CENTER FOR DRUG EVALUATION AND RESEARCH 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 (lumateperone) 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 Psychiatry / Office of Drug Evaluation-I Review Completion Date December 20, 2019 Established/Proper Name Lumateperone (Proposed) Trade Name Caplyta Pharmacologic Class Atypical Antipsychotic 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 Schizophrenia/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 2 Version date: October 12, 2018 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 Pharmacokinetics ....................................................... 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 ..........................................................................................................