; Anal fistula infection; Anorectal infection; Appendiceal abscess; Appendicitis; Appendicitis perforated; Application site infection; Arteriovenous fistula site infection; Arteriovenous graft site abscess; Arteriovenous graft site infection; Arthritis infective; Ascariasis; Ascites infection; Babesiosis; Bartholin’s abscess; Blastocystis infection; Blister infected; Blood culture positive; Borrelia infection; Brain abscess; Breast abscess; Breast cellulitis; Bronchial infection; Bronchiolitis; Bronchitis; Bronchitis acute; Burn infection; Bursitis infective; Carbuncle; Cardiac infection; Catheter related infection; Catheter site abscess; Catheter site infection; Cellulitis; Cellulitis gangrenous; Cellulitis laryngeal; Cellulitis of male external genital organ; Cellulitis orbital; Central line infection; Central nervous system infection; Cervicitis; Chest wall abscess; Cholangitis; Cholangitis acute; Cholangitis suppurative; Cholecystitis; Cholecystitis acute; Cholecystitis chronic; Cholecystitis infective; Cholecystocholangitis; Chronic sinusitis; Chronic tonsillitis; Colonic abscess; Community acquired infection; Conjunctivitis infective; Creutzfeldt-Jakob disease; Culture urine positive; Culture wound positive; Cutaneous ; Cystitis; Dacryocystitis; Dacryocystitis infective; Dental gangrene; Dermatitis infected; Device related infection; Diabetic foot infection; Diarrhoea infectious; Disseminated tuberculosis; Diverticulitis; Diverticulitis intestinal haemorrhagic; Douglas abscess; Ear infection; Ear lobe infection; Echinococciasis; Eczema infected; Emphysematous cholecystitis; Empyema; Endocarditis; Endophthalmitis; Enteritis infectious; Enterobiasis; Enterocolitis haemorrhagic; Enterocolitis infectious; Epidemic nephropathy; Epiglottitis; Erysipelas; External ear cellulitis; Extradural abscess; Eye abscess; Eye infection; Eyelid boil; Eyelid infection; Febrile infection; Folliculitis; Furuncle; Gallbladder

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

empyema; Gastric infection; Gastric ulcer helicobacter; Gastroenteritis; Gastroenteritis cryptosporidial; Gastrointestinal infection; Genital abscess; Genital infection; Genital infection female; Genital infection male; Genitourinary tract infection; ; Gingival abscess; Gingival infection; Graft infection; Groin abscess; Groin infection; Haematoma infection; Haemorrhoid infection; Helminthic infection; Hepatic cyst infection; Hepatitis chronic active; Hookworm infection; Hordeolum; Hydrocele male infected; Impetigo; Implant site abscess; Implant site infection; Incision site abscess; Incision site cellulitis; Incision site infection; Infected bites; Infected cyst; Infected dermal cyst; Infected epidermal cyst; Infected fistula; Infected naevus; Infected sebaceous cyst; Infected skin ulcer; Infected varicose vein; Infection; Infection parasitic; Infectious colitis; Infectious peritonitis; Infectious pleural effusion; Infective exacerbation of bronchiectasis; Infective exacerbation of chronic obstructive airways disease; Infective glossitis; Infective myositis; Infective tenosynovitis; Infective thrombosis; Infective uveitis; Influenza like illness; Infusion site cellulitis; Infusion site infection; Injection site abscess; Injection site cellulitis; Injection site infection; Intervertebral discitis; Joint abscess; Kidney infection; Labyrinthitis; Laryngitis; Latent tuberculosis; ; Lice infestation; Lip infection; Liver abscess; Localised infection; Lower respiratory tract infection; Lung abscess; Lung infection; Lymph gland infection; Lymph node abscess; Lymph node tuberculosis; Lymphangitis; ; Mastitis; Mastoiditis; Mediastinitis; Meningitis; Meningitis bacterial; Meningitis tuberculous; Meningitis viral; Mucosal infection; Muscle abscess; Mycobacterial infection; Mycobacterium abscessus infection; Mycobacterium avium complex infection; Myringitis; Nail infection; Nasal abscess; Nasopharyngitis; Necrotising fasciitis; Nematodiasis; Neurocysticercosis; Nipple infection; Nosocomial infection; Oesophageal infection; Omphalitis; Oophoritis; Opisthorchiasis; Oral infection; Orchitis; Osteomyelitis; Osteomyelitis acute; Osteomyelitis chronic; Otitis externa; Otitis media; Otitis media acute; Otitis media chronic; Pancreatic abscess; Paraoesophageal abscess; Parasitic gastroenteritis; Parasitic infection intestinal; Paraspinal abscess; Paronychia; Parotid abscess; Parotitis; Pelvic abscess; Pelvic infection; Pelvic inflammatory disease; Penile abscess; Penile infection; Perianal abscess; Pericarditis infective; Peridiverticular abscess; Perineal abscess; Perineal infection; Perinephric abscess; Periodontal infection; Periorbital cellulitis; Perirectal abscess; Peritoneal abscess; Peritoneal infection; Peritoneal tuberculosis; Peritonitis; Peritonsillar abscess; Peritonsillitis; Periumbilical abscess; Pharyngeal abscess; Pharyngitis; Pharyngotonsillitis; Phlebitis infective; Pilonidal cyst; Plasmodium

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

falciparum infection; Post procedural cellulitis; Post procedural infection; Postoperative abscess; Postoperative infection; Postoperative wound infection; Proctitis infectious; Prostate infection; Pseudomembranous colitis; Psoas abscess; Pulmonary tuberculoma; Pulmonary tuberculosis; Pulpitis dental; Puncture site infection; Pyelocystitis; Pyelonephritis; Pyelonephritis acute; Pyelonephritis chronic; Pyoderma; Pyometra; Pyonephrosis; Pyopneumothorax; Rash pustular; Rectal abscess; Renal cyst infection; Renal tuberculosis; Respiratory tract infection; Retroperitoneal abscess; Rhinitis; Rocky mountain spotted fever; Salpingitis; Salpingo-oophoritis; Scrotal abscess; Scrotal infection; Sebaceous gland infection; Septic embolus; Septic necrosis; Sexually transmitted disease; Shunt infection; Sialoadenitis; Sinobronchitis; Sinusitis; Skin infection; Soft tissue infection; Splenic abscess; Stitch abscess; Strongyloidiasis; Subacute endocarditis; Subcutaneous abscess; Subdiaphragmatic abscess; Superinfection; Superinfection lung; Taeniasis; Testicular abscess; Tongue abscess; Tonsillitis; Tooth abscess; Tooth infection; Tracheitis; Tracheobronchitis; Tropical eosinophilia; Tuberculosis; Tuberculosis of central nervous system; Tuberculosis of genitourinary system; Tuberculous pleurisy; Typhus; Upper respiratory tract infection; Ureteritis; Urethritis; Urinary bladder abscess; Urinary tract infection; Uterine infection; Vaginal abscess; Vaginal infection; Vulval abscess; Vulval cellulitis; Vulvitis; Vulvovaginitis trichomonal; Wound abscess; Wound infection; Eczema impetiginous; Infected bite; Perichondritis; Root canal infection; Stoma site abscess; Abdominal hernia infection; Abortion infected; Abscess of external auditory meatus; Abscess rupture; Abscess sweat gland; Acanthamoeba infection; Acanthamoeba keratitis; Acariasis; Acute endocarditis; Acute postoperative sialadenitis; Administration site cellulitis; Administration site infection; Administration site joint infection; Adrenal gland tuberculosis; African trypanosomiasis; Fasciolopsiasis; Infected seroma; Endocarditis helminthic; Malarial myocarditis; Pericarditis mycoplasmal; Pericarditis tuberculous; Streptobacillus infection; Metapneumovirus infection; Fungal balanitis; Fungal labyrinthitis; Fungal paronychia; Fungal peritonitis; Fungal pharyngitis; Fungal retinitis; Fungal rhinitis; Fungal sepsis; Fungal tracheitis; Fungal abscess central nervous system; Tongue fungal infection; Cerebral fungal infection; Mastitis fungal; Keratitis fungal; Proctitis fungal; Bronchitis fungal; Meningitis fungal; Overgrowth fungal; Tonsillitis fungal; Pancreatitis fungal; Otitis media fungal; Pericarditis fungal; Encephalitis fungal; Enterocolitis fungal; Eye infection fungal; Lymphadenitis fungal; Osteomyelitis fungal; Pyelonephritis fungal; Superinfection fungal; Hepatic infection fungal; Splenic infection

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fungal; Urogenital infection fungal; Necrotising fasciitis fungal; Central nervous system fungal infection; Biliary tract infection fungal; Respiratory tract infection fungal Infection, fungal Candida sepsis; Bronchopulmonary aspergillosis; Candida pneumonia; Pneumocystis jiroveci pneumonia; Pneumocystis jirovecii pneumonia; Pneumonia fungal; Pneumonia cryptococcal; Anal candidiasis; Anal fungal infection; Arthritis fungal; Aspergilloma; Aspergillosis; Axillary candidiasis; Balanitis candida; Bladder candidiasis; Body tinea; Bronchopulmonary aspergillosis allergic; Candida infection; Candidiasis; Candiduria; Cerebral toxoplasmosis; Coccidioidomycosis; Dermatophytosis; Ear infection fungal; Fungaemia; Fungal cystitis; Fungal infection; Fungal oesophagitis; Fungal rash; Fungal skin infection; Gastritis fungal; Gastrointestinal candidiasis; Gastrointestinal fungal infection; Genital candidiasis; Genital infection fungal; Intertrigo candida; Laryngitis fungal; Lower respiratory tract infection fungal; Mycetoma mycotic; Nail bed infection fungal; Nail tinea; Oesophageal candidiasis; Onychomycosis; Oral candidiasis; Oral fungal infection; Oropharyngeal candidiasis; Oropharyngitis fungal; Otitis externa fungal; Perianal fungal infection; Pulmonary mycosis; Respiratory moniliasis; Skin candida; Systemic candida; Systemic mycosis; Tinea capitis; Tinea cruris; Tinea faciei; Tinea infection; Tinea manuum; Tinea pedis; Tinea versicolour; Toxoplasmosis; Trichophyton infection; Trichophytosis; Upper respiratory fungal infection; Urinary tract infection fungal; Vaginal candidiasis; Vaginal mycosis; Vulvovaginal candidiasis; Vulvovaginal mycotic infection; Wound infection fungal; Dermatophytosis of nail; Microsporidia infection; Abscess fungal; Acute pulmonary histoplasmosis; Sinusitis fungal; Endocarditis histoplasma; Fungal endocarditis; Myocarditis toxoplasmal; Fungal balanitis; Fungal labyrinthitis; Fungal paronychia; Fungal peritonitis; Fungal pharyngitis; Fungal retinitis; Fungal rhinitis; Fungal sepsis; Fungal tracheitis; Fungal abscess central nervous system; Tongue fungal infection; Cerebral fungal infection; Mastitis fungal; Keratitis fungal; Proctitis fungal; Bronchitis fungal; Meningitis fungal; Overgrowth fungal; Tonsillitis fungal; Pancreatitis fungal; Otitis media fungal; Pericarditis fungal; Encephalitis fungal; Enterocolitis fungal; Eye infection fungal; Lymphadenitis fungal; Osteomyelitis fungal; Pyelonephritis fungal; Superinfection fungal; Hepatic infection fungal; Splenic infection fungal; Urogenital infection fungal; Necrotising fasciitis fungal; Central nervous system fungal infection; Biliary tract infection fungal; Respiratory tract infection fungal Insomnia Initial insomnia; Insomnia; Middle insomnia; Terminal insomnia

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Insomnia, sleep Initial insomnia; Insomnia; Middle insomnia; Terminal insomnia; disturbance, Abnormal dreams; Abnormal sleep-related event; Circadian rhythm abnormal dreams ; Delayed sleep phase; ; Hyposomnia; Irregular sleep phase; ; ; Poor quality sleep; Sleep disorder; Sleep talking; Sleep terror; Somnambulism; Breathing- related sleep disorder; ; Rapid eye movements sleep abnormal; Advanced sleep phase Nausea, vomiting Nausea; Procedural nausea; Procedural vomiting; Vomiting; Vomiting projectile Neck pain Neck pain Oropharyngeal pain Oropharyngeal pain Rash, eruption, Septic rash; Viral rash; Fungal rash; Rash pustular; Catheter site dermatitis dermatitis; Application site rash; Erythema migrans; Exanthem; Exfoliative rash; Fixed eruption; Genital rash; Heat rash; Pemphigoid; Photosensitive rash; Rash; Rash erythematous; Rash generalised; Rash macular; Rash maculo-papular; Rash morbilliform; Rash papular; Rash pruritic; Rash vesicular; Systemic lupus erythematosus rash; Toxic skin eruption; Vasculitic rash; Eyelid rash; Administration site rash Reflux, GERD Duodenogastric reflux; Gastrooesophageal reflux disease; Gastrooesophageal sphincter insufficiency Restlessness, Agitation; Agitation postoperative; Akathisia; Feeling jittery; agitation, Hyperkinesia; Restlessness; Agitated depression; Agitation neonatal hyperkinesia, akathisia Skin irritation Skin irritation Somnolence, fatigue, Muscle fatigue; Chronic fatigue syndrome; Fatigue; Sedation; sedation Somnolence Tachycardia Atrial flutter; Atrial tachycardia; Supraventricular tachyarrhythmia; Supraventricular tachycardia; Heart rate increased; Sinus tachycardia; Tachyarrhythmia; Tachycardia; Tachycardia paroxysmal; Ventricular flutter; Rebound tachycardia; Tachycardia foetal; Neonatal tachycardia; Foetal tachyarrhythmia Toothache Toothache URI, cold, rhinitis, Bacterial rhinitis; Pertussis; Pharyngitis bacterial; Pharyngitis upper respiratory mycoplasmal; Pharyngitis streptococcal; Respiratory tract infection tract infection, flu- bacterial; Sinusitis bacterial; Staphylococcal pharyngitis; Tonsillitis like illness streptococcal; Upper respiratory tract infection bacterial; Laryngitis viral; Respiratory tract infection viral; Viral pharyngitis; Viral rhinitis; Viral sinusitis; Viral upper respiratory tract infection; Adenoviral upper respiratory infection; Upper respiratory fungal infection; Acute

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Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

sinusitis; Chronic sinusitis; Epiglottitis; Influenza like illness; Laryngitis; Nasopharyngitis; Pharyngitis; Pharyngotonsillitis; Respiratory tract infection; Rhinitis; Sinobronchitis; Sinusitis; Tonsillitis; Upper respiratory tract infection; Maxillary sinusitis; Rhinitis hypertrophic; Rhinitis seasonal; Rhinitis ulcerative; Upper respiratory tract congestion; Laryngopharyngitis; Fungal pharyngitis; Fungal rhinitis UTI Urosepsis; Bacterial pyelonephritis; Cystitis bacterial; Cystitis escherichia; Cystitis klebsiella; Cystitis pseudomonal; Escherichia pyelonephritis; Escherichia urinary tract infection; Streptococcal urinary tract infection; Urethritis gonococcal; Urinary tract infection bacterial; Urinary tract infection enterococcal; Urinary tract infection pseudomonal; Urinary tract infection staphylococcal; Urogenital infection bacterial; Cystitis viral; Urinary tract infection viral; Adenoviral haemorrhagic cystitis; Fungal cystitis; Urinary tract infection fungal; Culture urine positive; Cystitis; Genitourinary tract infection; Kidney infection; Pyelocystitis; Pyelonephritis; Pyelonephritis acute; Pyelonephritis chronic; Pyonephrosis; Ureteritis; Urethritis; Urinary tract infection; Pyelonephritis fungal; Urogenital infection fungal

305 Version date: October 12, 2018

Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone)

Internal FDA Pathology Consult for Lumateperone: Brain and Spinal Cord Glass Slide Review of the 9-month Dog and 2-Year Rat Studies

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DEPARTMENT OF HEALTH & HUMAN SERVICES              

  

  October 04, 2019  Sabine Francke, D.V.M., Ph.D., FIATP and Steven Mog, D.V.M., DACVP, Office of Food Additive Safety, CFSAN (HFS-205)    Division of Psychiatry Products - NDA 209500 (ITI-007, Lumateperone) Pathology Consult Request (Brain and spinal cord glass slide review of the 9- month dog and 2-year rat study)  Darren Fegley, Ph.D., DABT; Jasmeet (Mona) Kalsi, Pharm.D.; Ikram Elayan, Ph.D., Division of Psychiatry Products, FDA/CDER/OND/DPP

References:

1. E-mail from Fegley to Francke/Mog, dated July 26, 2019, Subject: Pathology consult request – with one attachment: a. Pathology Consult Request.docx – review of slides provided by the Applicant and 4 specific questions from CDER /OND/ DPP

2. E-mail from Fegley to Mog/Francke, dated September 16, 2019, Subject: NDA 209500, Lumateperone (Applicants recent submissions) with 6 attachments: a. Rat Carc Resin tibial nerve.pdf – Resin embedding and slide preparation of tibial nerves from rat study 8328209 – authored by (b) (4) , dated 09042019 (final report)

b. Rat Carc right side ganglia and nerves.pdf – 104-week oral gavage carcinogenicity study in rats with ITI-007: targeted neuropathology evaluation of right-side ganglia and nerves – authored by (b) (4) , dated 09062019 (final report)

c. Rat Carc brain spinal cord heart sudan black stain.pdf - 104-week oral gavage carcinogenicity study in rats with ITI-007: targeted neuropathology review or brain and spinal cord and review of sudan black B stained sections from selected brain, spinal cord and hearts – authored by(b) (4) , dated 09092019 (final report)

d. Rat Carc eyes optic nerves left sciatic nerves.pdf - 104-week oral gavage carcinogenicity study in rats with ITI-007: targeted evaluation of eyes, optic nerves and left sciatic nerves – authored by (b) (4) , dated 07122019 (final report)

e. Study ITI-007-TOX-1901.pdf – Nature of pigmented material associated with the aniline metabolites of Lumateperone – authored by (b) (4) , dated 08292019

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f. Study ITI-007-CHEM-1902.pdf – Exploratory evaluation of chemical stability and color changes of substituted aniline metabolites of ITI-007 – authored by (b) (4) dated 08292019 (final report)

3. From Francke/Mog to Elayan /Fegley, dated July 17, 2019, Subject: Rat Carcinogenicity CNS, PNS, Eye Pathology (draft) reports (b) (4)

4. Memorandum from Francke/Mog to Fegley/Kalsi/Elayan, dated June 20, 2019, Subject: NDA 209500 (ITI-007, Lumateperone) Pathology Consult Request

Background: Based on your request (reference 1) both of us have reviewed the materials (slides and reports) referenced above. This review focused on the 9-month beagle dog study and the 2-year Sprague Dawley rat study with Lumateperone on which we have previously reported (reference 4). Specifically, for this response, we have evaluated targeted brain and spinal cord slides of these two studies which were obtained from the sponsor to answer your specific questions (reference 1). The study design of these two studies is summarized in the table below.

CFSAN Pathology: Study Design Summary Table of Nonclinical Studies Reviewed Species Study Final Study Laboratory Doses # Recovery Duration Report Signed mg/kg/day Animals # Animals Sex/Group Sex / Group Dog 9-Month 05/15/2017 Name change: (b) (4) Oral Capsule 4 None 0, 2.5, 5, 10, 15 TEM of brain (neurons) by (b) (4) ; High dose animals were removed on day 143 because of CNS signs persisting after dosing holiday – high dose animals were only about half of the 280 days on study (b) (4) Rat 104-Week 04/26/2018 Oral Gavage 55 None Males: 0, 5, 10, 20 Females: 0, 5, 15/10, 30/20* *mid and high dose was lowered to 10 and 20 mg/kg/day respectively on day 386 of treatment because of higher mortality (cardiopulmonary disease)

Your specific Questions: To accommodate your pressing timelines, we have conducted an expedited review in which we focused our evaluation on the verification of selected slide diagnoses and report information relevant to addressing your specific questions (reference 1) which are depicted in italicized blue font throughout the document. We also integrated in our answers to your questions, information we recently received and evaluated which was presented in the six attachments of reference 2. Specifically, we have evaluated and commented on the draft reports of references and 2d previously (reference 3).

Your expertise in pathology would be a great benefit to the Division in assisting us in understanding the histopathological findings identified in the nonclinical studies provided to support marketing authorization for lumateperone (NDA209500). In particular we would like you to evaluate slides processed and provided by the Applicant and address the following questions regarding the lysosomal accumulation of pigmented material in the central nervous system of dogs and rats treated with lumateperone for up to 9 months (dogs) or 2 years (rats).

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Question 1: Does the lysosomal accumulation of pigmented material in neurons in the brain and spinal cord of dogs contribute to the lesions observed in these tissues? We previously summarized the characteristics of lysosomal drug pigment accumulations, reported by the respective study pathologists (reference 4, pg. 3-4). Our independent slide evaluations, overall, confirmed these descriptions of the pigment. Briefly, the pigment in the CNS presented as finely granular to large globular compacted accumulations in the cytoplasm or the perikaryon space of affected cells. The pigment was described to be yellowish-brown, orange or red, material, located mainly in neurons, phagocytic cells (macrophages), and choroid plexus epithelial cells, as well as occasionally free in the extracellular space (indicative of release from degenerate/necrotic cells).

We also summarized in reference 4 (pg. 5-6), the lesion incidences reported respectively in the 3- month (lysosomal pigment accumulation, neuronal degeneration and necrosis in the brain and spinal cord) and 9-month dog studies (lysosomal pigment accumulation, perivascular cuffing and axonal degeneration in the brain and spinal cord). Specifically, the study pathologist (b) (4) of the 9-month dog study diagnosed the following treatment related changes in the CNS (brain and spinal cord, reference 4, pg. 7):

Pigment, Brain: M: 0,4,4,4,4 F:0,2,4,4,4 Pigment, Spinal Cord: M: 0,1,4,4,4 F:0,0,4,4,4 Axonal degeneration, Brain: M: 0,0,0,4,4 F:0,0,0,4,4 Axonal degeneration, Spinal Cord: M: 0,0,0,1,4 F:0,0,0,2,3 Perivascular cuffing, Brain: M: 2*,1,3,4,4 F:0,0,4,4,4 M: 1, 1,3,4,4 (CFSAN Pathology) Perivascular cuffing, Spinal Cord: M: 0,0,2,2,0* F:0,0,0,3,2 M: 0,0,2,2,2 (CFSAN Pathology)

*Upon slide review, we (CFSAN Pathology) identified: - only one control male (ED0002) with perivascular cuffing in the brain, instead of two animals; - an additional 2 high dose males (ED4002, ED4004) with perivascular cuffing in the spinal cord, instead of 0 recorded by the study pathologist.

Pathology comment: The results of the 3-month dog study described and depicted in photomicrographs co-localization of drug pigment in the same or nearby neurons (reference 1aii pg. 38, 39; Appendix III, Figures 1-17, pg. 1546-1554 cited from reference 4). We consider the 3-month dog study changes (neuronal degeneration and necrosis) to be precursor lesions to the perivascular cuffing and axonal degeneration reported in the 9-month study. For a better illustration of this connection, we have provided selected photomicrographs below from the study report of the 3-moth dog study and photomicrographs we took during our slide review of the 9-month dog study.

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Photomicrographs of the 3-month dog study:

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Photomicrographs of the 9-month dog study:

Brain, 10 mg/kg/day female dog ED3103 (200x, HE). Note the red drug pigment in neurons (white arrow) and adjacent perivascular cuffing or inflammation (black arrow).

Brain, 15 mg/kg/day female dog ED4101 (400x, HE). Note the perivascular cuff (lymphocytes/macrophages) has a few pigmented macrophages (white arrow).

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Brain, 15 mg/kg/day female dog ED4101 (400x, IBA-1 IHC). This perivascular cuff has IBA-1 positive macrophages and surrounding IBA-1 positive reactive microglia cells.

Pigment accumulation in the dog was described in several CNS cell types, including large polygonal neurons in the brainstem and deep cerebellar nuclei, Purkinje cells, neurons of the hippocampus and cerebral cortex. We (CFSAN Pathology) also observed the pigment in the choroid plexus of the rat and macrophages in the brain of both the dog and rat. Based on the photomicrographs of the 3-month dog study and our independent slide review of brain and spinal cord sections from the 9-month dog study, we conclude that the drug pigment contributed to the described lesions for the following reasons: • The pigment was almost always co-located in (or near) the lesions, while lesions without pigment were rare. • Pigment accumulation and CNS lesions were dose responsive in incidence and severity and the pigment accumulation appeared to precede the other CNS lesions. • The TEM report of brain tissue from the 9-month dog study (reference 1aiii pg. 4 cited from reference 4) reported increased size (hypertrophy) and number (hyperplasia) of pigment-laden lysosomes; this subcellular change indicates lysosomal storage of drug pigment beyond normal homeostatic capacity. The described lysosomal pigment accumulation represents an impaired lysosomal storage state exhibiting characteristics similar to lysosomal storage diseases resulting from endogenous or exogenous causes reported in the published literature.  An impaired lysosomal storage state is defined as the accumulation of material resistant to or exceeding the capacity of the machinery responsible for intracellular digestion, disposal and transport. The implication is that the catabolic machinery of the cell is fundamentally incompetent leading to steady progressive product accumulation, undegradable by the affected cell. All cells can be affected; but lysosomal storage impairment affects most characteristically 7

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long lived post mitotic cells such as multisystemic neurons (including those of the retina and peripheral ganglia) as well as cardiomyocytes. Limited capacity of neurons to discharge the stored material via exocytosis has been reported but in general “intractable constipation” is inevitable as long as the cause of the entrapment is not resolved. Therefore, if neurons are involved, clinical signs of neurological impairment become eventually evident, but may not correlate with significant histological evidence of neuronal death. Reginal neuronal death occurs early and is progressive resulting in functional disturbance as there is no recourse for neurons except to accumulate pigment until the cell or the animal dies (Maxie and Youssef, 2007, pg. 322-323). • As lysosomes reach Lumateperone pigment accumulation beyond capacity, cell degeneration and necrosis result in the release of pigment into the extracellular space. • In our opinion, early lysosomal ‘constipation’ and subtle neuronal loss followed by release of drug pigment into the extracellular space resulted in a sustained low grade reactive tissue response to cells with pigment (neurons, reactive microglia and macrophages), which manifested as increased staining of IBA-1 immunohistochemistry indicating an overall activation of microglial cells (the brain resident macrophage or phagocytic cell) as well as an increase in GFAP staining intensity, indicating a reactive state of astrocytes. With prolonged treatment time and/or higher doses, this was then followed by an initial reactive inflammatory (histiocytic) response (as coined for sciatic nerve by (b) (4) , reference 2d, pg. 9) to lysosomal pigment constipation which in sensitive species (such as the dog) culminates in inflammatory ‘perivascular cuffing’ (reference 4, pg. 6) of lymphocytes and macrophages which is classically seen in inflammatory conditions within which all classes of reactive leukocytes may be seen depending on the cause (Maxie and Youssef, 2007, pg. 297)

i. Alternatively, do these lesions appear to be unrelated to lysosomal accumulation of pigmented material and, therefore, related to a direct neurotoxicity by other means (e.g., anilines, proposed metabolic products in rats and dogs but not in humans). As outlined above, we believe that the reported lesions (perivascular cuffing and axonal degeneration) described in the brain and spinal cord of dogs are related to the lysosomal accumulation of pigmented material (drug pigment).

Question 2: Does the lysosomal accumulation of pigmented material in neurons in the spinal cord of rats contribute to the lesions observed in this tissue? Briefly, the study pathologist (b) (4) of the 2-year rat study diagnosed the following changes for the spinal cord (reference 1biv, pg. 48 cited from reference 4): Pigment, neuron, spinal cord: M: 0, 16, 36, 51 F: 2, 14, 52, 55 Axonal degeneration, dorsal funiculus, spinal cord: M: 0, 0, 2, 16 F: 0, 0, 3, 11 The targeted review pathologist (b) (4) of the 2-year rat study diagnosed the following for the spinal cord in male and female rats (reference 2c, pg. 15-20): Pigment, neuron, spinal cord: M: 0, 25, 41, 53 F:1*, 22, 53, 54 Axonal degeneration, dorsal funiculus, spinal cord: M: 0, 0, 3, 19 F: 0, 0, 4, 17 Axonal degeneration, ventral funiculus, spinal cord:

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M: 2, 3, 2, 0 F: 1, 0, 3, 13

* We (CFSAN Pathology) did not observe any pigment in this control animal (B39828) which also had a history of being found dead, cannibalized and autolyzed.

i. Is the location of lysosomal accumulation of pigmented material in neurons in the spinal cord of rats consistent with the location of axonal degeneration in this tissue? The initial evaluation by the study pathologist(b) (4) pointed to a more selective location of the described axonal degeneration specifically localizing to the dorsal funiculus of the spinal cord. The targeted review of the spinal cord by (b) (4) (reference 2c, pg. 15-20) additionally reported axonal degeneration in the spinal cord white matter, also affecting the ventral funiculus of high dose females. Therefore, consistent with lysosomal storage diseases, the targeted review and our slide review points to neurons potentially being affected anywhere in the spinal cord gray matter, without location predilection. Therefore, the reported axonal degeneration could occur anywhere in the white matter tracks. It should also be noted that both findings, neuronal pigmentation and axonal degeneration are dose responsive in both sexes where neuronal pigmentation consistently preceded axonal degeneration in incidence.

ii. Is the lysosomal accumulation of pigmented material in the spinal cord of rats associated with an inflammatory response in this tissue? The study pathologist (b) (4) and the targeted review pathologist(b) (4) did not diagnose an reactive (gliosis) or inflammatory (histiocytic inflammation) change specifically for spinal cord; however, “infiltration of pigmented macrophages” were reported in the brain by (b) (4) and confirmed by (b) (4) calling it “foci of granule-packed round cells (consistent with macrophages)”, in his final report (reference 2c pg. 6). However, in his draft report, (b) (4) referred to this observation as “foci of granule-packed glial cells” as well as “gliosis focal and gliosis multifocal”.

Pathology comment: We (CFSAN Pathology) observed a subtle increase in numbers of activated microglial cells (gliosis) or macrophage sometimes containing pigment that in our opinion constitutes a low grade reactive / inflammatory response mirroring, to a lesser degree, the processes described in the rat brain (see below). See photomicrograph below of spinal cord with reactive / inflammatory focus containing red pigment.

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Spinal cord, ventral horn, high dose female rat B39993 (400x, HE). Note the pigmented round cell cluster (black arrow) adjacent to a pigmented neuron (white arrow).

iii. If unrelated to the lysosomal accumulation of pigmented material, could they be related to a direct neurotoxicity (e.g., anilines) As stated above, we believe that there is a relationship between the lysosomal accumulation of pigment and the aniline drug metabolites resulting in neurotoxicity with high doses over time in sensitive animal species. We did not encounter evidence supporting direct drug neurotoxicity.

iv. Alternatively, are these findings consistent with background lesions that may be observed in aging rats? 1. If so, is it likely they are due to the CNS depressant effects of lumateperone (immobility or changes in posture that lead to nerve entrapment, increased inflammation, changes in microglia function, and autonomic dysfunction) and, therefore, not related to the lysosomal accumulation of pigmented material or other direct toxicity of lumateperone or it’s metabolites? We have no evidence that the treatment related findings identified in the spinal cord or other study tissues are consistent with background lesions. As outlined previously (reference 4 pg. 9) the increased incidences over concurrent controls clearly make these findings attributable to ITI-007 treatment.

Question 3: Is the lysosomal accumulation of pigmented material in the brain of rats associated with degenerative changes, inflammatory responses, or other adverse biological consequences in this tissue? Briefly, the study pathologist(b) (4) of the 2-year rat study diagnosed the following changes in the brain (reference 1biv, pg. 48 cited from reference 4):

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Pigment, neuron M: 0, 43, 43, 51 F: 4, 36, 53, 54 Infiltrate, macrophages, pigmented M: 0, 0, 5, 28 F: 0, 0, 15, 37

The targeted review pathologist (b) (4) of the 2-year rat study diagnosed the following for the brain in male and female rats (reference 2 c, pg. 19): Pigment, neuron M: 0, 42, 44, 51 F: 0, 40, 53, 54 Infiltrate, macrophages, pigmented M: 0, 0, 1, 26 F: 0, 0, 8, 39

The authors of the 2-year rat study report (reference 1biv, cited from reference 4) considered the finding of pigmented macrophage infiltrates (liver, lung, and brain) an adverse effect at and above 10 mg/kg/day. However, neither (b) (4) interpreted the relevance of this finding.

Pathology comment: Upon review of the rat brain sections we consider the finding of ‘infiltrate macrophages’ consistent with a diagnosis of “inflammation, histiocytic” as coined by the targeted review pathologist (b) (4) of the left sciatic nerve (reference 2d, pg. 9). Specifically, (b) (4) states that the term ‘histiocytic inflammation’ encompasses a spectrum of interrelated morphologic alterations. We believe that the term ‘inflammation histiocytic’ would also represent a more descriptive reflection of the microscopic alterations observed in the rat brain. As pointed out by the study pathologist for the 9-month dog study (b) (4) increased staining intensity of special immunohistochemistry stains (IBA-1 and GFAP) were indicative of a reactive, inflammatory processes in the dog brain (reference 4 pg. 6). In our opinion, the presence of drug pigment in neurons and phagocytic cells is associated with a subtle histiocytic reactive response that is best characterized as being inflammatory in nature.

The authors of the 2-year rat study did not specifically report neuronal loss, which is inherently difficult to assess in non-perfusion fixed brain tissue with non-stereological assessments. However, neuronal cell degeneration and necrosis was reported in the brain of the 3-month dog study (see selected photomicrographs reported by the 3-month study pathologist above) which ultimately would lead to neuronal loss. Similarly, neuronal loss was cited (reference 2b pg. 6) by the targeted review pathologist (b) (4) of the rat peripheral nervous system evaluating the Dorsal Root Ganglia (DRG). Specifically, (b) (4) states (reference 2b, pg.12):

“A substantial increase in satellite glial cell clusters (“residual nodules of Nageotte”) in mid- dose (Group 3) and high-dose (Group 4) animals is consistent with prior neuronal injury and loss (i.e., an adverse response).”

This statement points to the fact that neuronal injury and loss occurred at an earlier time point preceding the current 2-year evaluation endpoint.

Pathology comment: Upon independent slide review of the 2-year rat brain cerebellar cortex we observed: a) red drug pigment accumulation in Purkinje cells; b) increased numbers of pigmented macrophages (inflammation, histiocytic) adjacent to pigmented Purkinje cells; c) a subtle decrease of Purkinje cells (neuronal loss).

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See representative photomicrograph of control animal vs. treated animal with these changes below. We consider histiocytic inflammation and neuronal loss to be adverse biological consequences to the pigment accumulation.

Brain, cerebellar cortex, control female rat B39805 (200x, HE).

Brain, cerebellar cortex, high dose female rat B40019 (200x, HE). Note the red drug pigment in Purkinje cells/neurons (white arrow) and in adjacent pigmented macrophages (black arrow).

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i. If so, does the lysosomal accumulation of pigmented material in the brain of rats appear to contribute to these changes? Yes, as stated above we consider histiocytic inflammation and neuronal loss to be adverse biological consequences to the pigment accumulation

1. Alternatively, are any potentially observed findings consistent with a direct neurotoxicity? We conclude that there is a relationship between the lysosomal accumulation of pigment and the aniline drug metabolites resulting in neurotoxicity with high doses over time in sensitive animal species. We did not encounter evidence supporting direct drug neurotoxicity.

ii. If no, do you consider the lysosomal accumulation of pigmented material in neurons adverse in the absence of other apparent biological consequences? The slide review of the dog and rat study has not changed our position on the adversity determination pertaining to the lysosomal accumulation of pigmented material in neurons of the CNS (reference 4, pg. 10-11). Specifically, we reiterate that lysosomal pigment accumulations are considered adverse with and in absence of additional signs of neuronal damage in the brain and spinal cord unless mechanistic and cell functional tests demonstrate absence of functional cellular impairment.

Question 4: Is there consistency in the findings in the brain and/or spinal cord of rats and dogs that indicate any observed adverse effects are caused by a similar mechanism of action (e.g., lysosomal accumulation of pigmented material or direct neurotoxicity)? As outlined above, we interpret the entirety of changes observed in the dog and the rat at various study durations to be reflective of an impaired lysosomal storage state due to the accumulation of drug related pigment. We do not have evidence for direct neurotoxicity.

Supportive evidence for impaired lysosomal function resulting in lesions commonly observed with lysosomal storage states are:

Pigment accumulation: • Dose responsive pigment accumulation in neurons and phagocytic cells and selected epithelial cells shown to localize in lysosomes via TEM – in the 9-month dog and 6- month rat study. • The lysosomal accumulation affected postmitotic cells (neurons and retinal epithelium) more severely than other cells, therefore, leading clinical symptoms mainly affecting the CNS and peripheral nervous system - in the 9-month dog and 2-year rat study.

Cellular response to the pigment: • Activated glial response as per increased staining intensity of IBA-1 and GFAP immunohistochemical stains in the brain – in the 9-month dog study. • Perivascular cuffing (inflammation, lymphocytes and macrophages) in the CNS (brain and spinal cord) – in the 9-month dog study. • Gliosis (increased number of glial cell foci) in the spinal cord – in the 2-year rat study

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• Inflammation, histiocytic – characterized by increased numbers of pigmented macrophages in the brain – in the 2-year rat study.

Neurodegenerative changes / loss: • Neuronal degeneration and necrosis in the brain and spinal cord - in the 3-month dog study. • Axonal degeneration in the white matter of the brain – in the 9-month dog study and in the white matter of the spinal cord – in the 2-year rat study. • Evidence of neuronal loss secondary to previous injury in the CNS (brain) and peripheral nervous (dorsal root ganglion) system - in the 2-year rat study.

Additional Pathology comments: We agree with the sponsor (reference 2e, pg. 3) that:

““Pigmentation” is the term that was used to describe the appearance of red/eosinophilic intracellular substance in histologic stained sections. The pigment was variously described as pale to bright, pink to occasionally red or darker. Based on both light and electron microscopy studies, pigmentation was shown to be restricted to lysosomes and therefore is likely related to material accumulated and formed within this organelle. The density of this material was dose and treatment duration related, suggesting that this may be drug related material.”

However, we do not agree with the following sponsor’s conclusions (as stated in reference 2e, pg. 3):

• “There was no detectable swelling of neurons, no inflammatory response and no pathology associated with pigment deposition regardless of the density or drug dose.

• Independent primary, peer review, and expert neuropathologists concurred that there was no evidence that this material was associated with any neuronal degeneration, necrosis, or inflammatory reactions in mice, rats or dogs at any dose or treatment duration [mouse 3-month toxicity study (Study No. 11217); rat 1-month, 3-month, and 6-month toxicity studies (Study Nos. 06-S12-GC, 07-S12-MB and 11220, respectively); dog 1-month, 3-month, and 9-month toxicity studies (Study No. 06-S16-GA, 08-S16- MR and 11221, respectively) submitted to the NDA on September 27, 2018, Sequence No. 0005].

• Pigment deposition in rat brain, spinal cord and peripheral nerves was recently reconfirmed in a targeted neuropathology investigation from which it was concluded that accumulation of pigment was not associated with neuronal degeneration or neuronal necrosis and that pigment deposition does not equate to neurotoxicity ((b) (4) 2019).”

because they are incorrect for the following three reasons:

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1. Specifically, concluding from our review of the referenced materials, the 3-month dog study clearly described and depicted in photomicrographs swelling of neurons as well as neuronal degeneration and necrosis (see photomicrographs above, pages 4-5).

2. As outlined above, sufficient evidence by statements of various study pathologists, reviewing pathologists, and our (CFSAN Pathology’s) slide review supports that the neuronal pigment accumulation:

a) Is associated with treatment related histomorphological CNS and / or PNS changes identified by the study pathologists (axonal degeneration, perivascular cuffing in the 9-month dog study; infiltrate, macrophage (or better termed inflammation, histiocytic) in the brain, axonal degeneration in the spinal cord and peripheral nervous system in the 2-year rat study). It should be recalled that association is based on spatial relationship and should not be confused with causation.

b) Elicits a generalized subtle tissue specific inflammatory response (ranging from reactive microglia to inflammation, histiocytic) in both the 9-month dog and the 2-year rat study.

3. Lastly, the author of this sponsor statement (dated August 29, 2019) must not have been aware of the conclusions reached in the final targeted review of the right-side ganglia and peripheral nerves by (b) (4) dated September 6, 2019 (reference 2b, pg. 12), in which he specifically states:

“Accumulation of pigment did not induce overt neuronal degeneration or necrosis.”

In this summary statement, reflecting his histopathological evaluation of the PNS, (b) (4) states precisely that the pigment did not induce ‘overt’ (meaning readily apparent) neuronal degeneration and necrosis; he therefore, leaves the door open for the possibility that there could have been neuronal degeneration leading to neuronal necrosis and ‘subtle’ neuronal loss at an earlier time point.

The evaluation of both the CNS and PNS is complex involving many variables pertaining to the study design (e.g. the time point of evaluation). Also, the need to perform specialized techniques/stains to confirm ‘subtle’ findings of potential neuronal lesions or a reactive glial cell (inflammatory) response may be indicated. The difficulties involved with observing neuronal injury at the right time of occurrence have been published in the literature (Butt et al., 2013, pg. 906-912). Specifically, Butt et al. state:

“If the neuronal necrosis is due to initial exposure to a particular test article (which it often is), then the actual neuronal necrosis may be missed in any study longer than 7 days in duration (i.e., in animals sacrificed more than 7 days after initial dosing). If the neuronal necrosis is missed, then the remaining lesion may be detectable as neuronal cell loss, and possibly gliosis (if a sufficient glial reaction persists).”

In line with an underlying subtle presence of neuronal loss in the PNS of the 2-year rat study is (b) (4) follow-up summary sentence to the above quote (reference 2b, pg. 12):

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“A substantial increase in satellite glial cell clusters ("residual nodules of Nageotte") in mid- dose (Group 3) and high-dose (Group 4) animals is consistent with prior neuronal injury and loss (i.e., an adverse response).”

This statement identifies the satellite glial cell (SGC) clusters as a so-called ‘tombstoning change’, meaning that they are indicators of prior neuronal injury which led to degeneration, necrosis and ultimately neuronal cell loss at an earlier time point, leaving the drug pigment which the neurons contained behind. To illustrate this further, (b) (4) stated (reference 2b, pg.6):

“In many instances, the increased SGC clusters occurred in the absence of a centrally placed neuron, while in a few cases the cores of such SGC clusters consisted of large pigment blocks that were identical to that seen in the peri-nuclear cytoplasm of nearby intact neurons.”

This statement clearly ‘associates’ the pigment with neuronal loss in the peripheral nervous system ganglia of the 2-year rat study; a finding that would result from neuronal degeneration and necrosis which was previously reported in the 3-month dog study.

Furthermore, we would like to clarify a faulty assumption by the sponsor stating (reference 2e, pg. 4):

“Thus, the lysosomal appearance of pigmented drug-related material in tissue sections used for pathology assessment could be caused by aniline oxidation reaction products as a result of exposure to components of H&E staining chemistry. This process enhances visualization of pigment leading to an overestimation of any apparent risk of lysosomal deposition of drug related materials.”

This assumption, in our opinion reflects an ill-informed understanding of how the application of histopathological staining techniques relates to risk estimation. The mere process of visualization just enables an observation; the microscopic observation is a separate step from lesion interpretation, which informs the basis of a risk assessment. In this specific case (lumateperone lysosomal pigment accumulation), it is the sum of all changes (weight of evidence) ‘associated’ with the lysosomal pigment accumulation (direct and distant proximity) that leads to an estimation of biological lesion significance.

Overall, we found the fact that so many different study-, reviewing-, and targeted- reviewing pathologists were employed to evaluate and interpret the respective study findings in dog, rat and mouse studies with Lumateperone, seems to have substantially confused the overall study interpretations. We recommend that sponsors choose as much as possible the same pathologist for the review of consecutive studies with the same compound, for peer reviewing and for specialized pathology assessments to ensure consistent, overarching interpretation of the observed changes.

In summary, the described lysosomal pigment accumulation, represents an impaired lysosomal storage state exhibiting characteristics similar to lysosomal storage diseases. Lumateperone lysosomal ‘constipation’ and release of drug pigment due to early subtle neuronal loss resulted in an sustained low grade reactive tissue response to cells with pigment (neurons and macrophages), which manifested as increased staining of IBA-1 immunohistochemistry indicating an overall 16

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activation of microglial cells (the brain resident macrophage or phagocytic cell) as well as an increase in GFAP staining intensity, indicating a reactive state of astrocytes. With prolonged treatment time and/or higher doses, this is followed by a sustained low grade reactive inflammatory (histiocytic) response to lysosomal pigment which in sensitive species (such as the dog) culminates in inflammatory ‘perivascular cuffing’ of lymphocytes and macrophages.

Consistent with our previous assessment (reference 4), we, therefore, conclude based on the entirety of ITI-007 data evaluated that ITI-007 lysosomal pigment accumulations in the dog and rat central nervous system should be considered adverse both with and in the absence of additional signs of neuronal damage unless mechanistic and cell functional tests demonstrate absence of functional cellular impairment in the species tested.

Please let us know if you have any questions.

Digitally signed by Digitally signed Sabine Sabine Francke -S Steven by Steven Mog -S Date: 2019.10.07 Date: 2019.10.07 Francke -S 09:10:24 -04'00' 08:28:49 -04'00' Mog -S Sabine Francke, D.V.M., Ph.D., FIATP and Steven Mog D.V.M., DACVP

Literature References:

Butt MT, Sills R, Bradley A. Chapter 20, Nervous System. In: Sahota P, Popp J, Hardisty J, Gopinath C, eds. Toxicologic Pathology: Nonclinical Safety Assessment. Boca Raton: CRC Press; 2013: 895- 930.

Maxie MG and Youssef S. Chapter 3, Nervous system. In: Maxie MG ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, 5th edition, Volume 1. Elsevier New York, NY; 2007: 281- 458.

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Reference ID: 4537404 Signature Page 1 of 2 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

JASMEET K KALSI 12/20/2019 04:17:19 PM

DARREN B FEGLEY 12/20/2019 04:19:31 PM

IKRAM M ELAYAN 12/20/2019 04:27:28 PM

PAUL C BROWN 12/20/2019 04:28:12 PM

THOMAS BIRKNER 12/20/2019 04:29:19 PM

PEILING YANG 12/20/2019 04:29:57 PM

HSIEN MING J HUNG 12/20/2019 04:30:58 PM

HUIXIA ZHANG 12/20/2019 04:32:46 PM

VENKATESH A BHATTARAM 12/20/2019 04:33:45 PM

LUNING ZHUANG 12/20/2019 04:35:50 PM

MEHUL U MEHTA 12/20/2019 04:36:29 PM

DAVID H MILLIS 12/20/2019 04:37:04 PM

MICHAEL C DAVIS 12/20/2019 04:37:18 PM

Reference ID: 4537404 Signature Page 2 of 2 TIFFANY R FARCHIONE 12/20/2019 04:37:59 PM

ELLIS F UNGER 12/20/2019 04:44:29 PM

Reference ID: 4537404

Date: May 31, 2019

From: Neil Hartman, Marlene Kim, Rebecca Racz, and Naomi Kruhlak, Division of Applied Regulatory Science/Office of Clinical Pharmacology (OCP/DARS)

Through: James Weaver Ph.D., Consult Lead and Rodney Rouse D.V.M, Ph.D., Deputy Director (OCP/DARS)

To: Huixia Zhang and Luning (Ada) Zhuang (OTS/OCP/DCPI)

Subject: NDA 209500 - Lumateperone

Executive Summary

Lumateperone (ITI-007, IC200056) is an NME that exhibits selective and simultaneous modulation of serotonin, dopamine, and glutamate, as well as dopamine receptor phosphoprotein modulation (DPPM), acting as a pre-synaptic partial agonist and post-synaptic antagonist at D2 receptors. It is indicated to treat schizophrenia, with the potential to improve psychosocial function in patients suffering from a range of neuropsychiatric and neurodegenerative diseases (Intra-Cellular Therapies, 2019).

During clinical development, neurotoxicity, ocular toxicity, and cardiotoxicity were observed in dogs and rats; however, these effects were not directly evaluated in humans. The metabolic profile of the drug indicates that two aniline metabolites observed in dogs and rats are not observed in humans. The Sponsor asserts that these aniline metabolites are responsible for the observed animal toxicities and, therefore, the toxicities are not likely to be manifested in humans.

DARS was consulted to analyze the chemical structure of lumateperone and its metabolites to determine whether structural alerts for neurotoxicity, ocular toxicity and cardiotoxicity are present and whether the aniline metabolites are distinctive for these toxicities. DARS generated (quantitative) structure-activity relationship, or (Q)SAR, model predictions and performed a structure-based search to identify analogs that could serve as comparators to lumateperone. Additionally, a literature review for effects related to anilines was performed and a computational target-binding profile was generated for lumateperone and its metabolites to determine whether the observed toxicities are predicted as off-target effects.

(Q)SAR models for hERG channel inhibition and drug-induced phospholipidosis identified structural alerts for all but the glucuronide metabolite, suggesting that metabolites containing the aniline moiety do not exhibit distinctively different effects at these endpoints. Weak structural alerts were also identified for four metabolites for heart failure and palpitations. No structural alerts were identified for ocular toxicity or neurotoxicity. Additionally, the structural similarity search identified four marketed drugs that contain either a piperidine/butylbenzene backbone or a fused tetracyclic system similar to that in lumateperone. All four of the marketed drugs contain references in their labels to cardiac side effects, including QT-prolongation, and two of the structures contain references to ocular toxicity and/or neurological effects. Lastly, the computational target-binding assessment predicted off-target binding of lumateperone to the glutamate NMDA receptor 2B, which may be associated with neurotoxicity and cognition, and binding of two metabolites (one aniline and one other) to the vesicular acetylcholine transporter (VAT), which may be associated with cognitive impairment. A review of the published literature suggested that neurotoxicity associated with anilines only occurs at very high doses. Considering the sterically hindered, high molecular weight environment of the aniline in the two lumateperone metabolites, it is unlikely that these U.S. Food & Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20903 www.fda.gov

Reference ID: 4449450

two metabolites alone are responsible for the toxicities observed in dogs and rats.

In conclusion, DARS found no evidence to support the Sponsor’s assertion that the aniline metabolites alone are responsible for the toxicities observed in rats and dogs.

Background

Lumateperone (ITI-007, IC200056) is an NME that provides selective and simultaneous modulation of serotonin, dopamine, and glutamate—three neurotransmitter pathways implicated in severe mental illness. Lumateperone is also a dopamine receptor phosphoprotein modulator, or DPPM, acting as a pre-synaptic partial agonist and post-synaptic antagonist at D2 receptors. The Sponsor states that these characteristics contribute to the efficacy of lumateperone across a broad array of symptoms with favorable tolerability, resulting in improved psychosocial function (Intra-Cellular Therapies, 2019). Lumateperone is indicated for the treatment of schizophrenia. The Sponsor states that this compound has the potential to benefit patients suffering from a range of neuropsychiatric and neurodegenerative diseases.

Under clinical development, Lumateperone was shown to be well tolerated with a safety profile similar to placebo groups. However, neurotoxicity was recently observed in dogs and rats, as follows:

In dogs, the following was observed, but not limited to: • Axonal degeneration • Perivascular cuffing • Intracytoplasmic eosinophilic inclusions.

In rats, the following was observed, but not limited to: • Axonal degeneration • Retinal degeneration • Cardiomyopathy

The toxicities observed in dogs and rats have not been evaluated in humans. Consequently, the Agency is interested in determining whether these toxicities could potentially occur in humans. The Sponsor asserts that these toxicities are limited to rats and dogs due to the formation of aniline metabolites not observed in humans. In response, OCP/DCPI requested a structure-based assessment of lumateperone and its metabolites (Figure 1) to determine whether the aniline metabolites contain unique structural alerts for these toxicities not identified in the other structures.

Figure 1. Lumateperone and its metabolites H N O N N H

F Lumateperone (API)

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H H N N O H2N N OH H H N N H

F F IC201338 IC200131 (aniline metabolite identified in dogs and rats)

H H N N OH N O H2N HN N H H H

F F IC201337 (aniline metabolite identified in dogs and rats) IC200161

H H N N O OH HN N HN N H H O O

F F IC201308 IC201309 O OH H OH N O OH HN N OH H O H OH N O

N N F H IC200565 IC2001318

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Evaluation

(Q)SAR Evaluation Lumateperone and its eight metabolites were evaluated by the DARS Computational Toxicology Consultation Service for cardiotoxicity (heart failure, palpitations, hERG channel inhibition), phospholipidosis, neurotoxicity, ocular toxicity, and mitochondrial disruption using (Q)SAR models. Four software programs were used: Derek Nexus 6.0.1 (DX), Leadscope Model Applier 2.3.3-1 (LMA), CASE Ultra 1.7.0.5 (CU), and/or MC4PC 2.4.1.4 (MC). All available models for the listed endpoints were used within the four software platforms. All (Q)SAR model outputs were reviewed with the use of expert knowledge to provide additional supportive evidence on the relevance of any positive, negative, conflicting or inconclusive prediction and provide a rationale to support the final conclusion. The following tables report the individual predictions from each software, as well as the overall expert predictions for each endpoint, where applicable.1 No structural alerts were identified for the nine structures for neurotoxicity, ocular toxicity, and mitochondrial disruption. Therefore, no table is presented for those endpoints.

Table 1. Human cardiological adverse effect (Q)SAR predictions Heart hERG Failure Palpitations channel Heart Failure Overall Palpitations Overall inhibition Chemical Expert Expert Name LMA CU Prediction LMA CU Prediction DX Lumateperone ------+ IC200131 NC + Eqv NC + Eqv + IC201338 (aniline) - - - - Eqv - + IC201337 (aniline) Eqv + Eqv + + Eqv Eqv IC200161 NC - - NC - - + IC201308 NC Eqv - NC - - + IC201309 NC + Eqv NC + Eqv + IC200565 NC + Eqv NC + Eqv + IC2001318 ------NSA

Four metabolites of lumateperone are predicted to be equivocal for heart failure and palpitations due to a weak structural alert. In addition, lumateperone and all but one metabolite (the glucuronide) are predicted to be positive or equivocal for hERG channel inhibition.

1 + = positive; – = negative; Eqv = equivocal; NC = test chemical features are not adequately represented in the model training data set, leading to a no call; NSA = no structural alerts identified by DX, which cannot differentiate between a negative call and the inability to make a call because of no coverage.

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Figure 2. Aryl-alkylhydroxy alert from CU highlighted on four metabolites of lumateperone H H H N N N OH H N OH OH OH N N HN N HN N H H H

N H O H2N H

F F F F IC200131 IC201337 (aniline) IC201309 IC200565

IC200131, IC201337 (aniline), IC201309, IC200565 are predicted to be equivocal for heart failure and palpitations by CU based on the presence of the aryl-alkylhydroxy alert (highlighted in red in Figure 2). However, a review of the training set structures supporting this alert, including terfenadine and haloperidol, suggests that the alert is weak, leading to an overall equivocal prediction.

Additionally, IC201338 (aniline) and IC201308 are predicted to equivocal for heart failure and palpitations based on the presence of the heterocyclic ring structure; however, the training set chemicals supporting the prediction contain the alert in a different chemical environment. Therefore, the alert is dismissed.

Figure 3. DX structural alert for hERG highlighted on lumateperone H N O N N H F Lumateperone

DX predicted all chemicals, except for IC2001318 (aniline), to be positive or equivocal for hERG channel inhibition. The DX alert (highlighted in red in Figure 3) is based on a pharmacophore developed primarily from compounds that have been reported to be strong inhibitors of the hERG and from other, proprietary chemicals. DX predicts these chemicals will cause hERG channel inhibition in rats, rodents, dogs, and humans.

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Table 2. MC4PC Phospholipidosis QSAR Predictions Overall Chemical External Internal Phospholipidosis Name model model Toxicity Lumateperone + + + IC200131 + + + IC201338 (aniline) + + + IC201337 (aniline) + + + IC200161 + + + IC201308 + + + IC201309 + + + IC200565 + + + IC2001318 - - -

Lumateperone and all metabolites listed above, except for IC2001318, are predicted to be positive for phospholipidosis (Table 2) based on the presence of the fluorobenzene moiety in combination with the piperidine ring. This combination is consistent with the cationic amphiphilic drug (CAD) motif, characterized by a hydrophilic amine and hydrophobic ring, which has been strongly associated with the lysosomal phospholipid storage disorder phospholipidosis (Orogo et al., 2012). Halogen substitution on the aromatic ring is thought to further increase lipophilicity and drug permeability through electron withdrawal, thereby increasing a compound’s propensity to cause this effect. Notably, the QSAR models predict IC2001318 to be negative for phospholipidosis due to the mitigating effect of the glucuronide moiety.

Target Evaluation Lumateperone is known to target 5-HT2A1, D(2) dopamine receptor (isoform 1), and D(2) dopamine receptor (isoform 2). These targets were further analyzed using Molecular Health EFFECT for their association with toxicities similar to those seen in rats and dogs (Table 3). EFFECT is a web-based explorer used to analyze adverse events associated with drug targets using public FDA Adverse Event Reporting System (FAERS) data. The underlying data are current through 2017Q2. A significant association is determined by a case count greater than 50 and a Proportional Reporting Ratio (PRR) greater than 1.25.

Table 3. Association of cardiomyopathy and neurotoxicity with lumateperone’s known targets from EFFECT

MedDRA Preferred Term 5-HT2A (Case Count, PRR) D2 (Case Count, PRR) Cardiomyopathy 1195, 1.96 1213, 2.09 Vasculitis cerebral 24, 0.67 26, 0.77 Nerve degeneration 12, 1.27 8, 0.86 Phospholipidosis N/A N/A Retinal degeneration 33, 0.79 29, 0.72

Cardiomyopathy has a weakly significant association with both 5-HT2A and D2, as the PRR is above 1.25

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but remains quite small. However, the neurotoxicity terms did not show a significant association with either 5-HT2A or D2.

Additionally, the predicted targets of lumateperone and its metabolites were analyzed using two target prediction programs, SEAware and Clarity. SEAware by SEAChange Pharmaceuticals can predict binding to 2300 targets throughout the body. SEAware compares the drug of interest’s chemical structure to the structures of other drugs and chemicals that are known to bind to each of these targets. A prediction and associated confidence score are generated for each target based on the drug of interest’s structural similarity to known binders. Clarity by Chemotargets can predict binding and associated activity (i.e., agonism and antagonism) at 2000 targets throughout the body. Similar to SEAware, Clarity also compares the drug of interest’s chemical structure to the structures of other drugs and chemicals that are known to bind to each of these targets using six independent approaches. A prediction and associated confidence score is generated for each target along with potential activity and binding affinity (Ki). For this analysis, the confidence score cutoffs recommended by the respective software vendors were used, and only predictions made by both platforms are included. Target predictions for lumateperone are shown in Table 4.

One target predicted for lumateperone, the glutamate NMDA receptor 2B, may be associated with neurotoxicity and cognition adverse effects (Newcomer et al., 2000). Antagonism of NMDA-2B impaired reversal learning but improved paired associated learning in rats (Kumar et al., 2015). Additionally, activation of NMDA receptors may lead to epilepsy, neuronal cell death, and (Collingridge et al., 2013). Predictions made by SEAware and Clarity for glutamate NMDA receptor 2B were significant but had low confidence. Additionally, two metabolites of lumateperone, IC201338 and IC201308, were weakly but significantly predicted to bind to the vesicular acetylcholine transporter (VAT) by both SEAware and Clarity. The cholinergic system has been shown to play a role in Alzheimer’s disease and other types of cognitive impairment (Ferreira-Vieira et al., 2016). VAT knock-down mice have demonstrated cognitive and neuromuscular impairment, including object and social recognition (Prado et al., 2006). These predictions are for hypothesis generation only and are not to confirm any identified adverse event or target association.

Table 4. Target predictions for lumateperone SEA Clarity 3-beta-hydroxysteroid- Predicted Predicted delta(8),delta(7)-isomerase alpha Predicted Predicted Alpha-1a adrenergic receptor Known Known Alpha-1b adrenergic receptor Known Known Dopamine D1 receptor Known Known Dopamine D2 receptor Known Known Dopamine D3 receptor Predicted Predicted Dopamine D4 receptor Known Known Glutamate receptor ionotropic, Predicted Predicted NMDA 2B Serotonin 1a (5-HT1a) receptor Known Predicted Serotonin 2a (5-HT2a) receptor Known Known Serotonin 2c (5-HT2c) receptor Known Known Serotonin 7 (5-HT7) receptor Predicted Predicted U.S. Food & Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20903 www.fda.gov

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Serotonin transporter Known Known Sigma-1 receptor Predicted Predicted

Structural Similarity Assessment of Lumateperone to Other Marketed Drugs A global similarity and substructure search were performed for lumateperone using Clarivate Integrity and ChemIDPlus databases to determine potential structural comparators. The results were filtered to identify marketed drugs, drugs withdrawn from the market, and drugs under clinical development. Additionally, a review of the drug labels and references to neurotoxicity, cardiotoxicity, ocular toxicity, and endpoints related to the observed toxicities were extracted. No examples of structurally similar drugs containing both a piperidine/butylbenzene backbone and a fused tetracyclic system were identified; however, the search identified four marketed drugs that contain either a piperidine/butylbenzene backbone or a fused tetracyclic system: haloperidol, terfenadine, mianserin, and mirtazapine. Figure 4 shows the chemical structures of the drugs with shared features highlighted in red.

Figure 4. Structurally similar marketed drugs to lumateperone H N O N N H F Lumateperone

Cl OH OH OH O N N

F Haloperidol Terfenadine N N

N N N

Mianserin Mirtazapine Structural features shared with lumateperone are highlighted in red.

Haloperidol is an antipsychotic drug indicated for schizophrenia and the treatment of Tourette's Syndrome. According to the FDA label of haloperidol, the following have been reported in patients receiving HALDOL: • Cardiovascular Effects: Cases of sudden death, QT-prolongation, and • Additional adverse reactions reported in clinical trials are: o Eye disorders: Vision blurred o Nervous System Disorders: Nystagmus, Oculogyric crisis.

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Terfenadine is an indicated to treat allergies, hives, and other allergic inflammatory conditions. Side effects of terfenadine include: • Cardiovascular Effects: Irregular heartbeat, QT prolongation, arrhythmias, palpitations, cardiac arrest, and cardiac death • Seizures

Mianserin is an antidepressant that also has antihistaminic and hypnosedative effects. It is indicated for symptoms of depressive illness. It is contraindicated for patients with glaucoma. The label has a warning for patients with recent myocardial infarction, heart block, or arrhythmias. Side effects of mianserin include: • Blurred vision • During overdose o Constricted or dilated pupils o Nystagmus o ECG abnormalities o Serotonin toxicity

Mirtazapine is an antidepressant indicated for the treatment of major depressive disorder. Overdosing on mirtazapine can lead to QT prolongation.

Literature-Based Assessment of Neurotoxicity

An extensive literature search was performed in PubMed, Clarivate Integrity, and TOXNET to gather additional information on the potential toxicity of the metabolites of lumateperone and its relevance to humans. The Sponsor claims that neurotoxicity of lumateperone is observed in dogs and rats due to two metabolites that contain an aniline moiety (IC201337 and IC201338). These metabolites are not formed in humans. An examination of the literature showed that aniline itself could cause neurotoxicity in rats; however, this was only observed at very high doses (>800mg/kg, single dose) and only in younger animals (Makhdoumi et al., 2019; Okazaki et al., 2001). Aniline also causes other adverse effects, notably methemoglobinemia, and the neurotoxicity seen may be secondary to these other effects. Compounds containing aniline moieties may also be further metabolized in the body to reactive compounds which can form adducts with DNA and other macromolecules; these compounds are generally positive for bacterial mutagenicity (Enoch, 2010). However, an examination of metabolites IC201337 and IC201338 using three (Q)SAR models for bacterial mutagenicity (Derek Nexus 6.0.1, Leadscope Model Applier 2.3.3-1, and CASE Ultra 1.7.0.5) revealed that bacterial mutagenicity is unlikely with these compounds due to their high molecular weight and steric hindrance around the amine. Thus, they are unlikely to form reactive metabolites, making this an improbable mechanism for neurotoxicity. In addition, data from the Sponsor indicate that metabolites IC201337 and IC201338 are formed in only low levels in rats and dogs. Thus, regardless of the mechanism of the neurotoxicity, metabolites IC201337 and IC201338 are likely not responsible, suggesting that this adverse effect may still be seen in patients.

Literature-Based Assessment of Retinal Degeneration or Ocular Toxicity

All psychotropic drugs have the potential to induce unwanted ocular adverse effects. Many factors cause the eyes to be sensitive to psychotropic drugs, because the retina directly connects the eyes to the brain. Retinal functions are mediated by neurotransmitters and ion flux that are directly or indirectly affected by psychotropic drugs. In high doses, antipsychotics can cause retinopathy and the adverse effect is

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proportional to the total amount of drug taken over time (Richa et al., 2010). A computational analysis of ocular toxicity found that drugs with chemical properties similar to common antidepressive drugs have the potential to induce ocular phototoxicity (Solimeo et al., 2012), where “phototoxic processes are believed to be involved in both pigmentary retinopathy and retinal degeneration. Pigments are gradually deposited starting from the periphery to the central retina, producing loss of peripheral vision, decreased night vision, central scotomata and eventually total blindness.” (Richa et al., 2010). However, this is largely due to pupil dilation allowing more UV-light in the eyes and can be prevented by avoiding sunlight or wearing protective lenses.

Summary and Conclusions

(Q)SAR models identified structural alerts for hERG channel inhibition and drug-induced phospholipidosis for all but the glucuronide metabolite, suggesting that metabolites containing the aniline moiety do not exhibit distinctively different effects at these endpoints. Weak structural alerts were also identified for four metabolites for heart failure and palpitations. No structural alerts were identified for ocular toxicity or neurotoxicity. Additionally, the structural similarity search identified four marketed drugs that contain either a piperidine/butylbenzene backbone or a fused tetracyclic system similar to that in lumateperone. All four of the marketed drugs contain references in their labels to cardiac side effects, including QT-prolongation, and two of the structures contain references to ocular toxicity and/or neurological effects. Lastly, the computational target-binding assessment predicted off-target binding of lumateperone to the glutamate NMDA receptor 2B, which may be associated with neurotoxicity and cognition, and binding of two metabolites (one aniline and one other) to the vesicular acetylcholine transporter (VAT), which may be associated with cognitive impairment. A review of the published literature suggested that neurotoxicity associated with anilines only occurs at very high doses. Considering the sterically hindered, high molecular weight environment of the aniline in the two lumateperone metabolites, it is unlikely that these two metabolites alone are responsible for the toxicities observed in dogs and rats.

In conclusion, DARS found no evidence to support the Sponsor’s assertion that the aniline metabolites alone are responsible for the toxicities observed in rats and dogs.

References and Supporting Documents

Collingridge GL, Volianskis A, Bannister N, France G, Hanna L, Mercier M, et al. The NMDA receptor as a target for cognitive enhancement. Neuropharmacology. 2013; 64:13-26.

Drugs.com-Seldane (Generic Name: terfenadine). https://www.drugs.com/sfx/seldane-side-effects.html (accessed May 24, 2019).

EMC-Mianserin. https://www.medicines.org.uk/emc/product/2741/smpc (accessed May 24, 2019).

Enoch SJ, Cronin MTD. (2010) A review of the electrophilic reaction chemistry involved in covalent DNA binding. Crit Rev Toxicol. 40:728-748.

Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM. Alzheimer’s Disease: Targeting the Cholinergic System. Curr Neuropharmacol. 2016; 14(1):101-15.

Intra-Cellular Therapies. http://www.intracellulartherapies.com/products-and-technology/lumateperone/ U.S. Food & Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20903 www.fda.gov

Reference ID: 4449450

(accessed May 23, 2019).

HALDOL brand of haloperidol injection. FDA Label https://www.accessdata.fda.gov/drugsatfda docs/label/2019/015923s095lbl.pdf (accessed May 24, 2019).

Kumar G, Olley J, Steckler T, Talpos J. Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation. Psychopharmacology (Beri). 2015; 232(21- 22):3991-4003.

Makhdoumi P, Hossini H, Ashraf G, Limoee M. (2019) Molecular Mechanism of Aniline Induced Spleen Toxicity and Neuron Toxicity in Experimental Rat Exposure: A Review. Current Neuropharmacology. 17:201-213.

Neurotoxicity induced by a single oral dose of aniline in rats. J Vet Med Sci. 63(5):539-546. Orogo AM, Choi SS, Minnier BL, Kruhlak NL. (2012) Construction and consensus performance of (Q)SAR models for predicting phospholipidosis using a dataset of 743 compounds. Mol. Inf. 2012, 31, 725 – 739.

Newcomer JW, Farber NB, Olney JW. NMDA receptor function, memory, and brain aging. Dialogues Clin Neurosci. 2000; 2(3):219-232.

Okazaki Y, Yamashita K, Sudo M, Tsuchitani M, Narama I, Yamaguchi R, Tateyama S. (2001) Neurotoxicity induced by a single dose of aniline in rats. J Vet Med Sci. 63(5):539-546.

Prado VF, Martins-Silva C, de Castro BM, Lima RF, Barros DM, Amaral E, et al. Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron. 2006; 51(5):601-12.

REMERON® (mirtazapine) Tablets. https://www.accessdata.fda.gov/drugsatfda docs/label/2016/020415s030lbl.pdf (accessed May 24, 2019).

Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents. CNS drugs. 2010 Jun 1;24(6):501-26.

Solimeo R, Zhang J, Kim M, Sedykh A, Zhu H. Predicting chemical ocular toxicity using a combinatorial QSAR approach. Chemical research in toxicology. 2012 Nov 19;25(12):2763-9.

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Reference ID: 4449450 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

TRACEY B LEE 06/15/2019 11:00:10 AM

JAMES L WEAVER 07/08/2019 09:55:07 AM

DAVID G STRAUSS 07/08/2019 10:38:46 AM

Reference ID: 4449450

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Translational Sciences Office of Biostatistics

S TATISTICAL R EVIEW AND E VALUATION CARCINOGENICITY STUDIES

NDA/BLA #: NDA 209500/SN-0005 (IND 079690) Drug Name: CAPLYTA® (lumateperone) Capsules Indication(s): Treatment for schizophrenia Applicant: Intra-Cellular Therapies, Inc. Alexandria Center for Life Science, 430 East 29th Street, Suite 900, New York, NY 10016, USA Laboratory: (b) (4)

Date(s): Received 9/27/2018 Documents Reviewed: Studies 8328209 (rats) and 8328210 (mice) were submitted on 9/27/2018 (via SN-0005). The electronic tumor.xpt files were submitted on 12/17/2018 (vis SN-0022). Review Priority: Biometrics Division: Division of Biometrics VI Statistical Reviewer: Feng Zhou Concurring Reviewers: Karl Lin, Ph. D., Team Leader Medical Division: Division of Psychiatry Products (DPP) Nonclinical Team: Deepa Rao, Ph.D Project Manager: Jasmeet Kalsi Keywords: Carcinogenicity, Dose response

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 2 of 23

Table of Contents

1 SUMMARY ...... 3

2 BACKGROUND ...... 4

3 RAT STUDY- 8328209 ...... 4 3.1 SPONSOR’S ANALYSES ...... 4 3.1.1 Survival Analysis ...... 4 3.1.2 Tumor Data Analysis ...... 5 3.2 REVIEWER’S ANALYSES ...... 6 3.2.1 Survival Analysis ...... 6 3.2.2 Tumor Data Analysis ...... 6 4 MOUSE STUDY- 8328210 ...... 8 4.1 SPONSOR’S ANALYSES ...... 8 4.1.1 Survival Analysis ...... 8 4.1.2 Tumor Data Analysis ...... 9 4.2 REVIEWER’S ANALYSES ...... 9 4.2.1 Survival Analysis ...... 9 4.2.2 Tumor Data Analysis ...... 10 5 APPENDIX ...... 11 Table 1A: Intercurrent Mortality Rate in Male Rats ...... 11 Table 1B: Intercurrent Mortality Rate in Female Rats ...... 11 Table 2A: Intercurrent Mortality Rate in Male Mice ...... 11 Table 2B: Intercurrent Mortality Rate in Female Mice ...... 12 Table 3A: Intercurrent Mortality Comparison in Male Rats ...... 12 Table 3B: Intercurrent Mortality Comparison in Female Rats ...... 12 Table 4A: Intercurrent Mortality Comparison in Male Mice ...... 12 Table 4B: Intercurrent Mortality Comparison in Female Mice ...... 12 Table 5A: Tumor Rates and P-Values for Trend and Pairwise Comparisons in Male Rats ...... 13 Table 5B: Tumor Rates and P-Values for Trend and Pairwise Comparisons in Female Rats ...... 15 Table 6A: Tumor Rates and P-Values for Trend and Pairwise Comparisons in Males Mice ...... 17 Table 6B: Tumor Rates and P-Values for Trend and Pairwise Comparisons in Female Mice ...... 18 Figure 1A: Kaplan-Meier Survival Functions for Male Rats ...... 21 Figure 1B: Kaplan-Meier Survival Functions for Female Rats ...... 21 Figure 2A: Kaplan-Meier Survival Functions for Male Mice ...... 22 Figure 2B: Kaplan-Meier Survival Functions for Female Mice ...... 22 REFERENCES ...... 23

File Name: NDA209500Carcin

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 3 of 23

1 Summary

This review evaluates statistically the data of the 2-year oral carcinogenicity studies in rats and in mice. The review analyzed the dose-response relationship of tumor incidences and mortality (including tumor-related mortality). From the statistical point of view, the review concluded that ITI-007 decreased the survivals in female rats and male mice. The tumor analysis showed no statistically significant positive dose-response relationship or pairwise comparison difference between individual treated groups and the vehicle control group in incidence in all tumor types tested for either sex in rats or mice.

Rat Study: Rats (55/sex/dose) were dosed by oral gavage with ITI-007 daily for up to 104 weeks. The respective ITI-007 dose in the vehicle control (VC), low (LD), mid (MD), and high- dose (HD) groups was 0, 5, 10, or 20 mg/kg/day for males and 0, 5, 15/10, or 30/20 mg/kg/day for females. For females, the dose for MD and HD groups were reduced due to the mortality. The male rats and female rats were terminated at Weeks 94 and 75, respectively.

The survival analyses showed a statistically significant dose response relationship in mortality in females only. Mortalities in female HD (30/20 mg/kg/day) group were statistically significant higher than those of the control group. The respective survival rates in the VC, LD, MD, or HD groups at the time they were terminated were 33%, 35%, 25%, or 24% in males and 31%, 27%, 55%, or 22% in females.

There was no statistically significant positive dose-response relationship or pairwise comparison difference between individual treated groups and the vehicle control group in incidence in all tumor types tested in either sex.

Mouse Study: Mice (55/sex/dose) were dosed by oral gavage with ITI-007 daily for up to 99 weeks. The respective ITI-007 dose in the vehicle control (VC), low (LD), mid (MD), and high- dose (HD) groups was 0, 5/2, 15/7, or 30/20 mg/kg/day for both males and females. Starting Day 36 of the dosing phase, all dose levels were reduced. The changes were made based on recommendations by the FDA Carcinogenicity Assessment Committee (CAC). The male rats and female rats were terminated at Weeks 89 and 91, respectively.

The survival analyses showed statistically significant dose response relationship in mortality in male mice only. Mortalities in male HD group were significantly higher than that of the control group. The respective survival rates in the VC, LD, MD, or HD groups at the time they were terminated was 36%, 36%, 40%, or 27% in males and 40%, 27%, 49%, or 27% in females.

There was no statistically significant positive dose-response relationship or pairwise comparison difference between individual treated groups and the vehicle control group in incidence in all tumor types tested in either sex.

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2 Background

Intra-Cellular Therapies, Inc. (ITI) was developing lumateperone (ITI-007) as a first-in-class, oral, once-daily, treatment for schizophrenia without many of the adverse effects seen with other antipsychotic agents. The sponsor (ITI) provided the nonclinical study 8328209: “104- week oral (gavage) carcinogenicity study in rats” and the study 8328210: “104-week oral (gavage) carcinogenicity study in mice” on 9/27/2018 via submission NDA 209500/SN-0005. The electronic tumor.xpt data files were submitted on 12/17/2018 via submission NDA 209500/SN-0022.

The phrase "dose response relationship" refers to the linear component of the effect of treatment, and not necessarily to a strictly increasing or decreasing mortality or tumor incidence rate as dose increases. Results of this review have been discussed with the pharmacologist Dr. Deepa Rao.

3 Rat Study- 8328209

Study Report: 8328209-pre-clincal-study-report-1.pds.pdf (statistical report on page 4962) SAS data: tumor.xpt

This study was conducted to evaluate the carcinogenic potential of the test article, ITI-007, after once daily oral gavage administration to male and female rats for up to 104 consecutive weeks. The test material was administered at doses of 0, 5, 10, or 20 mg/kg/day for males and 0, 5, 15, or 30 mg/kg/day for females. This review refers these dose groups as the vehicle control (VC), low (LD), mid (MD), or high (HD) dose groups, respectively. There were 55 rats/sex/dose in the main study. Following a trend towards higher mortality in the high-dose females, dose levels for females in 15 and 30 mg/kg/day were reduced to 10 and 20 mg/kg/day, respectively.

These doses were lowered beginning on Day 386 of the dosing phase. For all analyses, the two sexes were kept separate. For females, as MD and HD groups had dose levels lowered; the calculated adjusted overall average dose levels were used in the statistical analysis of survival and tumor incidence data. The calculated adjusted overall average dose levels were 13.0 and 27.4 mg/kg/day for MD and HD groups respectively. For all other groups, actual dose levels were used in the statistical analysis.

Assessment of toxicity was based on dose analysis, morbidity, mortality, injury, body weight, food consumption, clinical observations and masses, ophthalmology, clinical pathology, toxicokinetics, macroscopic observations, and microscopic evaluations.

3.1 Sponsor’s Analyses

3.1.1 Survival Analysis Tests to compare survival were performed, with a two-sided risk for increasing and decreasing mortality with dose. Tests were performed for dose response and for each dosed group against control using Kaplan-Meier product-limit estimation curves, along with log- rank and Wilcoxon tests. These tests were performed using the LIFETEST procedure in File Name: NDA209500Carcin

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SAS. The time to death or sacrifice (in weeks) was the dependent variable. The treatment group was included as the stratum. Animals with a death or sacrifice status recorded as a planned sacrifice (terminal) or an accidental death were censored in the analysis.

Sponsor’s concluded results: For males, there were no statistically significant dose responses among treatment groups or differences pairwise comparisons between individual treated groups and the control group in survival.

For females, the high-dose group (30/20 mg/kg/day) had higher mortality than that of the control group (43 of 55 versus 38 of 55 in control), with P = 0.0002 and P = 0.0010 for the Log-Rank and Wilcoxon tests respectively. For females, the mid-dose group (15/10 mg/kg/day) had lower mortality than that of the control group (25 of 55 versus 38 of 55 in control), with P = 0.0052 and P = 0.0043 for the Log-Rank and Wilcoxon tests respectively. For females, the test for trend was also significant, P = 0.0108 and P = 0.0048 for the Log- Rank and Wilcoxon tests, respectively.

3.1.2 Tumor Data Analysis

Only tumors from tissues listed in the protocol to be examined for all animals were analyzed. For each given tumor type, statistical analysis was performed if the incidence in at least one dosed group was increased by at least two occurrences over the control group.

Neoplastic findings classified as fatal and incidental were processed using the death rate method and the prevalence method, respectively. The processing of incidental tumors was done by creating a single separate interval for the time following the experimental period (terminal sacrifice period) and by dividing the experimental period into the following fixed intervals [FDA's draft Guidance for industry. 2001]: weeks 1-52, weeks 53-70, weeks 71-85, and 86 to before terminal sacrifice, and the terminal sacrifice. Using the derived outcomes from the processing of both fatal and incidental tumors, a test statistic was built to perform a global survival-adjusted trend test on tumor data observed in a “mortality dependent” context [Peto et al, 1980].

All p-values are reported using upper-tailed test, unless otherwise indicated. Evaluation criteria (levels of significance) were applied differently for rare tumors (background rate of 1% or less) and common tumors (background rate greater than 1%) The evaluation criteria from the FDA are given in Table F (FDA) 15.

Sponsor’s concluded results: There was no ITI-007-related effect on the distribution of neoplastic or non-neoplastic findings.

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3.2 Reviewer’s Analyses

To verify the sponsor’s analyses and to perform additional analyses suggested by the reviewing pharmacologist, this reviewer analyzed the SAS data sets of these studies received on 12/17/2018 via submission NDA 209500/ SN-0022.

Since dose levels for females in 15 and 30 mg/kg/day were lowered to 10 and 20 mg/kg/day, respectively beginning on Day 386 due to the high mortality, the calculated adjusted overall average dose levels were used in the statistical analysis of survival and tumor incidence data. The calculated adjusted overall average dose levels were 13.0 and 27.4 mg/kg/day for MD and HD respectively

3.2.1 Survival Analysis

The survival distributions of rats in all treatment groups were estimated using the Kaplan-Meier product limit method. For control, low, medium, and high dose groups, the dose response relationship was tested using the likelihood ratio test and the homogeneity of survival distributions was tested using the log-rank test. The Kaplan-Meier curves for survival rates are given in Figures 1A and 1B in the appendix for male and female rats, respectively. The intercurrent mortality data are given in Tables 1A and 1B in the appendix for male and female rats, respectively. Results of the tests for dose response relationship and homogeneity of survivals, are given in Tables 3A and 3B in the appendix for male and female rats, respectively.

Reviewer’s findings: Termination started as early as week 94 and week 75 for males and females, respectively. This reviewer’s analysis showed the numbers (percentages) of death that occurred prior to termination of the group were 37 (67%), 36 (65%), 41 (75%), or 42 (76%) in male rats and 38 (69%), 40 (73%), 25 (45%), or 43 (78%) in female rats in the VC, LD, MD, and HD groups, respectively. The survival analyses show a statistically significant dose response relationship in mortality in females only (p=0.0135). The HD (30/20 mg/kg/day) group had a statistically significant higher mortality rate when compared to vehicle control for female rats (p=0.0003). The MD (15/10 mg/kg/day) group had a statistically significant lower mortality rate when compared to vehicle control (p=0.0059).

3.2.2 Tumor Data Analysis The tumor data were analyzed for dose response relationships and pairwise comparisons of control group with each of the treated groups. Both the dose response relationship tests and pairwise comparisons were performed using the Poly-k method described in the papers of Bailer and Portier [2] and Bieler and Williams [3]. In this method an animal that lives the full

study period ( wmax ) or dies before the terminal sacrifice but develops the tumor type being

tested gets a score of sh =1. An animal that dies at week wh without developing the tumor k   before the end of the study gets a score of s = wh <1. The adjusted group size is defined as h    wmax 

Σ sh . As an interpretation, an animal with score sh =1 can be considered as a whole animal

while an animal with score sh < 1 can be considered as a partial animal. The adjusted group size

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Σ sh is equal to N (the original group size) if all animals live up to the end of the study or if each animal that dies before the terminal sacrifice develops at least one tumor of the tumor type being tested, otherwise the adjusted group size is less than N. These adjusted group sizes are then used for the dose response relationship (or the pairwise) tests using the Cochran-Armitage test. One critical point for Poly-k test is the choice of the appropriate value of k, which depends on the tumor incidence pattern with the increased dose. For long term 104 week standard rat and mouse studies, a value of k=3 is suggested in the literature. Hence, this reviewer used k=3 for the analysis of this data. For the calculation of p-values the exact permutation method was used.

Multiple testing adjustments currently follow the rule displayed in Table 12.6. 5, 6

The adjusted levels of significance for testing a positive dose response in the 2-year rat study are 0.005 and 0.025 for a common tumor and a rare tumor, respectively. The adjusted levels of significance for the pairwise comparison in the 2-year rat study are 0.01 and 0.05 for a common tumor and a rare tumor, respectively. A rare tumor is defined as one in which the tumor rate is less than 1% in the vehicle control group.

The tumor rates and the p-values of the tested tumor types are listed in Tables 5A and 5B in the appendix for male and female rats, respectively.

Reviewer’s findings: Following table displays the tumor types showing p-values less than or equal to 0.05 either for dose response relationships or for pairwise comparisons between treated groups and control.

Tumor Types with P-Values ≤ 0.05 for Dose Response Relationship or Pairwise Comparisons of Treated Groups and Controls in Rats Organ name Tumor name 0 mg/kg/day 5 mg/kg/day 10 mg/kg/day 20 mg/kg/day Male Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - C vs. L P - C vs. M P - C vs. H Skin/Subcutis B-Papilloma, Squamous Cell 1/55(30) 0/55 (29) 2/55 (26) 4/55 (30) 0.0344 0.4915 0.4455 0.1766 Thyroid B-Adenoma, Follicular Cell 1/55(30) 3/55 (30) 4/53 (27) 4/54 (29) 0.1209 0.3060 0 1450 0.1660 M-Carcinoma, Follicular Cell 0/55(30) 0/55 (29) 2/53 (25) 0/54 (28) 0.4875 NC 0 2020 NC

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Organ name Tumor name 0 mg/kg/day 5 mg/kg/day 10 mg/kg/day 20 mg/kg/day Male Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - C vs. L P - C vs. M P - C vs. H Adenoma+Carcinoma, Follicular-Cell 1/55(30) 3/55 (30) 6/55 (28) 4/55 (30) 0.1269 0.3060 0.0415 0.1766 Organ name Tumor name 0 mg/kg/day 5 mg/kg/day 15/10 mg/kg/day 30/20 mg/kg/day Female Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - L vs. C P - M vs. C P - H vs. C Whole Body Hemangioma/Hemangiosarcoma 0/55(24) 0/55 (19) 0/55 (31) 2/55 (15) 0.0268 NC NC 0.1417 & X/ZZ (YY): X=number of tumor bearing animals; YY=mortality weighted total number of animals; ZZ=unweighted total number of animals observed; NC = Not calculable.

Based on the criteria of adjustment for multiple testing discussed above, there was no statistically significant positive dose-response relationship or pairwise comparison difference between individual treated groups and the vehicle control group in incidence in all tumor types tested in either sex.

4 Mouse Study- 8328210

Study Report: 8328210-pre-clincal-study-report-1.pdf (statistical report on page 5472) SAS data: tumor.xpt

This study was conducted to evaluate the carcinogenic potential of the test article, ITI-007, after once daily oral gavage administration to male and female mice for up to 99 consecutive weeks. The test material was administered at doses of 0, 5, 15, or 30 mg/kg/day. Starting Day 36 of the dosing phase, the dose levels were reduced to 2, 7, and 20 mg/kg/day, respectively. The changes were made based on recommendations by the FDA Carcinogenicity Assessment Committee (CAC). This review refers these dose groups as the vehicle control (VC), low (LD), mid (MD), and high (HD) dose groups, respectively. There were 55 mice/sex/dose in the main study.

Assessment of toxicity was based on dose analysis, morbidity, mortality, injury, body weight, food consumption, clinical observations and masses, ophthalmology, clinical pathology, toxicokinetics, macroscopic observations, and microscopic evaluations.

4.1 Sponsor’s Analyses

4.1.1 Survival Analysis

The sponsor used the same survival analysis methods for the rat study in this mouse study.

For all analyses, the two sexes were kept separate. As individual each dosed groups had dose levels lowered; the calculated adjusted overall average dose levels were used in the statistical analysis of survival and tumor incidence data. For males, the calculated adjusted overall average dose levels were 2.2 mg/kg/day, 7.4 mg/kg/day and 20.6 mg/kg/day for LD, MD, and HD respectively. For females, the calculated adjusted overall average dose levels were 2.2 mg/kg/day, 7.4 mg/kg/day and 20.5 mg/kg/day for LD, MD, and HD, respectively.

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Sponsor’s concluding: For males, the high-dose group (30/20 mg/kg/day) had higher mortality than those of the control group (40 of 55 versus 35 of 55 in control), with P = 0.0026 and P = 0.0040 for the Log-Rank and Wilcoxon tests respectively. The test for trend was also significant, P = 0.0010 and P = 0.0005 for the Log-Rank and Wilcoxon tests, respectively.

For females, there were no statistically significant dose responses among treatment groups or pairwise differences between individual treated groups and control group in survival.

4.1.2 Tumor Data Analysis The sponsor used the same tumor data analysis methods for the rat study in this mouse study.

Sponsor’s findings: No test article-related neoplasia occurred. Although a significant positive trend (5%) of uterine leiomyoma/leiomyosarcoma incidence was noted in females LD, MD, and HD groups, the lack of a dose relationship, the incidence of this combination of tumors in females administered 15/7 mg/kg/day was not statistically significant, and zero occurrence in the highest dose level suggests this was a biologic variation and not a test article-related effect.

4.2 Reviewer’s Analyses

To verify the sponsor’s analyses and to perform additional analyses suggested by the reviewing pharmacologist, this review analyzed the SAS data sets of these studies received on 12/17/2018 via submission NDA209500/SN-0022.

Since starting Day 36 of the dosing phase, the dose levels were reduced to 2, 7, and 20 mg/kg/day for LD, MD, and HD respectively, the calculated adjusted overall average dose levels were used in the statistical analysis of survival and tumor incidence data. For males, the calculated adjusted overall average dose levels were 2.2 mg/kg/day, 7.4 mg/kg/day and 20.6 mg/kg/day for LD, MD, and HD respectively. For females, the calculated adjusted overall average dose levels were 2.2 mg/kg/day, 7.4 mg/kg/day and 20.5 mg/kg/day for LD, MD, and HD respectively.

4.2.1 Survival Analysis The Kaplan-Meier curves for survival rates of all treatment groups are given in Figures 2A and 2B in the appendix for male and female mice, respectively. The intercurrent mortality data of all treatment groups are given in Tables 2A and 2B in the appendix for male and female mice, respectively. Results of the tests for dose response relationship and homogeneity of survivals for control, low, medium, and high dose groups are given in Tables 4A and 4B in the appendix for male and female mice, respectively.

Reviewer’s findings: Termination started as early as week 89 and week 91 for males and females, respectively. This reviewer’s analysis showed the numbers (percentages) of death that File Name: NDA209500Carcin

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occurred prior to termination of the group were 35 (64%), 35 (64%), 33 (60%) or 40 (73%) in male mice and 33 (60%), 40 (73%), 28 (51%), or 40 (73%) in female mice in the VC, LD, MD, or HD groups, respectively. The survival analyses show a statistically significant dose response relationship in mortality in male mice only (p=0.0017). The HD (30/20 mg/kg/day) group had a statistically significant higher mortality rate when compared to vehicle control for male mice (p=0.0031).

4.2.2 Tumor Data Analysis The tumor data were analyzed for positive dose response relationships and pairwise comparisons of the water control group and the vehicle control group separately with each of the treated groups using the same method that was used for the rat study. The tumor rates and the p-values of the tested tumor types are listed in Tables 6A, and 6B in the appendix for male and female mice, respectively.

Reviewer’s findings: Following table displays the tumor types showing p-values less than or equal to 0.05 either for dose response relationships or for pairwise comparisons of treated groups and control.

Tumor Types with P-Values ≤ 0.05 for Dose Response Relationship or Pairwise Comparisons of Treated Groups and Controls in Mice Organ name Tumor name 0 mg/kg/day 5/2 mg/kg/day 10/7 mg/kg/day 30/20 Vehicle (C) Low (L) Mid (M) mg/kg/day P - Trend P - C vs. L P - C vs. M High (H) P - C vs. H Uterus B-Polyp, Endometrial Stromal 2/55(33) 2/55 (31) 5/55 (38) 6/55 (29) 0.0281 0.6694 0 2773 0.0907 & X/ZZ (YY): X=number of tumor bearing animals; YY=mortality weighted total number of animals; ZZ=unweighted total number of animals observed; NC = Not calculable.

Based on the criteria of adjustment for multiple testing discussed above, there was no statistically significant positive dose-response relationship among treatment groups or pairwise comparison differences between individual treated groups and the vehicle control group in incidence in all tumor types tested in either sex.

Feng Zhou Mathematical Statistician

Concurring Reviewer: Karl Lin, Ph.D., Team Leader, Biometrics-6 cc: Dr. Deepa Rao Dr. Yi Tsong Dr. Karl Lin Ms. Patrician

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5 Appendix

Table 1A: Intercurrent Mortality Rate in Male Rats Vehicle Control Low Mid High Week / No. of Cum No. of Cum No. of Cum No. of Cum Type of Death Death % Death % Death % Death % 0 - 52 5 9.09 3 5.45 9 16.36 7 12.73 53 - 78 11 29.09 18 38.18 16 45.45 11 32.73 79 - 92 17 60.00 13 61.82 14 70.91 18 65.45 93 - 104 4 67.27 2 65.45 2 74.55 6 76.36 Terminal sacrifice 18 32.73 19 34.55 14 25.45 13 23.64 Total 55 55 55 55 ** All Cum. %Cumulative Percentage except for Terminal sacrifice

Table 1B: Intercurrent Mortality Rate in Female Rats Vehicle Control Low Mid High Week / No. of Cum No. of Cum No. of Cum No. of Cum Type of Death Death % Death % Death % Death % 0 - 52 6 10.91 7 12.73 1 1.82 12 21.82 53 - 78 19 45.45 24 56.36 13 25.45 31 78.18 79 - 92 13 69.09 8 70.91 11 45.45 Accidental Death 1 1.82 Terminal sacrifice 17 30.91 15 27.27 30 54.55 12 21.82 Total 55 55 55 55 ** All Cum. %Cumulative Percentage except for Terminal sacrifice

Table 2A: Intercurrent Mortality Rate in Male Mice Vehicle Control Low Mid High Week / No. of Cum No. of Cum No. of Cum No. of Cum Type of Death Death % Death % Death % Death % 0 - 52 3 5.45 1 1.82 4 7 27 12 21.82 53 - 78 13 29.09 13 25.45 15 34.55 12 43.64 79 - 92 12 50.91 12 47.27 8 49.09 14 69.09 93 - 104 7 63.64 8 61.82 5 58.18 Accidental Death 1 1.82 1 1.82 2 3.64 Terminal sacrifice 20 36.36 20 36.36 22 40.00 15 27.27 Total 55 55 55 55 ** All Cum. %Cumulative Percentage except for Terminal sacrifice

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Table 2B: Intercurrent Mortality Rate in Female Mice Vehicle Control Low Mid High Week / No. of Cum No. of Cum No. of Cum No. of Cum Type of Death Death % Death % Death % Death % 0 - 52 5 9.09 6 10.91 2 3.64 1 1.82 53 - 78 15 36.36 13 34.55 9 20.00 20 38.18 79 - 92 8 50.91 14 60.00 12 41.82 18 70.91 93 - 104 5 60.00 7 72.73 4 49.09 Accidental Death 1 1.82 1 1.82 Terminal sacrifice 22 40.00 15 27.27 27 49.09 15 27.27 Total 55 55 55 55

** All Cum %Cumulative Percentage except for Terminal sacrifice

Table 3A: Intercurrent Mortality Comparison in Male Rats Test All Dose Vehicle Control Vehicle Control Vehicle Control Groups vs. Low vs. Mid vs. High Dose-Response (Likelihood Ratio) 0.2414 0.5474 0.9323 0 2160 Homogeneity (Log-Rank) 0.5535 0.5436 0.9318 0 2121 #All Cum. % Cumulative Percentage except for Terminal sacrifice; * = Significant at 5% level; ** = Significant at 1% level.

Table 3B: Intercurrent Mortality Comparison in Female Rats Test All Dose Vehicle Control Vehicle Control Vehicle Control Groups vs. Low vs. Mid vs. High Dose-Response (Likelihood Ratio) 0.0135 0.1887 0.0059 0.0003 Homogeneity (Log-Rank) <.0001 0.1815 0.0052 0.0002 #All Cum. % Cumulative Percentage except for Terminal sacrifice; * = Significant at 5% level; ** = Significant at 1% level.

Table 4A: Intercurrent Mortality Comparison in Male Mice Test All Dose Vehicle Control Vehicle Control Vehicle Control Groups vs. Low vs. Mid vs. High Dose-Response (Likelihood Ratio) 0.0017 0.8618 0.8905 0.0031 Homogeneity (Log-Rank) 0.0039 0.8600 0.8892 0.0026 #All Cum. % Cumulative Percentage except for Terminal sacrifice; * = Significant at 5% level; ** = Significant at 1% level.

Table 4B: Intercurrent Mortality Comparison in Female Mice Test All Dose Vehicle Control Vehicle Control Vehicle Control Groups vs. Low vs. Mid vs. High Dose-Response (Likelihood Ratio) 0.0944 0.2745 0.1658 0.0844 Homogeneity (Log-Rank) 0.0045 0.2685 0.1615 0.0794 #All Cum. % Cumulative Percentage except for Terminal sacrifice; * = Significant at 5% level; ** = Significant at 1% level.

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Table 5A: Tumor Rates and P-Values for Trend and Pairwise Comparisons in Male Rats Organ name Tumor name 0 mg/kg/day 5 mg/kg/day 10 mg/kg/day 20 mg/kg/day Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - C vs. L P - C vs. M P - C vs. H Adrenal, Cortex B-Adenoma 1/55(30) 0/53 (28) 0/55 (25) 0/55 (28) 0.7297 0.4828 0.4545 0.4828

Adrenal, Medulla B-Pheochromocytoma 10/55(33) 8/53 (31) 7/54 (27) 8/55 (31) 0.6048 0.5478 0 5326 0.5478 M-Malignant Pheochromocytoma 0/55(30) 4/53 (29) 0/54 (24) 0/55 (28) 0.7693 0.0522 NC NC B+M-Pheochromocytoma 10/55(33) 10/55 (32) 7/55 (27) 8/55 (31) 0.7113 0.5734 0.7449 0.7505

Brain M-Malignant Glioma 0/55(30) 1/55 (29) 1/55 (25) 0/55 (28) 0.4875 0.4915 0.4545 NC Duodenum M-Carcinoma 1/55(30) 0/55 (29) 0/54 (24) 0/55 (28) 0.7297 0.4915 0.4444 0.4828 Epididymis M-Malignant Mesothelioma 1/55(30) 0/55 (29) 0/55 (25) 0/55 (28) 0.7321 0.4915 0.4545 0.4828

Hemolympho- M-Histiocytic Sarcoma 1/55(30) 0/55 (29) 1/55 (26) 0/55 (28) Reticular System 0.6064 0.4915 0.7175 0.4828 M-Leukemia, Granulocytic 0/55(30) 2/55 (30) 1/55 (26) 0/55 (28) 0.5751 0.2458 0.4643 NC M-Malignant Lymphoma 1/55(30) 1/55 (29) 0/55 (25) 1/55 (29) 0.4412 0.7458 0.4545 0.7458

Kidney B-Adenoma, Tubule Cell, Amp 0/55(30) 1/55 (29) 1/55 (25) 0/55 (28) 0.4875 0.4915 0.4545 NC B-Lipoma 1/55(30) 0/55 (29) 0/55 (25) 0/55 (28) 0.7321 0.4915 0.4545 0.4828 M-Liposarcoma 0/55(30) 1/55 (29) 0/55 (25) 0/55 (28) 0.4732 0.4915 NC NC Lipoma+Liposarcoma 1/55(30) 1/55 (29) 0/55 (25) 0/55 (28) 0.9300 0.7458 1.0000 1.0000

Liver M-Carcinoma, Hepatocellular 0/55(30) 0/55 (29) 0/55 (25) 1/55 (29) 0.2566 NC NC 0.4915

Lung B-Adenoma, Bronchiolo-Alveo 0/55(30) 1/55 (29) 1/55 (25) 0/54 (28) 0.4875 0.4915 0.4545 NC

Mammary Gland B-Fibroadenoma 0/55(30) 1/55 (29) 2/55 (26) 0/55 (28) 0.4332 0.4915 0 2110 NC M-Carcinoma 1/55(30) 0/55 (29) 0/55 (25) 0/55 (28) 0.7321 0.4915 0.4545 0.4828

Mandibular Salivary M-Malignant Schwannoma 1/55(30) 0/55 (29) 0/55 (25) 0/55 (28) Gland 0.7321 0.4915 0.4545 0.4828 Pancreas B-Adenoma, Islet Cell 1/55(30) 2/55 (29) 4/55 (26) 4/55 (29) 0.0894 0.4871 0 1346 0.1660 M-Carcinoma, Islet Cell 0/55(30) 1/55 (29) 0/55 (25) 0/55 (28) 0.4732 0.4915 NC NC Adenoma+Carcinoma, Islet Cell 1/55(30) 3/55 (30) 4/55 (26) 4/55 (29) 0.1206 0.3060 0 1346 0.1660

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Organ name Tumor name 0 mg/kg/day 5 mg/kg/day 10 mg/kg/day 20 mg/kg/day Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - C vs. L P - C vs. M P - C vs. H Parathyroid B-Adenoma 1/54(29) 0/53 (28) 1/55 (25) 0/54 (28) 0.6128 0.4912 0.7163 0.4912

Pituitary B-Adenoma 41/55(48) 34/54 (43) 35/55 (43) 32/55 (43) 0.8712 0.6982 0 5931 0.8534 M-Carcinoma 1/55(30) 0/54 (28) 1/55 (25) 0/55 (28) 0.6064 0.4828 0.7071 0.4828 Adenoma+Carcinoma 42/55(48) 34/55 (44) 36/55 (44) 32/55 (43) 0.9185 0.9420 0.8527 0.9696

Prostate M-Malignant Schwannoma 1/54(29) 0/55 (29) 0/55 (25) 0/55 (28) 0.7387 0.5000 0.4630 0.4912

Skin/Subcutis B-Adenoma, Sebaceous 1/55(30) 0/55 (29) 0/55 (25) 0/55 (28) 0.7321 0.4915 0.4545 0.4828 B-Fibroma 9/55(33) 6/55 (31) 4/55 (26) 4/55 (29) 0.8913 0.6734 0.7801 0.8383 B-Keratoacanthoma 4/55(31) 5/55 (30) 2/55 (26) 2/55 (29) 0.8178 0.4783 0 5762 0.6317 B-Lipoma 0/55(30) 2/55 (29) 1/55 (26) 2/55 (29) 0.1958 0.2373 0.4643 0.2373 B-Neural Crest Tumor 0/55(30) 0/55 (29) 1/55 (25) 0/55 (28) 0.4732 NC 0.4545 NC B-Papilloma, Squamous Cell 1/55(30) 0/55 (29) 2/55 (26) 4/55 (30) 0.0344 0.4915 0.4455 0.1766 Keratoacanthoma+ Papilloma, 4/55(31) 5/55 (30) 4/55 (27) 5/55 (30) Squamouscell 0.4030 0.4783 0 5647 0.4783 M-Carcinoma, Basal Cell 1/55(31) 0/55 (29) 0/55 (25) 0/55 (28) 0.7257 0.4833 0.4464 0.4746 M-Fibrosarcoma 1/55(30) 2/55 (30) 0/55 (25) 1/55 (28) 0.5198 0.5000 0.4545 0.7368 Carcinoma,Basal Cell+Fibrosarcoma 2/55(31) 2/55 (30) 0/55 (25) 1/55 (28) 0.8059 0.6813 1.0000 0.8617 M-Hemangiosarcoma 0/55(30) 0/55 (29) 0/55 (25) 1/55 (28) 0.2500 NC NC 0.4828

Spleen B-Hemangioma 0/55(30) 0/55 (29) 1/55 (25) 0/55 (28) 0.4732 NC 0.4545 NC

Testis B-Interstitial Cell Tumor 0/55(30) 0/55 (29) 0/55 (25) 1/55 (28) 0.2500 NC NC 0.4828 Thymus B-Thymoma 1/51(27) 0/53 (28) 0/55 (25) 0/54 (28) 0.7500 0.5091 0.4808 0.5091

Thyroid B-Adenoma, C-Cell 7/55(33) 7/55 (31) 5/53 (26) 4/54 (29) 0.7757 0.5666 0.4423 0.6641 M-Carcinoma, C-Cell 1/55(30) 1/55 (29) 0/53 (24) 0/54 (28) 0.7862 0.7458 0.4444 0.4828 Adenoma+Carcinoma, C-Cell 8/55(33) 8/55 (31) 5/55 (27) 4/55 (29) 0.8965 0.5566 0.8015 0.9146 B-Adenoma, Follicular Cell 1/55(30) 3/55 (30) 4/53 (27) 4/54 (29) 0.1209 0.3060 0 1450 0.1660 M-Carcinoma, Follicular Cell 0/55(30) 0/55 (29) 2/53 (25) 0/54 (28) 0.4875 NC 0 2020 NC File Name: NDA209500Carcin

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 15 of 23

Organ name Tumor name 0 mg/kg/day 5 mg/kg/day 10 mg/kg/day 20 mg/kg/day Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - C vs. L P - C vs. M P - C vs. H Adenoma+Carcinoma, Follicular-Cell 1/55(30) 3/55 (30) 6/55 (28) 4/55 (30) 0.1269 0.3060 0.0415 0.1766

Zymbal Gland M-Carcinoma, Squamous Cell 0/55(30) 0/55 (29) 1/55 (26) 0/55 (28) 0.4779 NC 0.4643 NC

Whole Body Hemangioma/Hemangiosarcoma 0/55(30) 0/55 (29) 1/55 (25) 1/55 (28) 0.1734 NC 0.4545 0.4828 & X/ZZ (YY): X=number of tumor bearing animals; YY=mortality weighted total number of animals; ZZ=unweighted total number of animals observed; NC = Not calculable.

Table 5B: Tumor Rates and P-Values for Trend and Pairwise Comparisons in Female Rats Organ name Tumor name 0 mg/kg/day 5 mg/kg/day 15/10 mg/kg/day 30/20 mg/kg/day Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - L vs. C P - M vs. C P - H vs. C Abdominal Cavity M-Fibrosarcoma 1/55(25) 0/55 (19) 0/55 (31) 0/55 (14) 0.7191 0.4318 0.5536 0.3590 Adrenal, Cortex B-Adenoma 0/55(24) 1/55 (20) 0/54 (30) 0/55 (14) 0.5000 0.4545 NC NC

Adrenal, Medulla B-Pheochromocytoma 2/54(25) 0/55 (19) 1/54 (31) 1/55 (15) 0.4980 0.6829 0.5815 0.3117 M-Malignant Pheochromocytoma 0/54(24) 0/55 (19) 1/54 (31) 0/55 (14) 0.5114 NC 0.5636 NC B+M-Pheochromocytoma 2/55(26) 0/55 (19) 2/55 (32) 1/55 (15) 0.4417 1.0000 0.7687 0.7561

Brain B-Oligodendroglioma 0/55(24) 1/55 (20) 0/55 (31) 0/55 (14) 0.5056 0.4545 NC NC

Cervix B-Granular Cell Tumor 0/55(24) 0/55 (19) 1/55 (31) 0/55 (14) 0.5114 NC 0.5636 NC

Gingiva M-Osteosarcoma 0/55(24) 0/55 (19) 1/55 (32) 0/55 (14) 0.5169 NC 0.5714 NC

Hemolympho- M-Histiocytic Sarcoma 0/55(24) 1/55 (20) 1/55 (31) 0/55 (14) Reticular System 0.4101 0.4545 0.5636 NC M-Leukemia, Granulocytic 0/55(24) 1/55 (20) 0/55 (31) 0/55 (14) 0.5056 0.4545 NC NC M-Malignant Lymphoma 2/55(26) 0/55 (19) 1/55 (31) 1/55 (15) 0.4895 0.6717 0.5668 0.2988

Kidney M-Carcinoma, Transitional C 0/55(24) 0/55 (19) 1/55 (31) 0/55 (14) 0.5114 NC 0.5636 NC M-Nephroblastoma 0/55(24) 0/55 (19) 0/55 (31) 1/55 (15) 0.1685 NC NC 0.3846

Lymph Node, B-Hemangioma 0/55(24) 0/55 (19) 0/55 (31) 1/55 (15) Mesenteric 0.1685 NC NC 0.3846

Mammary Gland B-Adenoma 2/55(25) 0/55 (19) 2/53 (30) 1/55 (15) 0.4458 0.6829 0.3780 0.3117

File Name: NDA209500Carcin

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Organ name Tumor name 0 mg/kg/day 5 mg/kg/day 15/10 mg/kg/day 30/20 mg/kg/day Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - L vs. C P - M vs. C P - H vs. C B-Fibroadenoma 17/55(33) 20/55 (31) 19/53 (38) 8/55 (20) 0.8838 0.2123 0.4560 0.7013 M-Carcinoma 14/55(32) 18/55 (31) 13/53 (36) 6/55 (18) 0.8998 0.1884 0.6534 0.6610 Adenoma+Carcinoma 16/55(33) 18/55 (31) 15/55 (38) 7/55 (19) 0.8996 0.3029 0.8422 0.8654

Mandibular Salivary B-Fibroma 1/55(25) 0/55 (19) 0/55 (31) 0/55 (14) Gland 0.7191 0.4318 0.5536 0.3590 Muscle, Biceps M-Hemangiosarcoma 0/55(24) 0/55 (19) 0/55 (31) 1/55 (15) Femoris 0.1685 NC NC 0.3846

Ovary B-Granulosa/Theca Cell Tumor 1/55(25) 0/55 (19) 0/55 (31) 0/55 (14) 0.7191 0.4318 0.5536 0.3590 Pancreas B-Adenoma, Islet Cell 1/55(25) 0/55 (19) 1/55 (31) 0/55 (14) 0.5605 0.4318 0.3019 0.3590 Parathyroid B-Adenoma 0/54(24) 0/54 (19) 2/55 (32) 0/51 (13) 0.4046 NC 0.3221 NC Pituitary B-Adenoma 44/55(49) 39/55 (45) 36/55 (47) 9/55 (20) 1.0000 0.5608 0.9286 0.9998 M-Carcinoma 3/55(26) 2/55 (20) 1/55 (31) 0/55 (14) 0.9467 0.3735 0.7581 0.7368 Adenoma+Carcinoma 47/55(50) 41/55 (46) 37/55 (47) 9/55 (20) 1.0000 0.8913 0.9948 1.0000 Skin/Subcutis B-Fibroma 1/55(25) 1/55 (20) 1/55 (31) 0/55 (14) 0.6681 0.6970 0.3019 0.3590 B-Keratoacanthoma 0/55(24) 0/55 (19) 2/55 (32) 1/55 (15) 0.1342 NC 0.3221 0.3846 B-Lipoma 0/55(24) 1/55 (20) 0/55 (31) 0/55 (14) 0.5056 0.4545 NC NC

Thyroid B-Adenoma, C-Cell 4/55(26) 5/55 (22) 8/55 (34) 5/55 (17) 0.1575 0.3887 0.3276 0.2335 B-Adenoma, Follicular Cell 0/55(24) 0/55 (19) 1/55 (31) 0/55 (14) 0.5114 NC 0.5636 NC M-Carcinoma, C-Cell 1/55(25) 0/55 (19) 2/55 (32) 0/55 (14) 0.5240 0.4318 0.5933 0.3590 Adenoma+Carcinoma, C-Cell 5/55(26) 5/55 (22) 10/55 (35) 5/55 (17) 0.2022 0.5211 0.2981 0.3396

Uterus B-Polyp, Endometrial Stromal 2/55(25) 1/55 (20) 1/55 (31) 0/55 (14) 0.8429 0.4151 0.5815 0.5951 M-Leiomyosarcoma 0/55(24) 1/55 (20) 0/55 (31) 0/55 (14) 0.5056 0.4545 NC NC M-Sarcoma, Endometrial Stro 0/55(24) 1/55 (20) 0/55 (31) 0/55 (14) 0.5056 0.4545 NC NC Polyp-Endometrialstromal+ Sarcoma, 2/55(25) 2/55 (21) 1/55 (31) 0/55 (14) Endometrialstro 0.9303 0.6265 0.9170 1.0000

Whole Body Hemangioma/Hemangiosarcoma 0/55(24) 0/55 (19) 0/55 (31) 2/55 (15) 0.0268 NC NC 0.1417 & X/ZZ (YY): X=number of tumor bearing animals; YY=mortality weighted total number of animals; ZZ=unweighted total number of animals observed; NC = Not calculable.

File Name: NDA209500Carcin

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 17 of 23

Table 6A: Tumor Rates and P-Values for Trend and Pairwise Comparisons in Males Mice Organ name Tumor name 0 mg/kg/day 5/2 mg/kg/day 10/7 mg/kg/day 30/20 mg/kg/day Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - C vs. L P - C vs. M P - C vs. H Adrenal, Cortex B-Adenoma 2/55(34) 0/54 (33) 1/55 (32) 0/52 (20) 0.7595 0.7463 0.4769 0.6080 B-Adenoma, Subcapsular Cell 1/55(33) 3/54 (34) 2/55 (33) 1/52 (20) 0.4629 0.3181 0 5000 0.6168

Adrenal, Medulla B-Pheochromocytoma 0/54(33) 1/54 (33) 0/55 (32) 0/52 (20) 0.4407 0.5000 NC NC

Duodenum B-Adenoma 0/53(32) 1/54 (34) 1/55 (33) 0/50 (19) 0.3738 0.5152 0 5077 NC

Femur B-Osteoma 0/54(33) 0/55 (34) 1/54 (32) 0/55 (21) 0.4417 NC 0.4923 NC

Foot M-Fibrosarcoma 1/55(33) 0/55 (34) 0/55 (32) 0/55 (21) 0.7250 0.5075 0.4923 0.3889

Harderian Gland B-Adenoma 7/55(35) 6/55 (37) 0/55 (32) 6/55 (24) 0.2882 0.5446 0 9923 0.4419 M-Carcinoma 1/55(33) 0/55 (34) 1/55 (33) 2/55 (22) 0.0904 0.5075 NC 0.3493 B-Adenoma+m-Carcinoma 8/55(35) 6/55 (37) 1/55 (33) 8/55 (26) 0.1513 0.8435 0 9986 0.3426

Heart M-Hemangiosarcoma 0/55(33) 1/55 (34) 0/55 (32) 0/55 (21) 0.4417 0.5075 NC NC

Hemolympho- M-Histiocytic Sarcoma 1/55(34) 4/55 (35) 0/55 (32) 2/55 (23) Reticular System 0.3789 0.1873 0.4848 0.3545 M-Leukemia, Granulocytic 0/55(33) 1/55 (35) 0/55 (32) 0/55 (21) 0.4380 0.5147 NC NC M-Malignant Lymphoma 3/55(34) 5/55 (37) 3/55 (32) 5/55 (23) 0.1049 0.4043 0.6340 0.1615

Kidney B-Adenoma, Tubule Cell 0/55(33) 0/55 (34) 0/55 (32) 1/55 (21) 0.1750 NC NC 0.3889

Liver B-Adenoma, Hepatocellular 6/55(35) 5/55 (35) 4/55 (33) 2/55 (22) 0.7882 0.5000 0 5940 0.6693 M-Carcinoma, Hepatocellular 6/55(36) 1/55 (34) 2/55 (33) 6/55 (24) 0.0570 0.9378 0.8404 0.3192 Adenoma+carcinoma,hepatocellular 11/55(37) 6/55 (35) 6/55 (35) 8/55 (25) 0.2660 0.9385 0 9385 0.5331

Lung B-Adenoma, Bronchiolo-Alveo 8/55(36) 10/55 (38) 8/55 (34) 6/55 (24) 0.4561 0.4453 0 5606 0.5202 M-Carcinoma, Bronchiolo-Alv 7/55(35) 7/55 (36) 4/55 (33) 3/55 (23) 0.7831 0.4061 0.7082 0.6230 Adenom+Carcinoma,bronchiolo-Alveo 14/55(37) 17/55 (40) 12/55 (35) 9/55 (26) 0.6903 0.4272 0.7116 0.6996 Pituitary B-Adenoma 0/55(33) 3/53 (34) 0/55 (32) 0/54 (21) 0.8294 0.1249 NC NC

File Name: NDA209500Carcin

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Organ name Tumor name 0 mg/kg/day 5/2 mg/kg/day 10/7 mg/kg/day 30/20 mg/kg/day Vehicle (C) Low (L) Mid (M) High (H) P - Trend P - C vs. L P - C vs. M P - C vs. H Seminal Vesicle M-Carcinoma 1/54(32) 0/55 (34) 0/55 (32) 0/55 (21) 0.7311 0.5152 0 5000 0.3962 Skin/Subcutis B-Hemangioma 0/55(33) 0/55 (34) 1/55 (32) 0/55 (21) 0.4417 NC 0.4923 NC B-Lipoma 1/55(33) 1/55 (34) 0/55 (32) 0/55 (21) 0.7689 0.2537 0.4923 0.3889 M-Carcinoma, Squamous Cell 1/55(34) 0/55 (34) 0/55 (32) 0/55 (21) 0.7190 0.5000 0.4848 0.3818 M-Hemangiosarcoma 0/55(33) 1/55 (35) 0/55 (32) 0/55 (21) 0.4380 0.5147 NC NC M-Osteosarcoma 1/55(33) 0/55 (34) 0/55 (32) 0/55 (21) 0.7250 0.5075 0.4923 0.3889 M-Sarcoma 3/55(34) 3/55 (36) 4/55 (34) 0/55 (21) 0.8733 0.3646 0 5000 0.7719 Hemangioma+hemangiosarcoma 0/55(33) 1/55 (35) 1/55 (32) 0/55 (21) 0.5408 0.5147 0.4923 NC

Stomach, Glandular M-Carcinoid 0/55(33) 1/55 (35) 0/55 (32) 0/55 (21) 0.4380 0.5147 NC NC M-Carcinoma 1/55(33) 0/55 (34) 0/55 (32) 0/55 (21) 0.7250 0.5075 0.4923 0.3889 M-Leiomyosarcoma 0/55(33) 0/55 (34) 1/55 (32) 0/55 (21) 0.4417 NC 0.4923 NC Stomach, M-Carcinoma 1/55(33) 0/55 (34) 0/55 (32) 0/55 (21) Nonglandular 0.7250 0.5075 0.4923 0.3889 Testis B-Interstitial Cell Tumor 0/55(33) 3/55 (35) 2/55 (32) 0/55 (21) 0.6871 0.1306 0 2385 NC Thymus B-Thymoma 0/46(28) 0/50 (31) 0/44 (26) 1/45 (18) 0.1748 NC NC 0.3913 M-Malignant Thymoma 0/46(28) 2/50 (32) 1/44 (26) 0/45 (18) 0.5594 0.2802 0.4815 NC Thyroid B-Adenoma, Follicular Cell 2/55(33) 1/54 (34) 0/55 (32) 0/55 (21) 0.9167 0.5114 0.7462 0.6310 Whole body Hemangioma/Hemangiosarcoma 0/55(33) 2/55 (35) 1/55 (32) 0/55 (21) 0.6390 0.2612 0.4923 NC & X/ZZ (YY): X=number of tumor bearing animals; YY=mortality weighted total number of animals; ZZ=unweighted total number of animals observed; NC = Not calculable.

Table 6B: Tumor Rates and P-Values for Trend and Pairwise Comparisons in Female Mice Organ name Tumor name 0 mg/kg/day 5/2 mg/kg/day 10/7 mg/kg/day 30/20 Vehicle (C) Low (L) Mid (M) mg/kg/day P - Trend P - C vs. L P - C vs. M High (H) P - C vs. H Adrenal, Cortex B-Adenoma, Subcapsular Cell 0/55(32) 1/55 (30) 0/54 (37) 1/55 (27) 0.2743 0.4839 NC 0.4576

Cervix B-Polyp, Cervical 0/55(32) 0/55 (30) 1/55 (37) 0/55 (26) 0.5040 NC 0 5362 NC M-Sarcoma, Stromal 4/55(34) 1/55 (30) 2/55 (38) 0/55 (26) 0.9531 0.7810 0.7150 0.9049

Femur B-Osteoma 0/54(32) 0/55 (30) 1/55 (37) 0/53 (26) 0.5040 NC 0 5362 NC

File Name: NDA209500Carcin

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 19 of 23

Organ name Tumor name 0 mg/kg/day 5/2 mg/kg/day 10/7 mg/kg/day 30/20 Vehicle (C) Low (L) Mid (M) mg/kg/day P - Trend P - C vs. L P - C vs. M High (H) P - C vs. H Harderian Gland B-Adenoma 3/55(33) 5/55 (32) 6/54 (38) 4/55 (28) 0.3652 0.3366 0 3156 0.4062 M-Carcinoma 0/55(32) 0/55 (30) 2/54 (37) 0/55 (26) 0.4600 NC 0 2839 NC Adenoma+carcinoma 3/55(33) 5/55 (32) 8/55 (39) 4/55 (28) 0.3617 0.3366 0 1556 0.4062

Hemolympho- M-Histiocytic Sarcoma 3/55(34) 1/55 (30) 7/55 (39) 2/55 (27) Reticular System 0.4266 0.6445 0 2163 0.3897 M-Malignant Lymphoma 14/55(40) 19/55 (40) 9/55 (40) 5/55 (29) 0.9916 0.1819 0.8384 0.9139

Liver B-Adenoma, Hepatocellular 0/55(32) 0/55 (30) 1/55 (37) 0/55 (26) 0.5040 NC 0 5362 NC B-Hemangioma 1/55(33) 0/55 (30) 0/55 (37) 0/55 (26) 0.7381 0.4762 0 5286 0.4407 M-Carcinoma, Hepatocellular 0/55(32) 1/55 (30) 0/55 (37) 1/55 (27) 0.2743 0.4839 NC 0.4576 Adenoma+carcinoma,hepatocellular 0/55(32) 1/55 (30) 1/55 (37) 1/55 (27) 0.2631 0.4839 0 5362 0.4576

Lung B-Adenoma, Bronchiolo-Alveo 6/55(34) 9/55 (33) 9/55 (39) 11/55 (32) 0.0906 0.2576 0 3907 0.1016 M-Carcinoma, Bronchiolo-Alv 4/55(34) 4/55 (32) 4/55 (38) 5/55 (29) 0.2498 0.6104 0.4203 0.3964 Adenom+carcinom, bronchiolo-Alveo 10/55(36) 13/55 (35) 12/55 (40) 13/55 (33) 0.2200 0.2780 0 5167 0.2216

Lymph Node, M-Hemangiosarcoma 0/53(31) 1/54 (31) 2/54 (37) 0/54 (26) Mesenteric 0.5308 0.5000 0 2924 NC

Mammary Gland, M-Carcinoma 0/51(31) 0/47 (26) 1/50 (35) 2/54 (27) Female 0.0555 NC 0 5303 0.2123

Muscle, Biceps M-Osteosarcoma 0/55(32) 0/55 (30) 1/55 (38) 0/55 (26) Femoris 0.5079 NC 0 5429 NC Ovary B-Adenoma 2/54(32) 2/55 (31) 2/55 (38) 1/55 (27) 0.6424 0.6815 0 3749 0.4355 B-Hemangioma 0/54(32) 1/55 (30) 1/55 (37) 2/55 (28) 0.0983 0.4839 0 5362 0.2136 B-Luteoma 1/54(33) 1/55 (30) 1/55 (37) 1/55 (27) 0.4658 0.7296 0 2758 0.7017 B-Theca Cell Tumor 0/54(32) 0/55 (30) 1/55 (38) 0/55 (26) 0.5079 NC 0 5429 NC M-Hemangiosarcoma 1/54(32) 0/55 (30) 0/55 (37) 0/55 (26) 0.7440 0.4839 0 5362 0.4483 Hemangioma+hemangiosarcoma 1/55(33) 1/55 (30) 1/55 (37) 2/55 (28) 0.2158 0.7296 0.7814 0.4376

Pancreas B-Adenoma, Islet Cell 0/55(32) 1/55 (30) 0/54 (37) 0/55 (26) 0.5040 0.4839 NC NC

Parathyroid B-Adenoma 0/52(31) 0/53 (29) 1/53 (36) 0/54 (26) 0.5082 NC 0 5373 NC File Name: NDA209500Carcin

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 20 of 23

Organ name Tumor name 0 mg/kg/day 5/2 mg/kg/day 10/7 mg/kg/day 30/20 Vehicle (C) Low (L) Mid (M) mg/kg/day P - Trend P - C vs. L P - C vs. M High (H) P - C vs. H Pituitary B-Adenoma 1/54(32) 1/55 (30) 2/54 (37) 0/55 (26) 0.6980 0.7377 0 5551 0.4483 Skin/Subcutis B-Adenoma, Sebaceous 0/55(32) 0/55 (30) 1/55 (37) 0/55 (26) 0.5040 NC 0 5362 NC M-Carcinoma 0/55(32) 1/55 (31) 0/55 (37) 0/55 (26) 0.5000 0.4921 NC NC M-Carcinoma, Basal Cell 1/55(33) 0/55 (30) 0/55 (37) 1/55 (27) 0.3813 0.4762 0 5286 0.7017 M-Carcinoma, Squamous Cell 0/55(32) 0/55 (30) 1/55 (37) 0/55 (26) 0.5040 NC 0 5362 NC M-Hemangiosarcoma 0/55(32) 2/55 (31) 0/55 (37) 1/55 (27) 0.3944 0.2381 NC 0.4576 M-Sarcoma 1/55(33) 2/55 (31) 0/55 (37) 0/55 (26) 0.8885 0.4762 0 5286 0.4407 M-Carcinoma+m-Carcinoma,basalcell 1/55(33) 1/55 (31) 0/55 (37) 1/55 (27) 0.4701 0.7381 1.0000 0.7017 M-Carcio+m-Carcinoma,squamouscell 1/55(33) 0/55 (30) 1/55 (37) 1/55 (27) 0.3568 1.0000 0.7814 0.7017 Spleen M-Hemangiosarcoma 0/55(32) 1/55 (30) 1/55 (37) 0/55 (26) 0.4600 0.4839 0 5362 NC Stomach, Glandular B-Polyp 1/55(33) 0/54 (30) 1/55 (37) 0/55 (26) 0.5970 0.4762 0 2758 0.4407

Thyroid B-Adenoma, Follicular Cell 1/55(33) 0/55 (30) 1/54 (37) 1/55 (27) 0.3568 0.4762 0 2758 0.7017 Uterus B-Decidual Reaction/Deciduo 0/55(32) 0/55 (30) 0/55 (37) 1/55 (27) 0.2143 NC NC 0.4576 B-Hemangioma 0/55(32) 1/55 (31) 1/55 (38) 0/55 (26) 0.4567 0.4921 0 5429 NC B-Leiomyoma 0/55(32) 0/55 (30) 2/55 (38) 0/55 (26) 0.4607 NC 0 2911 NC B-Polyp, Endometrial Stromal 2/55(33) 2/55 (31) 5/55 (38) 6/55 (29) 0.0281 0.6694 0 2773 0.0907 M-Hemangiosarcoma 1/55(33) 0/55 (30) 0/55 (37) 1/55 (27) 0.3813 0.4762 0 5286 0.7017 M-Leiomyosarcoma 0/55(32) 0/55 (30) 1/55 (38) 0/55 (26) 0.5079 NC 0 5429 NC M-Sarcoma, Endometrial Stro 2/55(33) 1/55 (30) 0/55 (37) 0/55 (26) 0.9346 0.4637 0.7814 0.6914 B-Leiomyoma+m-Leiomyosarcoma 0/55(32) 0/55 (30) 3/55 (39) 0/55 (26) 0.4888 NC 0 1599 NC B-Polyp,endometrialstromal+m- 4/55(33) 3/55 (31) 5/55 (38) 6/55 (29) Sarcoma,endometrialst 0.1172 0.7602 0 5914 0.2843 Vagina M-Carcinoma, Squamous Cell 0/55(32) 0/55 (30) 1/55 (37) 0/55 (26) 0.5040 NC 0 5362 NC M-Hemangiosarcoma 0/55(32) 0/55 (30) 1/55 (37) 0/55 (26) 0.5040 NC 0 5362 NC Whole body Hemangioma/Hemangiosarcoma 3/55(34) 6/55 (32) 5/55 (39) 4/55 (29) 0.4415 0.2079 0.4360 0.4093

& X/ZZ (YY): X=number of tumor bearing animals; YY=mortality weighted total number of animals; ZZ=unweighted total number of animals observed; NC = Not calculable.

File Name: NDA209500Carcin

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 21 of 23

Figure 1A: Kaplan-Meier Survival Functions for Male Rats

Figure 1B: Kaplan-Meier Survival Functions for Female Rats

File Name: NDA209500Carcin

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 22 of 23

Figure 2A: Kaplan-Meier Survival Functions for Male Mice

Figure 2B: Kaplan-Meier Survival Functions for Female Mice

File Name: NDA209500Carcin

Reference ID: 4407968 NDA 209500 ● lumateperone (ITI-007) ● Intra-Cellular Therapies, Inc.● Carcinogenicity Study Page 23 of 23

References

1. Peto, R., M.C. Pike, N.E. Day, R.G. Gray, P.N. Lee, S. Parish, J. Peto, Richards, and J.Wahrendorf, “Guidelines for sample sensitive significance test for carcinogenic effects in long-term animal experiments”, Long term and short term screening assays for carcinogens: A critical appraisal, International agency for research against cancer monographs, Annex to supplement, World Health Organization, Geneva, 311-426, 1980. 2. Bailer AJ, Portier CJ (1988). “Effects of treatment-induced mortality and tumor- induced mortality on tests for carcinogenicity in small samples.” Biometrics, 44, 417-431. 3. Bieler, G. S. and Williams, R. L. (1993). “Ratio estimates, the delta method, and quantal response tests for increased carcinogenicity”. Biometrics 49, 793-801. 4. Tarone RE, “Test for trend in life table analysis”, Biometrika 1975, 62: 679-82 5. Lin K.K. and Rahman M.A.,” Overall false positive rates in tests for linear trend in tumor incidence in animal carcinogenicity studies of new drugs”, Journal of Biopharmaceutical Statistics, 8(1), 1-15, 1998. 6. Rahman, A.M., and K.K. Lin (2008), "A Comparison of False Positive Rates of Peto and Poly-3 Methods for Long-Term Carcinogenicity Data Analysis Using Multiple Comparison Adjustment Method Suggested by Lin and Rahman", Journal of Biopharmaceutical Statistics, 18:5, 849-858. 7. Food and Drug Administration Draft Guidance for Industry (2001) Statistical aspects of the design, analysis, and interpretation of chronic rodent carcinogenicity studies of pharmaceuticals. Center for Drug Evaluation and Research (CDER): Maryland. 8. McConnell EE, Solleveld HA, Swenberg JA, et al (1986) Guidelines for combining neoplasms for evaluation of rodent carcinogenicity studies. J Natl Cancer Inst; 76(2):283-289. 9. Peto R, Pike MC, Day NE, et al (1980) Guidelines for simple, sensitive significance tests for carcinogenic effects in long-term animal experiments. International Agency for Cancer Research (IARC) Monogr Eval Carcinog Risk of Chem Hum Suppl; 311-426.

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Reference ID: 4407968