CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

213969Orig1s000

INTEGRATED REVIEW NDA 213969 Zokinvy (lonafarnib) Integrated Review Table 1. Administrative Application Information Category Application Information Application type NDA Application number(s) 213969 Priority or standard Priority Submit date(s) 3/20/2020 Received date(s) 3/20/2020 PDUFA goal date 11/20/2020 Divis ion/office Division of Rare Diseases and Medical Genetics (DRDMG) Review completion date 11/20/2020 Established/proper name Lonafarnib (Propose d) proprie tary Zokinvy name Pharmacologic class Small molecule Code name EBP994 Applicant Eiger BioPharmaceuticals, Inc. Dosage Capsules, 50 mg and 75 mg. form(s)/formulation(s) Dosing re gimen 115 mg/m2, dose up to 150 mg/m2 for HGPS Applicant proposed Treatment of Hutchinson-Gilford progeria syndrome indication(s)/ population(s) (HGPS) and progeroid laminopathies (PL) Proposed SNOMED 238870004 |Hutchinson-Gilford syndrome (disorder) indication Regulatory action Approval Approved dosage (if 115 mg/m2, dose up to 150 mg/m2 for HGPS applicable) Approved indication(s)/ Hutchinson-Gilford Progeria syndome and processing- population(s) (if applicable) deficient progeroid laminopathies Approved SNOMED term 238870004 |Hutchinson-Gilford syndrome (disorder) for indication (if applicable)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table of Contents Table of Tables...... v Table of Figures ...... ix Glossary ...... 1 I. Executive Summary ...... 3 1. Summary of Regulatory Action ...... 3 2. Benefit-Risk Assessment...... 4 2.1. Benefit-Risk Framework ...... 4 2.2. Conclusions Regarding Benefit-Risk...... 8 II. Interdisciplinary Assessment ...... 10 3. Introduction ...... 10 3.1. Review Issue List...... 11 3.1.1. Key Review Issues Relevant to Evaluation of Benefit ...... 11 3.1.2. Key Review Issues Relevant to Evaluation of Risk...... 11 3.2. Approach to the Review ...... 12 4. Patient Experience Data...... 15 5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology...... 16 5.1. Nonclinical Assessment of Potential Effectiveness ...... 20 6. Assessment of Effectiveness...... 20 6.1. Dose and Dose Responsiveness ...... 20 6.1.1. ProLon1 and ProLon2...... 20 6.2. Clinical Trials Intended to Demonstrate Efficacy...... 24 6.2.1. ProLon1 and ProLon2...... 24 6.2.1.1. Design, ProLon1 and ProLon2 ...... 24 6.2.1.2. Eligibility Criteria, ProLon1 and ProLon2 ...... 27 6.2.1.3. Statistical Analysis Plan...... 27 6.2.1.4. Results of Analyses, ProLon1 and ProLon2 ...... 30 6.3. Key Review Issues Relevant to Evaluation of Benefit...... 40 6.3.1. Mitigating Disparities Between Treated and Untreated HGPS patients...... 40 6.3.2. Post Hoc Nature of the Analysis Plan ...... 41 6.3.3. Criteria and Algorithm for Matching Treated Patients to Controls...... 42 6.3.4. Disparity in Censoring Rate in the Treated and Untreated Cohort ...... 44 6.3.5. Limited Stratified Analysis...... 46 6.3.6. Data Discrepancy Identified by Clinical Inspection ...... 47 6.3.7. Reduced Efficacy Due to Drug Interactions ...... 49 6.3.8. Bioavailability of Drug Suspension ...... 50

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 6.3.9. Extrapolating the Indication to Processing-Deficient Progeroid Laminopathies ...... 52 7. Risk and Risk Management ...... 55 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data ...... 55 7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug- Specific Factors...... 57 7.3. Potential Safety Concerns Identified Through Postmarket Experience...... 58 7.4. FDA Approach to the Safety Review ...... 58 7.4.1. Reviewer’s Approach to the Safety Evaluation:...... 58 7.5. Adequacy of Clinical Safety Database...... 59 7.6. Safety Findings and Concerns Based on Review of Clinical Database...... 59 7.6.1. Safety Findings and Concerns, ProLon1 and ProLon2...... 60 7.6.1.1. Overall Adverse Event Summary, ProLon1 and ProLon2 ...... 60 7.6.1.2. Deaths, ProLon1 and ProLon2...... 61 7.6.1.3. Serious Adverse Events, ProLon1 and ProLon2 ...... 63 7.6.1.4. Dropouts and/or Discontinuations Due to Adverse Events, ProLon1 and ProLon2 ...... 69 7.6.1.5. Treatment-Emergent Adverse Events, ProLon1 and ProLon2 ...... 71 7.6.1.6. Laboratory Abnormalities, ProLon1 and ProLon2...... 76 7.6.1.7. Adverse Events of Special Interest, ProLon1 and ProLon2 ...... 92 7.7. Key Review Issues Relevant to Evaluation of Risk...... 98 7.7.1. QTc Safety Assessment...... 98 7.7.2. Adverse Reactions Due to Drug Interactions...... 99 7.7.3. Hypertension and Mortality...... 100 7.7.4. Dosing in Hepatic Impairment...... 101 7.7.5. Dosing in Renal Impairment...... 102 7.7.6. Nephrotoxicity...... 103 7.7.7. Retinal Toxicity ...... 103 7.7.8. Impaired Fertility...... 104 7.7.1. Embryo-Fetal Toxicity ...... 105 8. Therapeutic Individualization ...... 105 8.1. Intrinsic Factors ...... 105 8.2. Drug Interactions ...... 106 8.3. Plans for Pediatric Drug Development ...... 110 8.4. Pregnancy and Lactation...... 110 9. Product Quality ...... 112 9.1. Device or Combination Product Considerations...... 113 10. Human Subjects Protections/Clinical Site and Other Good Clinical Practice Inspections/Financial Disclosure...... 113

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

11. Advisory Committee Summary...... 114 III. Appendices...... 114 12. Summary of Regulatory History...... 114 13. Pharmacology Toxicology: Additional Information and Assessment ...... 117 13.1. Summary Review of Studies Submitted Under IND...... 117 13.1.1. Pharmacology...... 117 13.1.2. ADME/PK...... 118 13.1.3. Toxicology ...... 121 13.1.3.1. General Toxicology ...... 121 13.1.3.2. Carcinogenicity...... 130 13.1.3.3. Reproductive and Developmental Toxicology...... 131 13.2. Individual Reviews of Studies Submitted to the NDA...... 141 14. Clinical Pharmacology: Additional Information and Assessment...... 142 14.1. In Vitro Studies...... 142 14.2. In Vivo Studies ...... 143 14.2.1. Drug-Drug Interaction Studies...... 149 14.3. Pharmacometrics Review...... 155 14.4. Bioanalytical Methods...... 164 15. Trial Design: Additional Information and Assessment ...... 167 16. Efficacy: Additional Information and Assessment ...... 170 16.1. Controlled Substance Consultation...... 172 17. Clinical Safety: Additional Information and Assessment...... 173 18. Mechanism of Action/Drug Resistance: Additional Information and Assessment...... 173 19. Other Drug Development Considerations: Additional Information and Assessment...... 175 20. Data Integrity-Related Consults (Office of Scientific Investigations, Other Inspections)...... 176 21. Labeling Summary of Considerations and Key Additional Information ...... 177 22. Postmarketing Requirements and Commitments...... 181 23. Financial Disclosure ...... 182 24. References...... 183 25. Review Team...... 187

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Table of Tables Table 1. Administrative Application Information...... i Table 2. Benefit-Risk Framework...... 4 Table 3. Clinical Trials Submitted in Support of Efficacy and/or Safety Determinations for Lonafarnib ...... 13 Table 4. Patient Experience Data Submitted or Considered ...... 15 Table 5. Summary of Pharmacologic Activity, Clinical Pharmacology, and Pharmacokinetics...... 16 Table 6. Mean (SD) Exposures of Lonafarnib at Steady-State Following BID Dosing, HGPS and PL Patients, Study ProLon1...... 23 Table 7. Patient Disposition, ProLon1 and ProLon2...... 31 Table 8. Baseline Demographic and Clinical Characteristics: ProLon1, ProLon2, Contemporaneous Control, and Untreated Fixed 50th Percentile Match ...... 32 Table 9. Efficacy Results of Survival Time (Fixed 50th Percentile Matching Algorithm)...... 36 Table 10. Supportive Efficacy Analysis Results (Fixed 50th Percentile Matching Algorithm)...... 37 Table 11. Efficacy Results of Survival Time (Fixed 75th Percentile Matching Algorithm)...... 37 Table 12. Efficacy Results of Survival Time (Without Matching the Treated and Untreated Patients)...... 38 Table 13. Efficacy Results of Survival Time by Trial (Fixed 50th Percentile Matching Algorithm)...... 39 Table 14. Summary of Variant Status, Treated Group, and Untreated Historical Cohort...... 43 Table 15. Survival Data Discrepancies ...... 47 Table 16. Efficacy Results of Survival Time (Fixed 50th Percentile Matching Algorithm)...... 48 Table 17. Survival Analysis Summary, Main Analysis Population...... 49 Table 18. Duration of Exposure, Safety Population, ProLon1 and ProLon2 ...... 59 Table 19. Overview of Adverse Events, Safety Population, ProLon1 and ProLon2...... 60 Table 20. Deaths, Safety Population, ProLon1 and ProLon2...... 61 Table 21. Serious Adverse Events, Safety Population, ProLon1 and ProLon2 ...... 64 Table 22. ProLon1 and ProLon2, Serious Adverse Reactions as Determined by the Investigator ...... 64 (b) (6) Table 23. Liver Enzyme Levels, Patient # ...... 65 Table 24. ProLon1 SAEs as Determined by the Investigator...... 66 Table 25. ProLon2 SAEs as Determined by the Investigator...... 67

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Table 26. Patient Disposition, Safety Population, ProLon1 and ProLon2 ...... 69 Table 27. Adverse Events Leading to Discontinuation from ProLon2, Provided by Applicant...... 69 Table 28. Discontinuations Not Mentioned by Applicant, ProLon2 ...... 71 Table 29. Overview of TEAEs, ProLon1 and ProLon2 Subgroups...... 72 Table 30. Details of ProLon1 Dose Reductions...... 72 Table 31. Details of ProLon2 Dose Reductions...... 72 Table 32. Adverse Drug Reactions As Assessed by Investigator, Safety Population, ProLon1 and ProLon2...... 73 7DEOH  $GYHUVH 5HDFWLRQV LQ • RI 3DWLHQWV LQ 3UR/RQ DQd ProLon21...... 75 Table 34. ProLon1 Patients With Low Neutrophil Count (109/L)...... 78 Table 35. Low Neutrophil Counts in ProLon2 Patients...... 81 Table 36. Incidence of Grade Shifts in ALT (Increased), Safety Population, ProLon1 ....82 Table 37. Incidence of Grade Shifts in AST (Increased), Safety Population, ProLon1 ....82 Table 38. Incidence of Grade Shifts in ALT (Increased), Safety Population, ProLon2[1] ...... 82 Table 39. Incidence of Grade Shifts in AST (Increased), Safety Population, ProLon2 ....83 Table 40. ALT Progression for Patient #(b) (6) With ALTULN But <3x ULN (Grade 1) at Baseline...... 86 (b) (6) Table 44. ALT Progression for Patient # ...... Error! Bookmark not de fine d. (b) (6) Table 45. ALT Progression for Patient # With ALT >3x ULN at Baseline...... 86 Table 46. Laboratory Results for AST and ALT, Safety Population, ProLon1 and ProLon2 ...... 86 Table 47. Patients With ALT or AST Greater Than ULN and Adverse Event Categorization as Unevaluable, ProLon2 ...... 87 Table 48. Incidence of Grade Shifts in Creatinine (Increased), Safety Population, ProLon1 ...... 88 Table 49. Incidence of Grade Shifts in Creatinine (Increased), Safety Population, ProLon2 ...... 89 (b) (6) Table 50. Patient Calcium Values Over Study Visits ...... 92 Table 51. Potentially Clinically Significant ECG Findings (QTcB) 1 of 2...... 94 Table 52. Potentially Clinically Significant ECG Findings (QTcF) 2 of 2 ...... 94 Table 53. Myelosuppressive AEs by Patient, Any Intercurrent Events ...... 96 Table 54. Effect of Lonafarnib on Pharmacokinetics of Coadministered Drugs ...... 108 Table 55. Nonclinical Data Supporting Labeling on Pregnancy and Lactation...... 111

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Table 56. Safety Pharmacology Studies...... 118 Table 57. Single-Dose Pharmacokinetics of Lonafarnib in Rats...... 119 Table 58. Single-Dose Pharmacokinetics of Lonafarnib in Monkeys ...... 119 Table 59. Features and Methods, Study 96034...... 121 Table 60. Observations and Results, Study 96034...... 122 Table 61. Toxicokinetic Parameters in Rats...... 125 Table 62. Features and Methods, Study 96036...... 126 Table 63. Observations and Results, Study 96036...... 126 Table 64. Toxicokinetic Parameters in Monkeys...... 128 Table 65. Genetic Toxicology ...... 130 Table 66. Methods of Fertility and Early Embryonic Developmental Study in Male Rats, Study 02295...... 131 Table 67. Observations and Results, Study 02295...... 132 Table 68. Methods of Fertility and Early Embryonic Developmental Study in Female Rats, Study 02293...... 133 Table 69. Observations and Results, Study 02293...... 133 Table 70. Methods of Oral Embryo-Fetal Developmental Study in Rats, Study 02292..134 Table 71. Observations and Results, Study 02292...... 134 Table 72. Methods of Oral Embryo-Fetal Developmental Study in Rabbits, Study 96046...... 135 Table 73. Observations and Results, Study 96046...... 135 Table 74. Fetal Variations and Malformations ...... 137 Table 75. TK Parameters From the Rabbit Embryofetal Development Study ...... 138 Table 76. Methods of Oral Pre- and Postnatal Developmental Study in Rats, Study 96047...... 139 Table 77. Observations and Results, Study 96047...... 140 Table 78. Features and Methods, Study 2555-15001 ...... 141 Table 79. Observations and Results, Study 2555-15001 ...... 142 Table 80. Mean Pharmacokinetic Parameters of Lonafarnib Following Single-Dose Oral Administration of 100 mg Lonafarnib, Study P02673 ...... 145 Table 81. Summary of Lonafarnib Pharmacokinetic Parameter Following a Single Dose of Lonafarnib (50 mg) and Ritonavir (100 mg) in Patients With Mild and Moderate Hepatic Impairment and Normal Hepatic Function, Study EIG-LNF- 003...... 146 Table 82. Summary of Lonafarnib Pharmacokinetic Parameter Following a Single Dose of Lonafarnib (50 mg) and Ritonavir (100 mg) in Patients With Severe and Moderate Renal Impairment and Normal Renal Function, Study EIG-LNF-006 .....147 Table 83. Food Effect on Lonafarnib Following Single-Dose Administration of Lonafarnib 75 mg, Group 2, Study EIG-LNF-017 ...... 148 vii Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 84. PK Parameters of Lonafarnib Following Single Dose Administration of Lonafarnib 100 mg in Fed and Fasted Conditions, Study P00042...... 149 Table 85. PK Parameters of Lonafarnib Following Single Dose Administration of Lonafarnib 50 mg With or Without Ketoconazole, Study P00393...... 150 Table 86. Effect of Ketoconazole on PK of Lonafarnib, Study P00393 ...... 150 Table 87. PK Parameters of Lonafarnib Following Single Dose Administration of Lonafarnib 50 mg and Ritonavir 100 mg With or Without Rifampin, Study EIG- LNF-007 ...... 151 Table 88. Effect of Rifampin on PK of Lonafarnib, Study EIG-LNF-007...... 151 Table 89. Effect of Lonafarnib on Midazolam Exposures, Group 1, Study EIG-LNF- 016...... 152 Table 90. Effect of Lonafarnib on Fexofenadine Exposures, Group 2, Study EIG- LNF-016 ...... 153 Table 91. PK Parameters of Single-Dose Loperamide With or Without Concomitant Multiple-Dose Lonafarnib, Group 2, Study EIG LNF 015 ...... 154 Table 92. Effect of Lonafarnib on Omeprazole Exposures, Group 1, Study EIG-LNF- 017...... 154 Table 93. Final Model Parameter Estimates for Lonafarnib PK ...... 155 Table 94. Parameter Estimates for Review Team's PPK Model in Sensitivity Analysis.161 Table 95. Summary of Continuous Baseline Demographic Characteristics for the Population in the Simulations for Dosing Regimens...... 162 Table 96. Bioanalytical Method Validation and Performance for Determination of Lonafarnib Concentration in Human Plasma ...... 164 Table 97. Discrepant Last Lonafarnib Treatment Date for Patients, ProLon1 ...... 176 Table 98. Major Prescribing Information Changes ...... 177 Table 99. Covered Clinical Studies: BCH 07-01-0007 (ProLon1) and Group 2 of BCH 09-06-0298 (ProLon2)...... 182 Table 100. Reviewers of Integrated Assessment ...... 187 Table 101. Additional Reviewers of Application...... 188 Table 102. Signatures of Reviewers ...... 189

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table of Figures

Figure 1. Predicted Lonafarnib AUCIJ at Steady-State Across Body Weight and BSA Groups ...... 22

Figure 2. Predicted Lonafarnib Cmax at Steady-State Across Body Weight and BSA Groups ...... 23 Figure 3. Patient Flow in Clinical Studies of Lonafarnib ...... 26 Figure 4. Kaplan-Meier Survival Curves of Treated Versus Matched Untreated Groups ...... 35 Figure 5. Kaplan-Meier Survival Curves by Variant Status ...... 43 Figure 6. Cumulative Censoring Rate Over Time for Treated Versus Matched Untreated Group (Unadjusted)...... 45 Figure 7. Cumulative Censoring Rate Over Time for Treated Versus Matched Untreated Group (Adjusted) ...... 46 Figure 8. Kaplan-Meier Survival Curves for Follow-Up Time (in Years) Censored at Last Follow-Up...... 48 Figure 9. Mean Lonafarnib Concentration-Time Profile by Dose and Formulation at Steady State, Study ProLon1 ...... 52 Figure 10. ProLon1 Patients Mean Hemoglobin (g/L)1 Trend...... 78 Figure 11. ProLon1 Patients Mean Neutrophil Count (109/L)1 Trend ...... 79 Figure 12. ProLon1 Patients Mean Leukocyte Counts (109/L)1 Trend ...... 79 Figure 13. ProLon1 Patients Meant Platelet Count (109/L)1 Trend ...... 80 Figure 14. Mean Hemoglobin (g/L) trend compared to Lower Limit of Normal for ProLon2 Patients ...... 80 Figure 15. Mean Neutrophil Count (109/L) Trend Compared to Lower Limit of Normal for ProLon2 Patients...... 81 Figure 16. Hy’s Law Analysis of Patients on Lonafarnib, ProLon1...... 83 Figure 17. Hy’s Law Analysis of Patients on Lonafarnib Monotherapy, ProLon2...... 84 Figure 18. ProLon1 Creatinine Compared to ULN[1] ...... 88 Figure 19. Mean magnesium values in ProLon1 patients Compared to ULN...... 89 Figure 20. Mean Potassium Values in ProLon1 Patients...... 90 Figure 21. Mean Sodium Values in ProLon1 Patients...... 91 Figure 22. Mean Calcium Values in ProLon1 Patients...... 91 Figure 23. Structure of Lonafarnib ...... 112 Figure 24. Structure of Lonafarnib Metabolites...... 120 Figure 25. Final Model Visual Predictive Check...... 156 Figure 26. Goodness-of-Fit for the Final PPK Model...... 157 Figure 27. Correlation of Body Weight and Gender in PPK Analysis Dataset...... 158

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 28. Clearance and Body Weight Difference in Healthy Subjects and Patients With HGPS Based on the Applicant’s Final PPK Model ...... 158 Figure 29. Correlation Between Body Weight and Body Surface Area in the PPK Analysis Dataset...... 159 Figure 30. Boxplots of Exposure for 5 mg/kg BID Up to 10 kg and 50 mg BID From 10–20 kg ...... 160 Figure 31. Goodness-of-Fit Plots for Review Team’s PPK Model in Sensitivity Analysis ...... 161 )LJXUH  )LQDO 33. 0RGHO 3UHGLFWHG $8&IJ RI /RQDIDUQLE DW 6WHDG\-State Across Body Weight Tiers Under Different Dosing Regimens...... 162 )LJXUH  3UHGLFWHG 0HGLDQ RI $8&IJ DW 6WHDG\-State for Subjects With BSA Range of 0.25–0.9 m2 ...... 163 Figure 34. Patient Flow Chart, ProLon1 ...... 170 Figure 35. Patient Flow Chart, ProLon2 ...... 171 Figure 36. Patient Flow Chart, Progeroid Laminopathy...... 172 Figure 37. Disposition Status, ISS Study Populations...... 173 Figure 38. Post-Translational Processing Pathways Producing Lamin A and Progerin..174 Figure 39. Immunofluorescence Micrographs Showing Improvement of Aberrant Nuclear Morphology in Patients With HGPS and PL (MAD-B)...... 175

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Glossary

ADME absorption, distribution, metabolism, excretion AE adverse event AIDS acquired immunodeficiency syndrome ALT alanine aminotransferase ANC absolute neutrophil count APC absolute phagocyte count AR adverse reaction AST aspartate aminotransferase AUC area under the concentration-time curve BID twice daily BLA biologics license application BSA body surface area BW body weight CDER Center for Drug Evaluation and Research CL clearance Cmax maximum plasma concentration CMC chemistry, manufacturing, and controls CMH Cochran-Mantel-Haenszel CSR clinical study report CTCAE Common Terminology Criteria for Adverse Events DDI drug-drug interaction DMSO dimethyl sulfoxide EC50 half-maximal effective concentration ECG electrocardiogram ERG electroretinogram FDA Food and Drug Administration FTI farnesyltransferase inhibitor GFR glomerular filtration rate GLP good laboratory practices GOF goodness-of-fit HGPS Hutchinson-Gilford progeria syndrome HIV human immunodeficiency virus HLM human liver microsome IC50 half-maximal inhibitory concentration ICH International Council for Harmonisation IIV interindividua l variabilit y IND investigational new drug LOA letter of authorization LVH left ventricular hypertrophy NDA new drug application NOAEL no observed adverse effect level OCP Office of Clinical Pharmacology OR odds ratio

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) OVF objective function value PDE permitted daily exposure PI prescribing information PK pharmacokinetics PL progeroid laminopathies PPK population pharmacokinetics PTT partial thromboplastin time PRF Progeria Research Foundation PT prothrombin time RR risk ratio SAE serious adverse event SAP statistical analysis plan SGOT serum glutamic oxaloacetic transaminase SGPT serum glutamic pyruvic transminase TEAE treatment-emergent adverse event Tmax time to maximum concentration TQT thorough QT ULN upper limit of normal V volume of distribution VPC visual predictive check WBC white blood cell

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

I. Executive Summary

1. Summary of Regulatory Action

Eiger BioPharmaceuticals, Inc. submitted this new drug application (NDA) for lonafarnib (tradename Zokinvy), seeking approval of this first-in-class farnesyltransferase inhibitor for the rare diseases known as Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies (PL). These patients experience accelerated cardiovascular disease from accumulation of defective progerin (in HGPS) or progerin-like proteins (in PL) in cells. Most patients die before the age of 15 years from heart failure, myocardial infarction, or stroke. The NDA was reviewed by the multidisciplinary review team. Each discipline recommends approval and the signatory authority for this application concurs with those recommendations. Substantial evidence of effectiveness for lonafarnib for HGPS was established using pooled data from two adequate and well-controlled trials that showed a survival advantage with lonafarnib compared to matched untreated controls, together with confirmatory evidence from mechanistic studies showing that lonafarnib prevents farnesylation and subsequent accumulation of progerin in the inner nuclear membrane, the canonical pathophysiologic pathway for this disease. Effectiveness for the processing-deficient PL population, which is exceedingly rare (fewer than 1 in 25 million) was based on our findings for HGPS (which is scientifically justified by the similar pathophysiology, mechanism of action, and disease manifestations) together with confirmatory evidence from mechanistic studies showing that fibroblasts from HGPS and PL patients respond similarly to lonafarnib. The available safety data show that lonafarnib is safe for its intended use. Common adverse reactions included gastrointestinal intolerance, decreased weight, electrolyte abnormalities, liver enzyme elevation, and myelosuppression. The lack of a control arm for the safety assessment limits the extent to which these events can be attributed to the drug versus the disease and its comorbidities. Nephrotoxicity, retinal toxicity, impaired fertility, and embryo-fetal toxicity were observed in nonclinical studies. There are also notable drug-drug interactions. All these risks can be adequately mitigated through labeling and further evaluated during routine pharmacovigilance. The NDA does not include a pre-approval carcinogenicity study or interpretable QT study. We are requiring these investigations postapproval so as to not further delay access to lonafarnib, which has shown a survival benefit for a rare, devastating condition with no other approved treatments. As described in the Benefit/Risk Framework below, we conclude that lonafarnib’s mortality benefit outweighs the risks when lonafarnib is used as recommended in the approved labeling.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 2. Benefit-Risk Assessment 2.1. Benefit-Risk Framework

Table 2. Benefit-Risk Framework Dimension Evidence and Uncertainties Conclusions and Reasons Analysis of x Hutchinson-Gilford progeria syndrome (HGPS) is a rare, x HGPS and PL are serious, life-shortening Condition autosomal dominant disorder caused by a single nucleotide diseases. substitution in the LMNA gene that causes accumulation of permanently farnesylated defective lamin A protein (called progerin), a protein important in the cytoskeletal structure of cell nuclei. x HGPS is characterized by postnatal growth retardation, osteoporosis, and lipodystrophy and is usually fatal due to accelerated cardiovascular disease resulting in heart failure, myocardial infarction, or stroke by around 15 years of age. x Processing-deficient PL due to variants in LMNA and ZMPSTE24 have persistent farnesylation of unprocessed prelamin A or prelamin A variants (progerin-like proteins) and a clinical phenotype similar to HGPS. Characterization of PL is limited by its extreme rarity and heterogeneity in its presentation. Current x There are no current treatment options, other than supportive x HGPS and PL patients have significant morbidiy Treatment care. and early mortality with no approved treatments Options other than supportive care and therapies directed towards the disease complications, such as antiplatelet agents and statins for cardiovascular disease. They need a therapy that treats the underlying disease process.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Benefit x The survival benefit in HGPS for lonafarnib, a x Lonafarnib demonstrated a clinically meaningful farnesyltransferase inhibitor, was established by comparing mortality benefit in patients with HGPS who mortality in 62 patients with HGPS pooled from two adequate currently have no approved treatment options. and well controlled trials (ProLon1 and ProLon2) with that of a x The clinical trial design and the survival endpoint contemporaneously well-matched untreated cohort. were appropriate, given the rarity of HGPS and its x The maximum follow-up time was 11 years (median: 3 years) high mortality. The large mortality benefit after 11 for ProLon1 and ProLon2 and 13 years (median: 2.6 years) for years of follow-up using a well-matched external the matched untreated cohort. control and mitigated sources of bias overcome the limitations of non-randomization. x The lifespan of HGPS patients treated with lonafarnib increased by an average of 3 months (95% confidence interval -11 days, 6 x Effectiveness of lonafarnib for the processing- months) through the first three years of follow-up and 2.5 years deficient PL population is based on our findings for (95% confidence interval 10 months, 4.1 years) through the HGPS (which is scientifically justified by the maximum follow-up time of 11 years compared to untreated similar pathophysiology, mechanism of action, and patients. disease manifestations) together with confirmatory evidence from mechanistic studies. x The analysis plan was not submitted prior to analyzing the data, which raises the likelihood of a type I error and concluding the x Availability of lonafarnib will provide the first drug is effective when it is not. These concerns were minimized approved treatment for HGPS and processing- by the objective mortality endpoint and steps taken by the trial deficient PL patients. investigators and applicant to mitigate potential sources of bias. x There were unanticipated issues with the data that became apparent during NDA review such as an imbalance between the treated and matched untreated groups in variant status (classic/unknown versus nonclassic) and higher censoring in the treatment group, both of which could bias towards showing a favorable effect in the treatment group. These sources of biases were adequately resolved with a revised algorithm that matched on variant status and by censoring follow-up time of the untreated patients at the follow-up time of the treated patients. x Confirmatory evidence of effectiveness for HGPS is derived from mechanistic studies showing that lonafarnib prevents farnesylation and subsequent accumulation of progerin in the inner nuclear membrane, the pathophysiologic pathway for this disease. x PL is very rare (1 in 25 million) and processing-deficient PL is even more rare with a heterogenous presentation, precluding

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Dimension Evidence and Uncertainties Conclusions and Reasons the feasibility to directly show a survival benefit in a clinical trial. Only one processing-deficient PL patient was included in the treatment group, and this patient had no matched control. Effectiveness of lonafarnib for the processing-deficient PL population was based on our findings for HGPS (which is scientifically justified by the similar pathophysiology, mechanism of action, and disease manifestations) together with confirmatory evidence from mechanistic studies showing that fibroblasts from HGPS and PL patients respond similarly to lonafarnib.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Risk and Risk x Safety concerns were identified based on nonclinical studies, x The safety database was adequate for a safety Management phase 1 trials (e.g., drug-drug interaction trials), use of higher assessment of lonafarnib for the proposed lonafarnib doses in cancer investigations, and from patients indication, patient population, dosage regimen, treated with lonafarnib in ProLon1 and ProLon2. and duration. x It was challenging to determine drug causality versus natural x The identified safety concerns do not outweigh the history of the disease or other non-drug effect for many of the benefit of improved mortality and can be safety events in ProLon1 and ProLon2 due to the lack of a adequately mitigated with labeling alone. control group for safety. x We are requiring a new thorough QT study, the x Safety concerns in nonclinical studies included nephrotoxicity in carcinogenicity study, and the CYP2C9 drug-drug rats, retinal toxicity in monkeys, impaired fertility and testicular interaction study post-approval. We are not toxicity in rats, male reproductive tract toxicity in monkeys, and requiring these investigations pre-approval so as embryo-fetal toxicity in rats and rabbits – all at or near clinically not to further delay approval of lonafarnib, which relevant exposures. has a mortality benefit for a serious, devastating disease without other treatment options. Labeling x There are several clinically significant drug interactions (e.g., will note that a carcinogenicity study has not been increased lonafarnib exposures with strong CYP3A inhibitors, conducted, that CYP2C9 inhibitors should be reduced lonafarnib exposures with strong CYP3A inducers, avoided, and to monitor for signs and symptoms of increased exposures to other drugs that are substrates for QT interval prolongation in settings that increase CYP3A such as certain statins and midazolam). lonafarnib exposures. x Adverse events reported by more than 50% of the ProLon1 and x Safety risks have not been identified that require ProLon2 patients included nausea, vomiting, diarrhea, fatigue, risk management beyond standard infections, and decreased appetite. Despite the high incidence pharmacovigilance. of adverse events, most patients did not discontinue due to adverse events. x Other noteworthy on-treatment findings included liver enzyme elevations, electrolyte abnormalities (hyperkalemia, hypokalemia, hyponatremia, hypercalcemia, or hypermagnesemia), and myelosuppression (e.g., reductions in neutrophil counts, white blood cell counts, lymphocytes, hemoglobin and hematocrit). These abnormalities often – but not always – improved while patients continued lonafarnib. It is not possible to definitively exclude a drug effect because of the lack of a control group for safety and because of biologic plausibility (e.g., based on nonclinical findings or seen more definitively with higher lonafarnib doses). x Hypertension was reported in a third of HGPS patients and was associated with a higher risk of mortality. It is unclear whether

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Dimension Evidence and Uncertainties Conclusions and Reasons this is a drug effect or related to the natural history of the disease. x QT prolongation was only studied with concomitant ritonavir and the effect of lonafarnib alone could not be determined. x A carcinogenicity study has not been conducted pre-approval. x The effect of CYP2C9 inhibitors on lonafarnib exposure have not been adequately studied pre-approval. x A review of deaths, serious adverse events, and discontinuations due to adverse events did not reveal any patterns to suggest a significant safety risk attributable to lonafarnib treatment. The nature and frequency of these events generally reflect the natural history of HGPS disease progression.

2.2. Conclusions Regarding Benefit-Risk Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are ultra-rare, fatal, autosomal dominant, premature aging diseases. HGPS occurs due to a variant in the LMNA gene that leads to the synthesis and accumulation of an abnormal farnesylated prelamin A protein called progerin. PL occurs due to a variant in a downstream enzyme to farnesyltransferase, that leads to accumulation of progerin-like protein (farnesylated, unprocessed prelamin A or prelamin A variants). These defective proteins accumulate in nuclear and cellular membrane matrices, leading to accelerated cardiovascular disease with high mortality by 15 years of age from heart failure, myocardial infarction, and stroke. No drugs or biologics have been approved for treatment of HGPS or PL. The benefit of lonafarnib (tradename Zokinvy), a farnesyltransferase inhibitor, is based on a comparison of mortality from 62 treated patients with HGPS (27 patients in ProLon1 and 35 patients in ProLon2) and the contemporaneously well-matched untreated patients from a separate natural history cohort. The life span of HGPS patients treated with lonafarnib increased by an average of 3 months (95% confidence interval -11 days, 6 months) through the first three years of follow-up and 2.5 years (95% confidence interval 10 months, 4.1 years) through the maximum follow-up of 11 years compared to untreated patients. Confirmatory evidence of effectiveness for HGPS is derived from mechanistic studies showing that lonafarnib prevents farnesylation and subsequent accumulation of progerin in the inner nuclear membrane, the pathophysiologic pathway for this disease. PL is very rare (1 in 25 million) and processing-deficient PL is even more rare with a heterogenous presentation, precluding the feasibility to directly assess a survival benefit in a clinical trial. Only one processing-deficient PL patient was included in the treatment

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) group, and this patient had no matched control. Effectiveness of lonafarnib for the processing-deficient PL population is based on our findings for HGPS (which is scientifically justified by the similar pathophysiology, mechanism of action, and disease manifestations) together with confirmatory evidence from mechanistic studies showing that fibroblasts from HGPS and PL patients respond similarly to lonafarnib. Safety concerns were identified based on nonclinical studies, phase 1 trials (e.g., drug-drug interaction trials), use of higher lonafarnib doses in cancer investigations and from 63 patients (62 patients with HGPS and 1 with PL) treated with lonafarnib in ProLon1 and ProLon2. Safety concerns in nonclinical studies include nephrotoxicity, retinal toxicity, impaired fertility, and embryo-fetal toxicity – all at or near clinically relevant exposures. Drug-drug interaction studies identified several clinically significant drug interactions, such as increased lonafarnib exposures with strong CYP3A inhibitors, reduced lonafarnib exposures with strong CYP3A inducers, and increased exposures to other drugs that are substrates for CYP3A such as certain statins and midazolam. Adverse events reported by more than 50% of the ProLon1 and ProLon2 patients included nausea, vomiting, diarrhea, fatigue, infections, and decreased appetite. Despite the high incidence of adverse events, most patients did not discontinue due to adverse events. Hypertension was reported in a third of HGPS patients and was associated with a higher risk of mortality. It is unclear whether this is a drug effect or related to the natural history of the disease. Other noteworthy on-treatment findings included liver enzyme elevations, electrolyte abnormalities (hyperkalemia, hypokalemia, hyponatremia, hypercalcemia, or hypermagnesemia), and myelosuppression (e.g., reductions in neutrophil counts, white blood cell counts, lymphocytes, hemoglobin and hematocrit). These abnormalities often – but not always – improved while patients continued lonafarnib. It is not possible to definitively exclude a drug effect because of the lack of a control group for safety and/or because of biologic plausibility (e.g., based on nonclinical findings or seen more definitively with higher lonafarnib doses). The safety risks can be adequately mitigated with labeling and routine postmarketing pharmacovigilance. Uncertainties with regard to safety include the lack of a pre-approval carcinogenicity study, uncertain impact of CYP2C9 inhibitors on lonafarnib exposures, and an inconclusive thorough QT study. We are not requiring these investigations pre-approval so as not to further delay approval of lonafarnib, which has a mortality benefit for a serious, devastating disease without other treatment options. Labeling will note that a carcinogenicity study has not been conducted, that CYP2C9 inhibitors should be avoided, and to monitor for signs and symptoms of QT interval prolongation in settings that increase lonafarnib exposures. In summary, we conclude that the benefits of lonafarnib outweigh its risks when used according to the agreed-upon labeling. The availability of lonafarnib for HGPS and processing-deficient PL will provide the first approved treatment option for this patient population.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

II. Interdisciplinary Assessment

3. Introduction

Lonafarnib is an orally administered farnesyltransferase inhibitor (FTI), which blocks post- translational farnesylation, a necessary step for processing of many cellular proteins (see Section 18 for details). The proposed indication is for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathy (PL). Lonafarnib is dosed orally at 115 mg/m2/day for the first 4 months to reduce the risk of gastrointestinal adverse reactions, then the dose is increased to 150 mg/m2/day. Lonafarnib is the first-in-class FTI to be approved. HGPS is an ultra-rare, sporadic, autosomal dominant disease with an estimated incidence of 1 in 4 million births (Hennekam 2006). The estimated worldwide prevalence is 1 in 20 million (Gordon et al. 2018). HGPS occurs due to a variant in the LMNA gene that leads to the synthesis and accumulation of an abnormal farnesylated prelamin A protein (progerin), which implants into the cell’s inner nuclear membrane as a scaffolding protein and causes structural instabilit y. Lonafarnib inhibits processing of progerin and prevents accumulation of progerin and progerin- like proteins (Gordon et al. 2014) while, normal lamin A protein continues to be produced from the unmutated LMNA gene. Patients with HGPS are usually identified by their “aging” look. They have normal appearance at birth, but by 9 to 12 months, patients manifest the pathognomonic phenotypic features of HGPS, including failure to thrive, alopecia (loss of hair from scalp and eyebrows), prominent forehead and scalp veins, small jaw, prominent eyes, beak-like nose, and circumoral cyanosis (Kieran et al. 2007a). Additional features seen in patients with HGPS are global lipodystrophy (loss of subcutaneous fat); thin, tight, sclerodermatous skin; limited joint mobility from contractures; low frequency conductive hearing loss; skeletal dysplasia; and short stature, growing to a final height of 3 to 3.5 feet. HGPS children have normal intellectual development but may experience cognitive decline from cerebrovascular compromise and stroke. HGPS is marked by accelerated cardiovascular disease that is fatal. Half of the children experience strokes by 8 years of age. Children with HGPS die at a mean age of 14.5 years (median age at death 14.6 years) from complications of accelerated atherosclerosis, attributed to heart attacks and strokes, 80% and 20% of the time, respectively (Silvera et al. 2013; Kieran et al. 2014). The Applicant has provided substantial evidence of effectiveness for lonafarnib for reducing the risk of death in patients with HGPS. Lonafarnib is also proposed for treatment of processing-deficient PL, which occurs from buildup of progerin-like protein with similar clinical manifestations to HGPS. In vitro fibroblast studies demonstrated similar responses to lonafarnib by PL fibroblasts as seen for HGPS. Due to the extreme rarity of PL, the similarity of disease mechanism, and the similar clinical manifestations, the review team agrees that the use of lonafarnib can be extrapolated to the treatment of patients with processing-deficient PL. The PL indication is worded differently to the HGPS indication because we do not have direct evidence of a survival benefit of lonafarnib in the processing- deficient PL patient population, as few PL patients were included in the trials and there were no matched patients in the natural history control.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) There are no approved therapies for HGPS and PL. Current treatment includes supportive care and treatment of complications, such as antiplatelet agents and statins for cardiovascular disease, antihypertensive agents, and growth hormone for failure to thrive. Lonafarnib was granted breakthrough therapy designation and priority review, for its potential to reduce the risk of death for a rare, fatal disease with no approved therapies. 3.1. Review Issue List

The review team identified the key review issues listed in Sections 3.1.1 and 3.1.2 below relevant to the evaluation of benefit and risk, respectively. Indepth assessment of these benefit and risk issues can be found in Section 6.3 and Section 7.7, respectively. 3.1.1. Key Review Issues Relevant to Evaluation of Benefit x Mitigating disparities between treated and untreated HGPS patients x Post hoc nature of the analysis plan x Criteria and algorithm for matching treated patients to controls x Disparity in censoring rate in the treated and untreated cohort x Limited stratified analysis x Data discrepancy identified by clinical inspection x Reduced efficacy due to drug interactions x Bioavailability of drug suspension x Meeting the substantial evidence standard for processing-deficient progeroid laminopathies 3.1.2. Key Review Issues Relevant to Evaluation of Risk x QTc safety assessment x Adverse reactions due to drug interactions x Hypertension and mortality x Dosing in hepatic impairment x Dosing in renal impairment x Nephrotoxicity x Retinal toxicity x Impaired fertility x Embryo-fetal toxicity

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 3.2. Approach to the Review Table 3 provides an overview of the clinical trials that form the basis of support for the benefit- risk assessment of lonafarnib. The table shows the initial study designs for ProLon1 and ProLon2, as explained in Section 6.2.1, the original trial endpoints were not used for evaluation of lonafarnib’s efficacy, efficacy instead was determined based on a mortality benefit. Mortality data through June 2019 from 62 treated patients (27 patients in ProLon1 and 35 patients in ProLon2) and from 1:1 matched, untreated patients from a separate natural history cohort provide the primary basis of efficacy of lonafarnib in the reduction of mortality in patients with HGPS. The safety evaluation focused on 63 treated patients (28 patients in ProLon1 and 35 patients in ProLon2) during lonafarnib monotherapy periods of the pivotal studies. Safety in the pivotal studies was evaluated for a duration of 144 weeks. No placebo treatment comparison for adverse events is available.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Table 3. Clinical Trials Submitted in Support of Efficacy and/or Safety Determinations for Lonafarnib Primary and Key No. of Subjects Number of Regimen (Number Secondary Planned; Actual Centers and Trial Identifier Trial Population Trial Design Treated), Duration Endpoints Randomized Countries 07-01-0007 Pediatric patients Control Type: Drug: NDA Defined Planned: 29 Centers: 1 NCT#00425607 with Hutchinson- No treatment Lonafarnib Endpoint: ProLon1 Gilford progeria concurrent (single- Time to all-cause Actual: 28 Countries: 16 syndrome (HGPS) arm) Dose: 115 mg/m2 mortality or other progeroid BID, after 4 mo. of laminopathies Randomization: treatment, Initially Planned No randomization 150 mg/m2 BID Primary: At least a (single-arm) 50% increase in the Number treated: 28 annual rate of weight Blinding: gain over the rate Open-label Duration (quantity documented at study and units): entry Biomarkers: 24 mo1 No biomarkers Initially Planned Secondary: Innovative design Changes in carotid features: artery None ultrasonography; corrected Carotid- Femoral Pulse Wave Velocity (PWVcf), DXA BMD, pQCT parameters, height; BMI, body composition by DXA scan, ABI, and FMD.

1The duration of ProLon1 is reported as 24 to 30 months in the clin ical s tud y rep ort. Fo r th is rev iew, we will refer to Pro Lo n 1 as a 2-year trial.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Primary and Key No. of Subjects Number of Regimen (Number Secondary Planned; Actual Centers and Trial Identifier Trial Population Trial Design Treated), Duration Endpoints Randomized Countries Group 2 of 09-06- Pediatric patients Control Type: Drug: NDA Defined Planned: 40 Centers: 1 0298 with Hutchinson- No treatment Lonafarnib Endpoint: NCT#00916747 Gilford progeria concurrent (single- Time to all-cause Actual: 35 Countries: 20 ProLon2 syndrome or other arm) Dose: 150 mg/m2 mortality progeroid BID laminopathies Randomization: Initially Planned No randomization Number treated: 35 Primary: (single-arm) At least a 50% Duration (quantity increase in the Blinding: and units): annual rate of weight Open-label 36 mo gain over the rate documented at study Biomarkers: entry No biomarkers Initially Planned Innovative design Secondary: features: Changes in carotid None artery ultrasonography; corrected Carotid- Femoral Pulse Wave Velocity (PWVcf), DXA BMD, pQCT parameters, height; BMI, body composition by DXA scan, ABI, and FMD. Source: Review team Abbreviations: ABI, ankle brachial index; aBMD, areal bone mineral density; BID, twice daily; DB, double-blind; DXA, dual-energy X-ray absorptiometry; FMD, flow mediated vasodilation; LTE, long-term extension study; MC, multicenter; mo, months; N, number of subjects; OL, open-label; PC, placebo-controlled; PG, parallel group; R, randomized

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 4. Patient Experience Data

Table 4. Patient Experience Data Submitted or Considered Data Submitted in the Application Check if Section Where Submitted Type of Data Discussed, if Applicable Clinical outcome assessment data submitted in the application ܈ Patient-reported outcome 6.2.1.4 Results of Analyses ܆ Observer-reported outcome 7.6 Safety Findings ܈ Clinician-reported outcome տ Performance outcome Other patient experience data submitted in the application տ Patient-focused drug development meeting summary ܆ Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel) ܆ Observational survey studies ܈ Natural history studies 6 Assessment of Effectiveness ܆ Patient preference studies տ Other: (please specify) տ If no patient experience data were submitted by Applicant, indicate here. Data Considered in the Assessment (But Not Submitted by Applicant) Check if Section Where Considered Type of Data Discussed, if Applicable ܆ Perspectives shared at patient stakeholder meeting տ Patient-focused drug development meeting summary report տ Other stakeholder meeting summary report տ Observational survey studies տ Other: (please specify)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology

The pharmacologic activity, pharmacokinetics (PK), and clinical pharmacology of lonafarnib that are relevant to the interpretation of benefit and risk are summarized in Table 5. Table 5. Summary of Pharmacologic Activity, Clinical Pharmacology, and Pharmacokinetics Characteristic Drug Information Pharmacologic Activity Established pharmacologic Lonafarnib is a farnesyltransferase inhibitor. class (EPC) Mechanism of action Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane. Active moieties The parent drug lonafarnib is the active moiety. The two most predominant metabolites were HM17 and HM21 accounting for 15% and 14% of plasma radioactivity, respectively, in the mass balance study. HM21 is an active metabolite. QT prolongation The Applicant has not conducted a thorough QT/QTc study to evaluate the effect of lonafarnib on QT interval prolongation (results from the thorough QT/QTc study with lonafarnib and ritonavir do not raise safety concerns but are inconclusive for lonafarnib monotherapy). We are requiring a postmarketing thorough QT/QTc study rather than another pre-approval study so as not to delay access to this drug that has shown a survival benefit for a rare, serious condition with no other approved treatments. See Section 7.7.1 for details. General Information Bioanalysis Liquid chromatography with tandem mass spectrometry methods for lonafarnib concentrations in human plasma were developed and validated. The performance of the bioanalytical methods used in clinical studies was acceptable. Healthy subjects vs patients PK differences in patients and healthy subjects were not identified.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Characteristic Drug Information Drug exposure at steady The pharmacokinetics of lonafarnib at steady state are summarized in the table below following multiple oral administration state following the twice daily (BID) of lonafarnib with food in patients with HGPS. therapeutic dosing regimen Pharmacokinetics of Lonafarnib at Steady State Following Multiple Oral Administration BID of Lonafarnib With Food in Patients With HGPS Median (Range) Mean (SD) Mean (SD) Mean (SD) Lonafarnib Dose Tmax (hr) Cmax (ng/mL) AUC0-8hr (ng*hr/mL) AUCtau (ng*hr/mL) 115 mg/m2 N 23232315 Results 2 (0, 6) 1777 (1083) 9869 (6327) 12365 (9135) 150 mg/m2 N 1818188 Results 4 (0, 12) 2695 (1090) 16020 (4978) 19539 (6434) Abbreviations: BID, twice daily; HGPS, Hutchinson-Gilford progeria syndrome; SD, standard deviation

Range of effective The recommended starting dose of lonafarnib is 115 mg/m2 BID. After 4 months, increase the dosage to 150 mg/m2 twice dosage(s) or exposure daily. Accumulation Following oral BID administration of lonafarnib for 5 days, the mean accumulation ratios ranged between 3 to 5 based on AUCtau, which is greater that the predicted accumulation of 1.7 based on the elimination half-life following single dose administration, possibly due to auto-inhibition of metabolism after multiple-dose administration. Time to achieve steady- Steady state was achieved by approximately 3 days after multiple dosing. state Bridge between to-be- The to-be-marketed capsules (50-mg and 75-mg) were used in the clinical efficacy and safety studies. The clinical studies marketed and clinical trial also used a suspension formulation by mixing the contents of the capsules with Ora Blend SF and Ora-Plus. formulations The proposed use by mixing the content of the capsules with orange juice or applesauce was supported by the results of in vitro compatibility studies.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Characteristic Drug Information Absorption Bioavailability The absolute bioavailability of lonafarnib following oral administration has not been determined.

Tmax The median Tmax was 2 to 4 hours in patients with HGPS.

Food effect (fed/fasted) Both the high-fat/high calorie and low-fat/low-calorie meals decreased the absorption and delayed the Tmax of lonafarnib by Geometric least square approximately 2 hours and 1 hour, respectively, following single dose administration. Lonafarnib was administered with food in mean and 90% CI the pivotal studies in patients with HGPS and PL. Effect of High-Fat/High-Calorie and Low-Fat/Low-Calorie Meals on the Pharmacokinetics of Single Dose Lonafarnib Geometric LSM Parameter N LNF + High Fat (Test) LNF Fasted (Ref) GMR 90% CI Cmax (ng/mL) 14 117 248 0.47 0.42–0.53 AUCt (ng*hr/mL) 14 1080 1500 0.72 0.65–0.80 AUCinf (ng*hr/mL) 13 1150 1560 0.74 0.67–0.82 Parameter N LNF + Low Fat (Test) LNF Fasted (Ref) GMR 90% CI Cmax (ng/mL) 14 194 248 0.78 0.66–0.93 AUCt (ng*hr/mL) 14 1250 1500 0.84 0.72–0.97 AUCinf (ng*hr/mL) 12 1240 1560 0.83 0.70–0.99 Abbreviations: CI, confidence interval; LNF, lonafarnib; LSM, least square mean; Ref, reference Distribution Volume of distribution The mean apparent volumes of distribution were 87.8 L and 97.4 L, respectively, at steady state following multiple oral administration of lonafarnib 100 mg and 75 mg twice daily in healthy subjects. Plasma protein binding In vitro plasma protein binding of lonafarnib was •9% over the concentration range between  WR  ȝJP/ Drug as substrate of Lonafarnib is not a substrate of transporters OATP1B1, OATP1B3, or BCRP, but is likely a marginal substrate of P-gp. transporters

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Characteristic Drug Information Elimination Mass balance results Following oral administration of 104 mg [14C]-lonafarnib under fasted conditions in healthy subjects, approximately 62% of the total radiolabeled dose was recovered in feces and <1% of the total radiolabeled dose was recovered in urine up to 240 hours post-dose. Clearance The apparent clearance of lonafarnib is 50 L/hr.

Half-life The mean terminal elimination half-life (T1/2) of lonafarnib was approximately 3 to 4 hours following a single dose and 4.2 to 5.6 hours following multiple dosing in healthy subjects. Metabolic pathway(s) Lonafarnib is primarily metabolized by CYP3A4, with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 also involved to a lesser extent. The magnitude of CYP2C9 contribution to lonafarnib metabolism has not been well characterized. Primary excretion pathways Lonafarnib is primarily excreted via feces with minimal excretion in urine. (% dosage) Intrinsic Factors and Specific Populations Body weight The population pharmacokinetics (PPK) model predicted that body weight and body surface area (BSA) had significant effects on the clearance of lonafarnib. The proposed BSA-based dosing regimens are expected to provide similar drug exposure (e.g., $8&IJ DW Vteady-state) across patient subgroups by body weight and BSA in ProLon1.

Age and gender Following single-dose administration of lonafarnib in healthy adults, systemic exposures (AUC and Cmax) to lonafarnib were higher in females (vs. males) and in the elderly • \HDUV; vs. young patients [18 to 45 years]). However, the PPK analysis did not identify age or gender as the covariate that could have significant effect on the PK of lonafarnib. No dosage adjustment based on age or gender is recommended. Renal impairment The effect of renal impairment on the PK of lonafarnib as monotherapy has not been studied. Hepatic impairment The effect of hepatic impairment on the PK of lonafarnib as monotherapy has not been studied. Drug Interaction Liability (Drug as Perpetrator) Inhibition/induction of Lonafarnib is a strong inhibitor for CYP3A (mechanism-based) and moderate inhibitor for CYP2C19. metabolism No induction was identified. Inhibition/induction of Lonafarnib is an inhibitor of P-gp, OATP1B1, OATP1B3, and BCRP. transporter systems No induction was identified.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 5.1. Nonclinical Assessment of Potential Effectiveness

Lonafarnib blocks post-translational farnesylation of lamin A with an IC50 of 1.9nM for human farnesyl protein transferase. The lamin protein family is localized in the inner nuclear membrane (Burke and Stewart 2002). In patients with HGPS, the variants produce an accumulation of an abnormal farnesylated form of prelamin A (i.e., progerin) in the nuclear envelope, which leads to cellular and structural damage and functional abnormalities. In contrast, patients with PL accumulate ‘progerin-like’ proteins, but show disease manifestations similar to those of HGPS. The Applicant stated that the term ‘progerin-like’ refers to permanently farnesylated, unprocessed prelamin A or permanently farnesylated prelamin A variants, which are different from progerin. Treatment with lonafarnib is expected to be beneficial for patients with HGPS or PL by blocking post-translational farnesylation of lamin A, thereby preventing the formation of progerin or ‘progerin-like’ proteins. Lonafarnib treatment of cultured fibroblasts from patients with PL significantly reduced the number of aberrant nuclei at concentrations of 2μM (1.28 μg/mL) or higher, which in HGPS and PL patients are clinically achievable at the recommended doses of 115 mg/m2 and 150 mg/m2 twice daily. 6. Assessment of Effectiveness 6.1. Dose and Dose Responsiveness 6.1.1. ProLon1 and ProLon2 Dose Selection for Pivotal Trials in Patients With HGPS and PL The dose regimens,115 mg/m2 and 150 mg/m2 twice daily (BID), were studied in the pivotal trials (ProLon1 and ProLon2) in patients with HGPS and PL. The median age at the start of treatment was 6 years (range: 2 to 17 years). In ProLon1, all patients received the starting dose 115 mg/m2 BID for 4 months; if the therapy was well tolerated, the patients were permitted to escalate the dose to 150 mg/m2 BID thereafter through year 2. In ProLon2, patients started with 150 mg/m2 BID with the flexibility of reducing the dose to 115, 90, or 70 mg/m2 if a drug-related toxicity was observed. The treatment duration lasted up to 3 years. Most patients in ProLon1 and ProLon2 were able to tolerate the 150 mg/m2 dose. Four patients in these trials ( (b) (6)) had lonafarnib dose reductions attributed to TEAEs, including vomiting, diarrhea, abdominal pain, constipation, colitis, dizziness, anorexia, musculoskeletal pain complaints (back pain), and depressed mood. Review of the lonafarnib dose exposure dataset identified an additional dose reduction in a ProLon1 patient ((b) (6) ), who had diarrhea approximately 2 weeks prior to dose reduction.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The dose selection for the pivotal studies was based on the findings of the maximal tolerated dose from phase 1 and phase 2 oncology clinical trials in adult and pediatric patients. The selected doses were reasonable from a safety perspective, as assessed as follows. x In adult patients with cancer, the maximum tolerated dose was 200 mg (approximately 115 mg/m2 for patients with a body surface area (BSA) of 1.7 m2) BID, which was determined to be the phase 2 dose in cancer trials. At this dose, diarrhea with resultant weight loss was the major toxicity and required the frequent use of loperamide to control drug-related diarrhea. At doses of 180 mg/m2 and above, the major toxicity was myelosuppression. Dose-limiting toxicities were observed at 400 mg BID and involved grade 4 thrombocytopenia, neutropenia, and vomiting. Reducing the dose to 300 mg BID resulted in dose-limiting toxicities consisting of grade 3 neutropenia and neurocortical toxicity (confusion and disorientation). Patients were unable to complete 28 days of treatment at the twice-daily dose of 300 and 400 mg (approximately 176 mg/m2 and 235 mg/m2, respectively, for patients with a body surface area of 1.7 m2). x In the dose-finding study involving pediatric patients (mean age of 12 years, ranging from 4 to 20 years) with central nervous system cancer, the maximum tolerated and recommended dose for phase 2 was 115 mg/m2 BID. The dose-limit ing toxicities were pneumonitis, thrombocytopenia, and myelosupresssion at 200 mg/m2, which was consistent with the data for adults treated with high-dose lonafarnib in oncology trials. Significant diarrhea and weight loss were not identified when loperamide was coadministered. Because the doses were selected based only on safety considerations, we do not know whether lower doses would be effective. However, the benefits of the tested doses outweigh their risks.

Proposed Dosing Regimens for Patients With HGPS and PL The proposed dosing regimen is identical to the one evaluated in ProLon1: an initial dose of 115 mg/m2 BID for 4 months followed by a maintenance dose of 150 mg/m2 BID. The dosage of 150 mg/m2 BID was also studied in ProLon2. The proposed dosing regimen is appropriate for the general patient population for which the indication is being sought. We considered whether the recommended starting dose in the approved labeling could be 150 mg/m2 BID for all patients but given that nearly one-half of the trial patients started at 115 mg/m2 BID, we decided to label the more conservative dosage regimen. The proposed dosing regimens for lonafarnib capsules require a BSA of at least 0.39 m2, mainly due to the limitations of the available dosage strengths, 50 mg and 75 mg. With the lower dosage strength of 50 mg, a BSA of at least 0.39 m2 is required in order to administer lonafarnib at 115 mg/m2. While the capsule contents may be mixed with a vehicle to administer to patients who cannot swallow capsules, it is important to ensure that the entire content, rather than a portion, is administered to avoid potential dose preparation and administration errors.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The proposed BSA-based dosing regimens are adequately supported by the efficacy and safety of lonafarnib demonstrated in the pivotal trials and the PK results, as discussed below. Exposure- response analyses for efficacy or safety of lonafarnib were not conducted due to limited available data. x Efficacy and safety of lonafarnib were demonstrated in the pivotal trials in which the proposed BSA-based dosing regimens were studied. Refer to Sections 6.2 and 7 for more details about the clinical efficacy and safety of lonafarnib. x The population pharmacokinetics (PPK) analysis from the Applicant included allometric body-weight or BSA scaling on the clearance and distribution parameters of lonafarnib. Body weight and BSA are highly correlated and have significant effects on the clearance of lonafarnib in describing the PK variabilit y of lonafarnib. The range for the body weight and the BSA of the patients in the pivotal trials were 6.8 kg–20.9 kg and 0.33 m2– 0.94 m2, respectively. The review team’s PK simulations based on the PPK model showed that, following the proposed BSA-based dosing regimens, the lonafarnib exposures (as measured by AUCtau and Cmax at steady-state) were comparable with overlapping distribution across the body weight groups (5 kg to 20 kg) and the BSA groups (0.37 m2 to 0.9 m2) (Figures 1 and 2). In addition, the predicted exposures at the proposed dosing regimens are similar to those observed in Study ProLon1 (Table 6). While it could have been reasonable to label dosing based on body weight given these results, the review team decided to label dosing based on BSA given that the BSA-based approach was used in the pivotal trials.

Figure 1. Predicted Lonafarnib AUCIJ at Steady-State Across Body Weight and BSA Groups

Source: PK simulation conducted by Review team th Note: The solid horizontal line in each box represents the simulated median value of AUCtau; each box represents the simulated 25 to 75th percentiles under each dosing regimen for each body weight tier. In the simulation, the demographic characteristics of the virtual population wasthe same as those from the Prolon1 study. The simulation was based on the Applicant’s final PPK model (for details,refer to Section 14.3). Abbreviations: AUC(tau), area underthe plasma concentration-time curve over dosing interval; BSA, body surface area

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Figure 2. Predicted Lonafarnib Cmax at Steady-State Across Body Weight and BSA Groups

Source: PK simulation conducted by Review team th Note: The solid horizontal line in each box represents the simulated median value of Cmax; each box represents the simulated 25 to 75th percentiles under each dosing regimen for each body weight tier. In the simulation, the demographic characteristics ofthe virtual population was the same as those from the ProLon1 study. The simulation was based on the Applicant’s final PPK model (for details,refer to Section 14.3). Abbreviations: BSA, body surface area For more details on PPK analysis and PK simulations, refer to Section 14.3. Table 6. Mean (SD) Exposures of Lonafarnib at Steady-State Following BID Dosing, HGPS and PL Patients, Study ProLon1 Lonafarnib Dose PK Parameter 115 mg/m2 150 mg/m2 Cmax (ng/mL) N2318 Results 1777 (1083) 2695 (1090)

AUCtau (ng·hr/mL) N158 Results 12365 (9135) 19539 (6434) Source: Summary results based on pharmacokinetic report “CSR07-01-0007-pk” of Study ProLon1. Abbreviations: AUCtau, area under the plasma concentration-time curve over dosing interval; BID, twice daily; HGPS, Hutchinson- Gilford progeria syndrome; PK, pharmacokinetic; PL, progeroid laminopathy; SD, standard deviation Proposed Maximum Daily Doses The Applicant’s proposed maximum daily dosages of 300 mg/day for HGPS and (b) (4) mg/day for PL are based on a QT safety threshold. A rationale was not provided for proposing a higher maximum daily dosage for patients with PL than for those with HGPS. As assessed below, the available data are insufficient to recommend the maximum daily doses proposed. x The QT safety threshold that the Applicant used to support the maximum daily doses was based on the conducted thorough QT study and the exposure-response model for QT effect. However, due to limitations of the QT study, as well as the uninterpretable exposure-response analysis results, the safety threshold identified through this model is not acceptable (see Section 7.7.2 for QT review issue).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) x Maximum daily doses of lonafarnib were not defined in the conducted pivotal clinical trials. The proposed dosing regimens, 115 mg/m2 (initial dose) and 150 mg/m2 (maintenance dose), are based on the body surface area of the patients. To reach the (b) (4) proposed maximum daily dose of 300 mg (HGPS) or (PL) at the proposed higher dose of 150 mg/m2, the corresponding BSA of the patients would be 1.0 m2 for HGPS and (b) (4) for PL. The BSAs among the patients in ProLon1 and ProLon2 ranged from 0.33 to 0.94 m2, which were consistent with the understanding that patients with HGPS and PL are expected to have low BSA. Therefore, a dose cap is not needed as the doses will be limited by the low BSA seen in this population. Proposed Dosing Regimens forHGPS and PL Patients at 12 Months Old The proposed dosing regimens are for adult and pediatric patients 12 months of age and older, although the patients studied in the pivotal trials (ProLon1 and ProLon2) were 2 to 17 years old. Expanding the indication to patients 12 months and older at the proposed dosing regimens is reasonable, as assessed from the clinical need and the pharmacokinetic perspectives. x Earlier intervention is believed to be helpful to patients due to the expected progressive disease courses of HGPS and PL. The Applicant provided a rationale to label for the youngest age possible, citing an earlier discussion with the European Medicines Agency in January 2019, where emphasis was placed on consideration for usage of the drug as early as possible for clinical benefit. In addition, the disease process in pediatric patients 12 months to less than 2 years old is similar to that in patients 2 years old and older. x The PK of lonafarnib is expected to be similar between younger pediatric patients (i.e., 12 months to 2 years of age) and patients older than 2 years. Lonafarnib is extensively metabolized and predominantly cleared by the liver. Although the metabolic capacity of many CYP isoforms is markedly diminished in very young children, the activity of these enzymes increases over time and the metabolic developmental process is isoenzyme specific. The metabolic processes for CYP3A, the primary enzyme involved in lonafarnib metabolism, become mature by 1 to 2 years of age for CYP3A (though CYP maturation in HGPS and PL patients is not known). Therefore, based on the current knowledge about developmental changes in liver enzymes in pediatric populations (Kearns et al. 2003; Upreti and Wahlstrom 2016), the metabolism of lonafarnib is expected to be similar between 12-month-old patients and older pediatric patients. In addition, in the PPK analysis based on the PK data from patients aged 2 years and older, body weight rather than age was identified as the significant covariate on the PK of lonafarnib. 6.2. Clinical Trials Intended to Demonstrate Efficacy 6.2.1. ProLon1 and ProLon2 6.2.1.1. Design, ProLon1 and ProLon2 The clinical benefit of lonafarnib in patients with HGPS was primarily based on the retrospective analysis comparing the survival data from two phase 2 trials (studies 07-01-0007 and 09-06- 0298) to those from a natural history cohort. Of note, these two trials were investigator-initiated trials, and the Applicant of this NDA was not involved with the design of these trials. The

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Applicant’s involvement with these trials started in June 2018 under IND 139923 for the purpose of filing an NDA to obtain approval of lonafarnib for HGPS and PL indications. Studies 07-01-0007 (ProLon1) and 09-06-0298 were designed to investigate the clinical benefit of lonafarnib treatment on weight gain and cardiovascular-related endpoints in patients with HGPS and PL. ProLon1 was initiated in May 2007 and completed in November 2009. Trial 09- 06-0298, initiated in March 2009, is still ongoing. In April 2018, the trial investigators published their findings on the survival benefit of lonafarnib treatment in HGPS patients based on their matched analysis of the mortality data of these trials and those of the untreated patients from a natural history cohort (Gordon et al. 2018). The endpoint and analyses for the NDA were discussed at pre-IND and IND meetings. The Agency agreed to the main endpoint of mortality for the NDA and stated that the protocol-defined endpoints should be considered exploratory because their clinical relevance is unclear. In addition, the Agency agreed with the Applicant’s planned analysis which included only HGPS patients because of the rarity of the PL patients (only one PL patient in ProLon1 was treated with lonafarnib monotherapy). Furthermore, the Agency requested the Applicant submit data and rationale to support extrapolating the lonafarnib treatment efficacy in HGPS patients to PL patients. The Agency also requested the Applicant provide evidence to demonstrate comparability of the treated patients and their matched untreated controls.

ProLon1 was a phase 2 open-label, single-arm, dose escalation monotherapy trial. A total of 29 patients at least 3 years of age were enrolled in this trial but one patient withdrew from the protocol before receiving therapy. Thus, 28 patients (26 with classic HGPS, 1 with nonclassic HGPS, and 1 with PL) received lonafarnib 115 mg/m2 twice daily for 4 months followed by 150 mg/m2 BID through year 2.

Following completion of ProLon1, patients with HGPS and PL were eligible to enroll in a second open-label phase 2 study (study 09-06-0298). Study 09-06-0298 was initiated in March 2009 and was originally designed to investigate a triple therapy regimen (lonafarnib, pravastatin, and zoledronic acid). However, the study was later amended in April 2014 to include lonafarnib monotherapy. This ongoing trial had two groups of patients: Triple Therapy Group 1 and Monotherapy Group 2. Triple Therapy Group 1 consisted of 47 patients at least one year of age (39 with classic HGPS, 4 with nonclassic HGPS, and 4 with PL). Among these patients, 26 were from ProLon1 and 21 were treatment-naïve. Monotherapy Group 2 (hereafter referred to as ProLon2) consisted of 35 treatment-naïve patients with HGPS who received lonafarnib monotherapy 150 mg/m2 BID for up to 3 years. After participation in Study 09-06-0298, 13 patients originally enrolled in ProLon1 and 23 patients from ProLon2 participated in study 0000170505 (hereafter referred to as Dual Therapy), an open-label study that investigated a dual therapy regimen of lonafarnib and everolimus. Patient flow in clinical trials involving lonafarnib treatment is presented in Figure 3.

A subset of ProLon1 and ProLon2 patients who received dual therapy and/or triple therapy returned to receiving lonafarnib monotherapy (Monotherapy Extension Trial).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 3. Patient Flow in Clinical Studies of Lonafarnib

Source: Figure 1 of Survival Analysis Report located at \\CDSESUB1\evsprod\NDA213969\0003\m5\53-clin-stud-rep\535-rep-effic- safety-stud\progeria\5353-rep-analys-data-more-one-stud\surv-analysis The excluded Progeroid Laminopathy patient in ProLon1 (patient(b) (6) ) had processing-deficient LMNA variant, but was not included in the efficacy analyses as the agreed-on efficacy analysis focused on HGPS patients only. Note: 26/28 – 26 of the 28 patients who completed ProLon1 enrolled in new triple therapy; 18/26 – 18 of the 26 ProLon1 patients who received Triple Therapy enrolled in the Monotherapy extension; 18/21 – 18 of the 21 new triple therapy patients enrolled in the monotherapy extension.

The main objective of the retrospective survival analysis was to evaluate whether lonafarnib monotherapy treatment (in ProLon1 and ProLon2) reduced mortality in patients with HGPS compared to a matched control from a separate natural history cohort. The full natural history cohort was identified from the Progeria Research Foundation International Progeria Registry and consisted of 196 patients who were born between 1976 and 2015. From this cohort, a total of 23 patients were excluded leaving a pool of 173 treatment- naïve patients (no prior exposure to lonafarnib) to be considered as possible matches in the analysis. For the main efficacy assessment, 81 of the 173 control patients born in 1991 or later (also referred to as the contemporaneous control) served as the pool for potential matches for the treated patients in ProLon1 and ProLon2. In the contemporaneous control, the birth year cutoff of 1991 was chosen to match the earliest birth year of the ProLon1 and ProLon2 cohort, which was 1991 in ProLon1. The Agency agreed to the use of the external contemporaneous control in the matched analysis because the trial investigators and Applicant took adequate measures to minimize potential sources of bias. The trial investigators undertook rigorous efforts to identify patients with HGPS globally and offered all patients the same opportunity to participate in the natural history study, reducing potential selection bias (see Section 6.3.1). Known potential confounders (age at treatment initiation, variant status, sex, and continent of residence) were adequately addressed in the analyses (see Section 6.2.1.3).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The main efficacy assessment was based on the survival data of treated patients in ProLon1 and ProLon2, matched one-to-one to the untreated patients in the contemporaneous control. See Section 6.2.1.3 for more details on the criteria and algorithms used to create the 1:1 match.

The main efficacy outcome was the time to all-cause mortality by the cut-off date of June 1, 2019. See Section 6.2.1.3 for details on the definition of follow-up time to all-cause mortality in the treated and matched untreated groups. Supporting efficacy outcomes included the following:

x The incidence of all-cause mortality by the cut-off date of June 1, 2019. x The incidence of all-cause mortality by the cut-off date of June 1, 2019, adjusted for patient-time. 6.2.1.2. Eligibility Criteria, ProLon1 and ProLon2 The eligibility criteria for ProLon1 and ProLon2 are summarized in Section 15. Much of the eligibility criteria for ProLon1 remained the same for ProLon2, apart from specifying a need for a LMNA or ZMPSTE24 variant and clinical signs of progeria for the PL patients. The redefining of PL variant eligibility between the studies had a minimal impact on the study patients, as there were just four patients with PL. Two patients with the LMNA variants were enrolled in ProLon1, including one who turned out not to have a processing-deficient variant and did not continue into Study 09-06-0298. Two siblings with a heterozygous ZMPSTE24 variant with processing deficiency were enrolled in Triple Therapy. 6.2.1.3. Statistical Analysis Plan Prior to the creation of the statistical analysis (SAP) for the NDA, the mortality data of ProLon1 and ProLon2 captured during lonarfarnib monotherapy ” \HDUV were analyzed and published by the trial investigators (Gordon et al. 2018). Consequently, during the pre-IND meeting the Agency stated, “Ideally, analysis plans for marketing applications should be submitted to the FDA for agreement before analyzing the data; this was a missed opportunity for the program and may be a review issue.” In their original SAP for the NDA submission, the Applicant proposed to conduct the same analysis as the trial investigators did in their paper (Gordon et al. 2018) using the mortality data of ProLon1 and ProLon2 captured during the lonafarnib monotherapy SHULRG ” \HDUV ZLWK D FXWRII GDWH RI -DQXDU\   IRU IROORZ-up (Gordon et al. 2018). The Agency agreed to the analysis based on the mortality data captured during the lonafarnib monotherapy period. Additionally, the Agency recommended that the SAP also include an analysis based on the mortality data with a longer follow-up time for all treated and untreated patients. The Applicant agreed with the Agency’s recommendation and revised the SAP with a cut-off date of June 1, 2019 for follow-up. The SAP was also revised based on Agency feedback pertaining to the matching approach and censoring. The revised SAP was deemed acceptable by the Agency prior to NDA submission, with the caveat that analyses were retrospectively planned and considered post-hoc. During the course of the NDA review, issues with the analyses were identified and adequately resolved (see Section 6.3).

The main efficacy analysis was performed in the contemporaneous intent-to-treat analysis population, including all treated patients with HGPS in ProLon1 and ProLon2 combined (N=62)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) and the 1:1 matched untreated HGPS patients selected from the contemporaneous control cohort (N=62).

Matching Criteria and Matching Algorithm for 1:1 Match According to the SAP, the matching criteria were defined by sex and continent of residency. To identify potential untreated candidate patients for matching, treated patients in ProLon1 and ProLon2 were first sorted by age at treatment initiation in descending order, and then the matching process started from the oldest patient at the top to the youngest patient at the bottom. Each treated patient was matched with a pool of untreated patients. The untreated patients had to be alive at the age of the treated patient when lonafarnib treatment was initiated and had to be of the same sex and continent of residency. If the matching pool had more than one candidate, the match was randomly selected. This matching method was considered as the primary matching method and was used in the Applicant’s main efficacy analysis. As supportive analyses, the SAP considered various alternative methods, including the fixed 50th and 75th percentile matching algorithms. In the fixed 50th percentile matching algorithm, the pool of matching candidates were first sorted by last known age in descending order, and the candidate in the 50th percentile was selected as a match (if the pool of candidates was even numbered, the older of the two middle patients was used as the single match). Similarly, the candidate in the 75th percentile was selected as a match in the fixed 75th percentile matching algorithm. The Agency, however, does not consider the SAP-defined matching criteria adequate based on the following two observations identified during our review of the NDA:

x The resultant matched untreated cohorts had more patients with the nonclassic variant than the treated cohort did. x This imbalance in variant status favored the treated cohort because the natural history data showed an increased risk of mortality in patients with the nonclassic variant compared to those with the classic/unknown variant (see more details in Section 6.3.3). Furthermore, during the NDA review the Agency determined that it prefers using the fixed 50th percentile matching algorithm as the primary matching algorithm instead of the random matching method because the untreated cohort would vary depending on how the random selection was implemented. Therefore, during the NDA review, the Agency requested the Applicant submit survival analyses based on the data of the treated and untreated patients who were matched by variant status (classic/unknown versus non-classic), sex, and continent of residency using the fixed 50th (primary) and 75th (supportive) percentile matching algorithms. In the Agency’s efficacy evaluation, the survival analysis based on the new matching criteria (by variant status, sex, and continent of residency) and the fixed 50th percentile matching algorithm was considered as the main analysis, and all other analyses were considered as supportive analyses. While the Agency does not generally deviate from an agreed upon SAP, wedetermined that these changes to the main analyses were necessary because the problematic issues discussed above were not appreciated prior to submission of the NDA and we had concerns for biased results if we followed the SAP.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Definition of Follow-Up Time to All-Cause Mortality The main efficacy outcome was time to all-cause mortality up to the database cut off date of June 1, 2019. According to the SAP, follow-up time for a matched pair of treated and untreated patients began at the age of the treated patient at lonafarnib initiation. The efficacy benefit of lonafarnib in the reduction of mortality was assessed during the monotherapy phase and long-term follow-up prior to initiation of dual therapy.

x For the efficacy assessment of lonafarnib monotherapy, follow-up time was censored at 3 years (the maximum duration of monotherapy treatment in ProLon2) or earlier at the time of either triple therapy initiation for patients in ProLon1 or dual therapy initiation for patients in ProLon2 (this follow-up time was referred to as follow-up time censored at 3 years). x For the efficacy assessment of long-term treatment benefit of lonafarnib, the SAP indicated that follow-up time was to be censored for treated and untreated patients at the last known age alive and was to include all deaths in the analysis. The treated patients could be on lonafarnib monotherapy, triple therapy, or dual therapy. However, contrary to the SAP-defined follow-up time, in the NDA and subsequently submitted datasets, the Applicant censored follow-up time for treated patients at the date of dual therapy initiation for those who were alive and the time to death for those who died (this follow- up time was referred to as censored at last follow-up). Therefore, this analysis included any time on triple therapy or monotherapy extension prior to initiation of dual therapy. This revised approach is acceptable as we expect it to favor the untreated patients because 20 of the patients who received dual therapy lived far beyond the timepoint of dual therapy initiation and their survival times were not included in the survival analysis. Because of the censoring approach the Applicant adopted in the NDA and subsequently submitted datasets, which included censoring upon initiation of dual therapy, the treated cohort had a substantially higher censoring rate over time than the matched untreated cohorts (see Section 6.3.4 for more details). This censoring imbalance favored the treated patients whose matched untreated controls died after the follow-up time of the treated patients. To address the resulting imbalance in the censoring rate, the Agency requested the Applicant submit survival analyses censoring the follow-up time of the untreated patients (who died and had longer follow- up time than their matched treated patients) at the follow-up time of the treated patients (this censoring approach is referred to as the Agency’s recommended censoring approach).

Efficacy Analysis Methods For the analysis of time to all-cause mortality censored at 3 years and time to all-cause mortality censored at last follow-up, the main efficacy analysis compared the survival distributions between the treated and matched untreated groups using a log-rank test at a two-sided significance level of 5%. Kaplan-Meier survival curves were created for the treated and matched untreated groups. The restricted mean survival time (the area under the survival curves at a given time period) and the 25th,50th (median), and 75th percentile survival times for the treated and matched untreated groups were presented (if estimable) along with the corresponding 95% confidence interval (CI) estimates. A Cox proportional hazards regression model was also fitted to estimate the hazard ratio between the treated and matched untreated groups.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The supportive analysis for the incidence of all-cause mortality (a binary outcome without considering the timings of deaths) was based on a Cochran-Mantel-Haenszel (CMH) test at a two-sided significance level of 5%. The risk differences and odds ratio in the incidence of all- cause mortality along with the corresponding 95% CIs were provided based on the CMH weight and normal approximation. The supportive analysis for the incidence rate of all-cause mortality adjusted for patient-time was reported as a risk ratio and corresponding 95% CI based on a Poisson regression model. The supportive analyses were performed on the contemporaneous intent-to-treat population using the fixed 50th percentile match and 75th percentile match. The efficacy analyses including the log-rank test, Cox-regression model, CMH test, and Poisson regression model were stratified by the matching variables (i.e., by sex and continent of residency in the NDA, and by variant status, sex, and continent of residency in the Applicant’s response to the Agency’s information requests dated June 3, 2020). However, because many strata had zero or one patient in one of the two treatment groups, the Agency requested that the Applicant submit the efficacy analyses stratified by the continent of residency only (see Section 6.3.5 for more details). Supporting analyses for the time to all-cause mortality from birth to last follow-up were also conducted between the following treated and different subsets of untreated patients without matching:

x Treated (ProLon1 and ProLon2; N=62) versus untreated (all contemporaneous historical control; N=81) x Treated (ProLon1 and ProLon2 plus triple therapy; N=80) versus untreated (all treatment- naïve patients in the historical control; N=173) x Treated (ProLon1 and ProLon2; N=62) versus untreated (all treatment-naïve patients in the historical control; N=173) 6.2.1.4. Results of Analyses, ProLon1 and ProLon2 This section summarizes the patient disposition, baseline demographics, and the results of the main and supporting efficacy analyses that establish the efficacy of lonafarnib in the reduction of mortality in patients with HGPS. All results presented in this section were based on the analyses conducted by the Agency. The p- values and CIs are presented for descriptive use only given the retrospective nature of the analysis plan. The results of the Agency’s efficacy analyses in Tables 8 to 11 and in Figure 4 were based on: x Data of the treated patients and their untreated controls who were 1:1 matched by variant status, sex, and continent of residency using the fixed 50th percentile (primary) and 75th percentile (supportive) matching algorithms x Using the Agency’s recommended censoring approach x Using continent of residency as the sole stratifying variable in the analyses 6.2.1.4.1. Disposition and Baseline Demographics Disposition information for the treated patients of ProLon1 and ProLon2 is presented in Table 7.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) A total of 62 patients with HGPS were treated with lonafarnib monotherapy (27 in ProLon1 and 35 in ProLon2). Of the total, 51 patients completed the studies (26 in ProLon1 and 25 in ProLon2) and 5 patients died during the monotherapy treatment period (1 in ProLon1 and 4 in ProLon2). Patients in ProLon1 received lonafarnib monotherapy for 24 to 30 months, and patients in ProLon2 received monotherapy treatment for up to 36 months.

Table 7. Patient Disposition, ProLon1 and ProLon2 Screening Disposition ProLon1 ProLon2 Combined Patients screened 29 36 64 Screening failures 0 1 1 Not treated 1 1 2 Patients treated 28 35 63 Patients included in survival analysis[1] 27 35 62 Completion status Completed 26 (96.3) 25 (71.4) 51 (82.3) Died prior to year 3[2] 1 (3.7) 4 (11.4) 5 (8.1) Primary investigator withdrew subject 0 (0.0) 2 (5.7) 2 (3.2) Withdrawal by parent/guardian 0 (0.0) 3 (8.6) 3 (4.8) Withdrawal by patient 0 (0.0) 1 (2.9) 1 (1.6) Source: Table 3 of Clinical Study Report and ADSL.xptand ADTTE.xpt.datasets located at \\CDSESUB1\evsprod\NDA213969\0003\m5\datasets\natural-his\analysi s\a d am \d ata se ts. [1] One patientwith PL in ProLon1 was excluded from the survival analysi s. [2] In ProLon2, three deaths were reported in Table 3 of the Applicant’s survival analysis report prior to year 3. However, four deaths were reported in the main survival analysis dataset (ADTTE.xpt) pri or to year 3. Note: Percentages are based on the number of patients included in the survival analysis

Patient demographic information is presented in Table 8 for the 62 patients in the treated group (combined ProLon1 and ProLon2), the 62 patients in the contemporaneous, fixed 50th percentile matched, untreated group (hereafter referred to as the matched untreated group), and for the entire contemporaneous historical control cohort that includes the matched and nonmatched patients (N=81).

In the matched treated and untreated pairs, a total of 46 pairs were matched by variant status, sex, and continent of residency, while 16 pairs were matched by variant status and sex only due to a small number of patients in some of the regions. As shown in Table 8, the treated and matched untreated groups were fully balanced in the mean age at treatment start and by variant status and sex, but some regional imbalances were observed in the treated and matched untreated groups. For example, the highest proportion of patients in the treated group were from North America (32%) whereas the highest proportion of patients in the untreated group were from Asia (38%). Additionally, the treated and matched untreated groups were well balanced in the mean age at the last follow-up time (about 11 years). The maximum follow-up time for patients in the treated group and the matched untreated group was 11.4 years (median: 3 years) and 12.9 years (median: 2.6 years), respectively. About 53% of patients in the treated and in the matched untreated group were male. The genotype was known for all patients in the treated group and for 57% of patients in the matched untreated group, and almost all patients in the treated and matched untreated group had classic/unknown variant (97%). This imbalance between the treated and matched untreated groups in variant status is discussed in more detail in Section 6.3.3.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 8. Baseline Demographic and Clinical Characteristics: ProLon1, ProLon2, Contemporaneous Control, and Untreated Fixed 50th Percentile Match Untreated Untreated Fixed 50th Treated Contemporaneous Percentile ProLon1 ProLon2 Combined Cohort Match Summary (N=27) (N=35) (N=62) (N=81) (N=62) Age at treatment start (years) Mean (SD) 7.5 (3.1) 6.7 (3.9) 7.0 (3.6) -- 7.0 (3.6) Median 7.4 6.3 6.7 -- 6.7 Range 3.1–16.2 2.1–17.5 2.1–17.5 -- 2.1–17.5 Age at last follow-up (years) Mean (SD) 15.6 (3.4) 8.7 (3.9) 11.7 (5.0) 10.5 (4.5) 11.2 (3.7) Median 15.4 8.2 11.1 10.7 11.3 Range 9.3–21.8 2.5–19.2 2.5–21.8 2.6–20.0 3.5–18.6 Follow-up time from treatment initiation to last follow-up (years) Mean (SD) 8.1 (2.6) 2.1 (1.0) 4.7 (3.5) -- 3.2 (2.5) Median 9.1 2.1 3.0 -- 2.6 Range 0.3–11.4 0.003–4.3 0.003–11.4 -- 0.003–12.9 Follow-up time from treatment initiation to year 3 (years) Mean (SD) 2.1 (0.4) 2.0 (0.9) 2.2 (0.7) 2.4 (1.0) Median 2.2 2.0 2.2 3.0 Range 0.3–2.5 0.003–3.0 0.003–3.0 0.02–3.0 Sex (n, %) Female 16 (59.3) 13 (37.1) 29 (46.8) 39 (48.1) 29 (46.8) Male 11 (40.7) 22 (62.9) 33 (53.2) 42 (51.9) 33 (53.2) Baseline weight (in kg) Mean (SD) 10.4 (2.7) 10.9 (3.0) 10.7 (2.8) -- -- Median 9.5 10.4 10.4 -- -- Range 6.6–17.6 6.8–22.2 6.6–22.2 -- -- BSA (in m2) Mean (SD) 0.52 (0.10) 0.53 (0.11) 0.53 (0.10) -- -- Median 0.50 0.52 0.51 -- -- Range 0.38–0.75 0.38–0.90 0.38–0.90 -- -- Birth year (n, %) <2000 13 (48.2) 2 (5.7) 15 (24.2) 28 (34.6) 25 (40.3) 2000–2010 14 (51.9) 17 (48.6) 31 (50.0) 29 (35.8) 22 (35.5) •2010 0 16 (45.7) 16 (25.8) 16 (19.8) 10 (16.1) Missing 0008 (9.9) 5 (8.1)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Untreated Untreated Fixed 50th Treated Contemporaneous Percentile ProLon1 ProLon2 Combined Cohort Match Summary (N=27) (N=35) (N=62) (N=81) (N=62) Continent (n, %) Africa 0 2 (5.7) 2 (3.2) 2 (2.5) 2 (3.2) Asia 4 (14.8) 12 (34.3) 16 (25.8) 31 (38.3) 22 (35.5) Australia 0 1 (2.9) 1 (1.6) 00 Europe 8 (29.6) 4 (11.4) 12 (19.4) 16 (19.8) 12 (19.4) North America 11 (40.7) 9 (25.7) 20 (32.3) 12 (14.8) 10 (16.1) South America 4 (14.8) 7 (20.0) 11 (17.7) 20 (24.7) 16 (25.8) Known genotype (n, %) N 0 0 0 34 (42.0) 27 (43.5) Y 27 (100) 35 (100) 62 (100) 47 (58.0) 35 (56.5) Variant (n, %) Classic/unknown 26 (96.3) 34 (97.1) 60 (96.8) 72 (88.9) 60 (96.8) Non-classic 1 (3.7) 1 (2.9) 2 (3.2) 9 (11.1) 2 (3.2) Source: Review team analysis based on ADSL.xpt and ADTTE.xpt. Abbreviations: BSA, body surface area; N, number of patients in treatment group; n, number of patients with given characteristic, SD, standard deviation

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 6.2.1.4.2. Main and Supportive Efficacy Results

Main Efficacy Re s ults Table 9 and Figure 4 summarize the main efficacy analysis results for the treated and matched untreated groups at the two censoring timepoints. Overall, there were 5 deaths in the treated group and 12 deaths in the matched untreated group for the follow-up time censored at 3 years, and 21 deaths in the treated group and 25 deaths in the matched untreated group for follow-up censored at last follow-up time. Figure 4 shows the Kaplan-Meier survival curves for follow-up time censored at 3 years (4A) and at last follow-up time (4B). As shown, at both censoring times, patients in the treated group had an improved survival compared to patients in the matched untreated group (stratified log rank test p=0.02 for follow-up censored at 3 years and p=0.005 for follow-up censored at last follow-up time). Table 9 shows that for the follow-up time censored at 3 years, the survival probability estimates were about 91% (95% CI: 84% to 99%) for patients in the treated group and 80% (95% CI: 70% to 91%) for patients in the matched untreated group. Because the survival probability estimates at 3 years of follow-up were more than 50% in both treatment groups, the median survival times in both groups were not estimable. For the follow-up time censored at the last follow-up, the survival probabilit y estimates at 5- and 10-years of follow-up were 79% (95% CI: 66% to 93%) and 44% (95% CI: 29% to 67%), respectively, for patients in the treated group. For patients in the matched untreated group, the 5- and 10-year survival probability estimates were 57% (95% CI: 42% to 77%) and 17% (95% CI: 6% to 46%), respectively. The median survival times (the time points at which the survival probability estimate drops below 50%) were approximately 7.8 years for the treated group and 5.3 years for the matched untreated group.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 4. Kaplan-Meier Survival Curves of Treated Versus Matched Untreated Groups (A) Time to All-Cause Mortality Censored at 3 Years

(B) Time to All-Cause Mortality Censored at Last Follow-Up

Source: Review team’sanalysis Additionally, at both censoring times, the restricted mean survival times (the area under the survival curves for a given time period) were higher for patients in the treated group than for those in the untreated group. For example, the restricted mean survival times at 3, 5, and 10 years of follow-up were 0.26 years (~3 months), 0.57 years (~7 months), and 2.21 years (~27 months) longer, respectively, for the treated patients than the untreated patients. The hazard ratio for the risk of death was 0.30 (95% CI: 0.10 to 0.89) for follow-up censored at 3 years and was 0.40 (95% CI: 0.21 to 0.77) for follow-up censored at the last follow-up.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 9. Efficacy Results of Survival Time (Fixed 50th Percentile Matching Algorithm) Censored at 3 Years Censored at Last Follow-Up Untreated Treated Untreated Treated Summary (N=62) (N=62) (N=62) (N=62) Number of deaths (%) 12 (19.4) 5 (8.1) 25 (40.3) 21 (33.9) RMST (years) 2.59 2.83 5.54 8.01 (95% CI)[1] (2.37, 2.81) (2.68, 2.98) (4.32, 6.75) (6.91, 9.10) (95% CI)[2] (2.36, 2.79) (2.68, 2.95) (4.29, 6.78) (6.32, 9.05) Difference in RMST (years) 0.24 2.47 (95% CI)[1] -- (-0.03, 0.50) -- (0.84, 4.11) (95% CI)[2] (-0.03, 0.50) (0.74, 3.87) Hazard ratio for risk of death[3] 0.30 0.40 (95% CI) -- (0.10, 0.89) -- (0.21, 0.77) P-value (HR) 0.03 0.006 P-value (log-rank test)[3] 0.02 0.005 Source: Review team’sanalysis based on ADTTE.xpt dataset located at \\CDSESUB1\evsprod\NDA213969\0010\m5\datasets\natural-his\analysi s\a d am \d ata se ts [1] 95% confidence intervals (CI) were based on normal approximation [2] Bootstrap CI based on 1000 bootstrap samples [3] Analyses stratified by continent of residency. Note: RMST was calculated based on the area under the survival curve from the beginning of follow-up to the minimum of the largest observed time on each of the two groups. The minimum of the largest observed time was 3 years for follow-up censored at 3.0 years and 11.4 years for follow-up censored at last follow-up. Abbreviations: CI, confidence interval; HR, hazard ratio; RMST, restricted mean survival time

Supportive Efficacy Results The incidence of all-cause mortality was defined as the percentage of patients who died in the treated and matched untreated group. This definition did not take the timing of deaths into account and considered patients with unknown vital status as non-deaths. The incidence of all- cause mortality and the incidence rate of all eligible deaths adjusted for patient-time were regarded as supportive of efficacy outcomes. Table 10 shows the summary of the percentage of death in the treated and matched untreated group. As shown, at both censoring times, the incidence of death in the treated group was lower than that in the matched untreated group. For example, for follow-up censored at 3 years, the percentage of death was lower by 14.1% (95% CI: 1.4% to 26.8%) in the treated group than in the matched untreated group. The odds ratio (OR) was 0.32 (95% CI: 0.11, 0.96), and the risk ratio (RR) was 0.48 (95% CI: 0.17 to 1.36). Similarly, for follow-up censored at last follow-up time, the percentage of death was lower by 10% (95% CI: -7.7% to 27.7%) in the treated group than in the matched untreated group. The OR was 0.7 (95% CI: 0.32 to 1.39), and the RR was 0.57 (95% CI: 0.32 to 1.02). These analyses results consistently trended in favor of the treated group, although the 95% CIs for four of these six analyses crossed the null.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 10. Supportive Efficacy Analysis Results (Fixed 50th Percentile Matching Algorithm) Censored at 3 Years Censored at Last Follow-Up Untreated Treated Untreated Treated Summary (N=62) (N=62) (N=62) (N=62) Number of deaths (%) 12 (19.4) 5 (8.1) 25 (40.3) 21 (33.9) Risk difference[1] (95% CI) -- -14.1 (-26.8, -1.4) -- -10.0 (-27.7, 7.7) Odds ratio[1] (95% CI) -- 0.32 (0.11, 0.96) -- 0.66 (0.32, 1.39) Risk ratio[2] (95% CI) --0.48(0.17, 1.36) -- 0.57 (0.32, 1.02) Source: Review team’sanalysis based on ADTTE.xpt dataset. [1] Based on CMH test stratified by continent of residency [2] Based on Poisson regression stratified by continent of residency. Abbreviation: CI, confidence interval As additional supportive analyses, a comparison of the time to all-cause mortality at each censoring timepoint was performed using the fixed 75th percentile matching algorithm and by including different subsets of untreated patients without matching.

Table 11 presents the results of the restricted mean survival times and their hazard ratios at the two censoring timepoints for the treated and matched untreated groups using the fixed 75th percentile matching. These results are consistently in favor of the treated group.

Table 11. Efficacy Results of Survival Time (Fixed 75th Percentile Matching Algorithm) Censored at 3-Years Censored at Last Follow-Up Untreated Treated Untreated Treated Summary (N=62) (N=62) (N=62) (N=62) Number of deaths (%) 11 (17.7) 5 (8.1) 30 (48.4) 21 (33.9) RMST (95% CI) 2.66 (2.45, 2.86) 2.83 (2.68, 2.98) 5.21 (4.54, 5.88) 6.57 (5.91, 7.24) Difference in RMST (95% CI) -- 0.17 (-0.08, 0.42) -- 1.36 (0.42, 2.31) Hazard ratio for risk of death[1] 0.37 (0.12, 1.12) 0.33 (0.17, 0.63) (95% CI) -- -- 0.08 0.001 P-value (HR) P-value (log-rank test)[1] 0.07 0.0006 Source: Review team’sanalysis based on ADTTE.xpt dataset. [1] Analysis stratified by continent of residence. Note: RMST was calculated based on the area under the survival curve from the beginning of follow-up to 3 years for follow-up time censored at 3.0 years and to 8.06 years for follow-up censored at last follow-up time. Abbreviations: CI, confidence interval; HR, hazard ratio; RMST, restricted mean survival time(in years)

Time to all-cause mortality from birth to last follow-up time was also compared between the following three subsets of treated and untreated patients without matching as additional supportive analyses: (1) Treated (ProLon1 and ProLon2; N=62) versus untreated (all contemporaneous historical control; N=81) (2) Treated (ProLon1, ProLon2, and triple therapy; N=80) versus untreated (all historical control; N=173) (3) Treated (ProLon1 and ProLon2; N=62) versus untreated (all historical control; N=173)

Table 12 presents the results of the restricted mean survival times and their hazard ratios for these three comparisons. The treatment differences in the mean survival times and the hazard ratios for each of the comparisons are consistently in favor of the treated group regardless of the subset.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 12. Efficacy Results of Survival Time (Without Matching the Treated and Untreated Patients) AB C Untreated Untreated Untreated(N=81) Treated(N=62) Treated(N=80) Treated (N=62) Summary (N=173) (N=173) Number of deaths, (%) 56 (69.1) 21 (33.9) 128 (74.0) 26 (32.5) 128 (74.0) 21 (33.9) RMST (95% CI) 12.4 (11.3, 13.4) 16.4 (15.2, 17.6) 13.6 (12.9, 14.4) 16.6 (15.5, 17.8) 13.6 (12.9, 14.4) 16.6 (15.3, 18.0) Difference in RMST (95% CI) -- 4.02 (2.45, 5.59) -- 2.99 (1.61, 4.37) -- 3.00 (1.48, 4.52) Hazard ratio for risk of death[1] (95% CI) 0.40 (0.22, 0.71) 0.46 (0.29, 0.72) 0.47 (0.29, 0.77) ------P-value 0.002 0.0008 0.003 P-value[1] (log-rank test) -- 0.002 -- 0.0006 -- 0.002 Source: Review team’sanalysis based on ADSL.xpt dataset. [1] Analysis stratified by variant status (classic/unknown versus nonclassic) and continent of residency. Abbreviations: CI, confidence interval; RMST, restricted mean survival time (in years)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Additional Supportive Subgroup Analysis

As a further supportive analysis, the time to all-cause mortality censored at 3 years and at the last follow-up time was compared between the treated and matched untreated groups in the ProLon1 and ProLon2 trials separately. As shown in Table 13, the results at both censoring times in ProLon1 and at the 3 years censoring time in ProLon2 are in favor of the treated group. However, in ProLon2, analysis at the last follow-up time appears to slightly favor the untreated group. This is likely due to the disparity in the definition of the last follow-up time in the two groups. This disparity favored the untreated group. The last follow-up time in ProLon2 was up to the initiation of dual therapy for patients who were alive (” 3 years) or the time of death (regardless of whether the patient died beyond the initiation of dual therapy) whereas it was up to the last known age alive in the untreated group. As shown in Figure 35 of Section 16, a total of 21 patients in ProLon2 lived beyond the initiation of dual therapy and their survival time after initiation of dual therapy was not included in the survival analysis. Of note, the Applicant did not include the survival time data after the initiation of dual therapy for the patients who were alive in their submitted datasets.

Table 13. Efficacy Results of Survival Time by Trial (Fixed 50th Percentile Matching Algorithm) Censored at 3 Years Censored at Last Follow-up ProLon 1 ProLon 2 ProLon 1 ProLon 2 Untreated Treated Untreated Treated Untreated Treated Untreated Treated (N=27) (N=27) (N=35) (N=35) (N=27) (N=27) (N=35) (N=35) Number of deaths, (%) 7 (25.9) 1 (3.7) 5 (14.3) 4 (11.4) 20 (74.1) 15 (55.6) 5 (14.3) 6 (17.1) RMST 2.04 2.37 2.71 2.76 4.36 8.19 3.81 3.65 (95% CI) (1.74, 2.33) (2.22, 2.52) (2.46, 2.96) (2.54, 2.98) (3.28, 5.45) (7.24, 9.14) (3.38, 4.24) (3.08, 4.23) Difference in RMST 0.33 0.06 3.83 -0.16 ------(95% CI) (0.00, 0.66) (-0.28, 0.39) (2.39, 5.27) (-0.87, 0.56) Hazard ratio for risk of death[1] 0.09 0.69 0.21 1.08 (95% CI) -- (0.01, 0.71) -- (0.18, 2.69) -- (0.09, 0.46) -- (0.31, 3.78) P-value 0.023 0.594 <0.001 0.9 P-value[1] (log-rank test) -- 0.005 -- 0.6 -- <0.001 -- 0.9 Source: Review team’s analysis based on ADTTE.xpt dataset [1] Analysis stratified by continent of residence Abbreviations: CI, confidence interval; RMST, restricted mean survival time (in years)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Conclusions Regarding Effectiveness: In summary, we conclude that substantial evidence of effectiveness is established for HGPS based on: x The adequate and well-controlled trials of ProLon1 and ProLon2 showing that the pooled patients have reduced mortality compared to a well-matched contemporaneous cohort. x Confirmatory evidence derived from lonafarnib’s mechanism of action within the pathway of the disease and from mechanistic studies showing that lonafarnib improves the nuclear morphology of in vitro fibroblasts from HGPS patients (See Section 18). See Section 6.3.9 for the basis for granting an indication for processing-deficient PL. See Section 6.3 for key review issues relevant to the evaluation of benefit and how they were resolved. 6.3. Key Review Issues Relevant to Evaluation of Benefit

The team concluded that lonafarnib has a survival benefit for patients with HGPS, based on the pivotal studies, ProLon1 and ProLon2. The analysis methods were planned post-hoc. The criteria used to match treated patients to an untreated group needed to be redefined during the review process to mitigate the impact of factors that may lead to selection bias. Extrapolation of the HGPS indication to treatment of processing-deficient PL was made based on the experiences of three patients with PL who have been on lonafarnib for over 10 years; the similarity of disease mechanism; case reports of clinical symptom similarit ies of PL and HGPS; and an in vitro study in which lonafarnib treatment of cultured fibroblasts from PL patients produced a significant reduction in the number of aberrant nuclei (see Sections 5.1 and 6.3.9). 6.3.1. Mitigating Disparities Between Treated and Untreated HGPS patients

Issue Potential disparities between treated and natural history cohort HGPS patients, particularly with regard to health status, access to healthcare, and follow-up that may lead to selection bias.

Background/Assessment

In pre-NDA discussions with the Applicant, we raised concerns about potential disparities in health status between the treated HGPS patients in ProLon1 and ProLon2 and the untreated matched HGPS patients in the external control. The treated HGPS patients could be healthier and have better access to healthcare. However, it appears that adequate measures were taken to minimize recruitment differences as a potential sources of bias. Recruitment of HGPS patients occurred globally for ProLon1, ProLon2, and the natural history study, with support for study participation in ProLon1 and ProLon2 including travel, such as flights, lodging, and translators. One limitation is that data on concomitant cardiovascular medications (e.g., aspirin, statins) in the control arm are not available. However, we assume that the specialized care of these patients

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) within geographic regions (one of the matching criteria) would be reasonably balanced between groups and there is no evidence that supportive care or diagnostic testing differences over time or between countries have an impact on life expectancy for HGPS. The use of a contemporaneous control makes any time period effects unlikely. With regard to natural history data verification of vital status, we agreed prior to the NDA submission that The Progeria Research Foundation would maintain the natural history study records and directly submit updated vital status data and records to FDA. The Progeria Research Foundation’s data were primarily maintained by director Dr. Leslie Gordon, through communications with local medical providers and guardians. Vital status or deaths are based on published case reports (7 patients) and non-literature sources (15 patients for vital status, 40 patients for deaths). Non-literature sources included email and telephone communications with the local primary medical provider or guardian. The natural history cohort data and patient narratives were reviewed by the Office of Surveillance and Epidemiology to verify accuracy. A high concordance was found by manual audit for the 62 untreated HGPS patients.

Conclusion Mitigation strategies were appropriately used against selection bias, in the comparison of treated and untreated HGPS patients. 6.3.2. Post Hoc Nature of the Analysis Plan

Issue The analysis plans for the marketing application were not submitted prior to analyzing the data.

Background

The SAP for the NDA focused on the post-hoc endpoint of time to mortality and was created after trial investigators published their findings (Gordon et al. 2018). The Agency reviewed and agreed to the SAP prior to the NDA submission. During the course of the review, unanticipated issues were identified (see Sections 6.3.3 to 6.3.6) and were adequately addressed by the review team using statistically appropriate analyses.

Assessment

In general, analysis plans should be submitted to the Agency in advance of conducting analyses to minimize the possibility of making a type I error and concluding the drug is effective when it is not. For the NDA, the review team concluded that the post-hoc analysis results were not likely due to chance based on the following considerations: x The analysis adequately addressed the known potential confounders (age at treatment initiation, variant status, sex, and continent of residence). x The magnitude of the estimated treatment effect was large, the treated HGPS patients showing an improvement of 2.5 years in mean lifespan through the last follow-up time (11 years). x The analysis results were supported by the mechanistic evidence of lonafarnib.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Conclusion The findings indicate an effect of Lonarfarnib on mortality and are not likely due to chance. There is also confirmatory evidence that lends support to a drug effect (see Section 18).

6.3.3. Criteria and Algorithm for Matching Treated Patients to Controls

Issue Imbalance between the treated and matched untreated groups in variant status.

Background In the Applicant’s NDA submission, treated patients in ProLon1 and ProLon2 were matched 1:1 to untreated historical control patients using a random matching algorithm to assess the mortality benefit of treatment with lonafarnib. Treated patients were first matched with untreated patients who were alive at the age when the treated patient began lonafarnib treatment and had the same sex and continent of residency as the treated patient. If a treated patient had more than one untreated match, the algorithm randomly selected one as the matched control. The Applicant’s main efficacy analysis was based on this random matching algorithm. For supportive analyses, the Applicant considered various alternative matching algorithms, including the fixed 50th and 75th percentile matching algorithms. In the fixed 50th (and 75th) percentile matching algorithms, candidate patients were first sorted by last known age in descending order and the candidate in the 50th (and 75th) percentile was selected as the match.

Assessment The Agency does not consider the Applicant’s matching criteria used in the NDA submission adequate based on the following two observations: x As shown in Table 14, the resultant matched untreated cohorts had more patients with nonclassic genetic variant than did the treated cohort (11% versus 3%) x This imbalance in variant status favored the treated cohort. As shown in Figure 5, the full natural history data (including patient data in ProLon1 and ProLon2 prior to receiving lonafarnib treatment) showed an increased risk of mortality in patients with nonclassic variant (green line) compared to those with the classic/unknown variant (median survival time: 8 years versus 15 years). Furthermore, the Agency recommends using the fixed 50th percentile matching algorithm as the primary matching algorithm instead of the random matching method because the untreated cohort selected based on the random matching method varied depending on how the random selection was implemented.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 5. Kaplan-Meier Survival Curves by Variant Status

Source: This figure, generated by the review team, was based on the natural history survival time (NHTIME) and censoring status (NHCNSR) in the ADSL dataset located at \\CDSESUB1\evsprod\NDA213969\0003\m5\datasets\natural- his\analysis\adam\datasets.

Conclusion To mitigate the imbalance in variant status, the Agency requested the Applicant to submit survival analyses after matching the treated and untreated patients by variant status (classic/unknown versus nonclassic), sex, and continent of residency using the fixed 50th (primary) and 75th (supportive) percentile matching algorithms. In the Agency’s efficacy evaluation, the survival analysis based on the new matching criteria (by variant status, sex, and continent of residency) and the fixed 50th percentile matching algorithm is considered the main analysis, and all other analyses are considered supportive analyses. Based on the revised matching criteria and using the 50th percentile matching algorithm, the treated and matched untreated groups were fully matched by variant status as shown in Table 14 below.

Table 14. Summary of Variant Status, Treated Group, and Untreated Historical Cohort Random Untreated Fixed 50th Percentile Treated Match[1] Untreated Match[2] Variant (N=62) (N=62) (N=62) Classic/unknown 60 (96.8) 55 (88.7) 60 (96.8) Non-classic 2 (3.2) 7 (11.3) 2 (3.2) Source: Review team analysis based on ADSL.xpt and ADTTE.xpt datasets. All values are expressed as n (%). [1] Matching by sex and continent of residency. [2] Matching by variantstatus, sex, and continent of residency.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 6.3.4. Disparity in Censoring Rate in the Treated and Untreated Cohort

Issue

The rate of censoring for the survival analysis was higher in the treated cohort than in the 1:1 matched untreated cohort. This censoring imbalance favored the treated patients whose matched untreated controls died after the follow-up time of the treated patients.

Background

For the analysis of time to all-cause mortality, follow-up time for a matched pair of treated and untreated patients began at the age of the treated patient at lonafarnib initiation. The efficacy of lonafarnib in reducing mortality was assessed during the monotherapy phase and at long-term follow-up. For the efficacy assessment of lonafarnib monotherapy, follow-up time was censored at 3 years or earlier at the time of triple therapy initiation for patients in ProLon1 or dual therapy initiation for patients in ProLon2. For the efficacy assessment of long-term treatment benefit of lonafarnib, the SAP-defined follow-up time was to censor treated and untreated patients at the last known age alive and to include all deaths in the analysis.

Assessment

Contrary to the SAP-defined follow-up time, in the NDA submission and in the subsequent submissions resulting from information requests, the last follow-up time for treated patients was (i) censored at the date of dual therapy initiation for those who were alive, and (ii) the time to death for those who died (regardless of being on dual therapy). The censoring approach adopted by the Applicant for the survival analyses – particularly the censoring at the date of dual therapy initiation for those who were alive – resulted in a substantially higher censoring rate over time for the treated cohort than for the matched untreated cohort (see Figure 6 below).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 6. Cumulative Censoring Rate Over Time for Treated Versus Matched Untreated Group (Unadjusted)

Source: Generated by the review team. Note: Treated and untreated control were matched by variant status, sex, and continent of residency using the fixed 50th percentile matching algorithm.

Conclusion

To address the imbalance in the censoring rates between the treated and matched untreated cohorts, the Agency requested the Applicant submit survival analyses after censoring the follow- up time of the untreated patients (who died and had longer follow-up time than their matched treated patients) at the follow-up time of the treated patients. As shown in Figure 7 below, the censoring rates over time in the treated and matched untreated groups appear to be more similar using the Agency’s recommended censoring approach. Thus, this censoring approach was used in the Agency’s efficacy evaluation.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 7. Cumulative Censoring Rate Over Time for Treated Versus Matched Untreated Group (Adjusted)

Source: Generated by the review team. Note: Treated and untreated control were matched by variant status, sex, and continent of residency using the fixed 50th percentile matching algorithm. 6.3.5. Limited Stratified Analysis

Issue Survival analyses stratified by matching variables resulted in many strata with zero or one patient in one of the two treatment groups due to the small sample size.

Background/Assessment The Applicant’s main analyses based on the log-rank test (for survival curve comparison) and the Cox-regression model (for hazard ratio estimates) were stratified by matching variables (sex and continent of residency in the NDA; and variant status, sex, and continent of residency in the Applicant’s response to the Agency’s information request dated June 3, 2020). However, many strata had zero or one patient in one of the two treatment groups due to small sample size.

Conclusion To address this issue, the Agency recommended the analyses be stratified by continent of residency alone because the treated and untreated groups were fully matched by variant status and sex (Table 8). The Applicant submitted these analyses on July 24, 2020, in a response to the Agency’s information request dated July 16, 2020. The Agency’s main efficacy evaluation focused on these analyses using continent of residency as the sole stratifying variable.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 6.3.6. Data Discrepancy Identified by Clinical Inspection

Issue The Agency’s clinical inspection team identified discrepancies in the last follow-up dates between the source document and the Applicant’s clinical database for a few patients.

Background/Assessment

In the Agency’s clinical inspection report dated October 6, 2020, discrepancies in the last follow- up dates were reported between the source documents and the Applicant’s clinical database for the following four patients in the table below. Table 15. Survival Data Discrepancies Last Follow-Up Date Last Follow-Up Date by Discrepancy Patient ID Submitted to Agency Source Documents Duration (b) (6) 1] 9/5/2017 6/6/2018 +274 days 2] 8/13/2016 4/10/2019 +970 days 2] 7/2/2018 6/13/2018 -19 days 2] 7/1/2018 6/11/2018 -20 days Source: Table 2 of Clinical Inspection Summary report dated October 6, 2020. [1] In Study 07-01-0007 [2] In Study 09-06-0298. ICF=informed consent form For these four patients, the survival summary at the last follow-up should have been based on the dates reported in the source documents (column 3), rather than the dates reported in the clinical (b) (6) database (column 2). Additionally, per the source document, the survival status for patient # should have been reported as ‘died’ as opposed to ‘censored’ as reported in the clinical database.

Conclusion To address the data discrepancies, the Agency requested the Applicant submit survival analyses using the last follow-up dates from the source documents for these four patients including (b) (6) updating the survival status of patient # from ‘censored’ to ‘died.’ The Applicant submitted these analyses on October 19, 2020, in a response to the Agency’s information request dated October 16, 2020. Thus, the Agency’s main efficacy evaluation was based on the updated last follow-up dates and survival status as reported in the source documents. Table 16 and Figure 8 below show the survival analysis results which addressed the key review issues highlighted in Sections 6.3.3, 6.3.4, 6.3.5, and 6.3.6. The Agency recommends that these results be presented in Section 14 of the prescribing information (PI).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 16. Efficacy Results of Survival Time (Fixed 50th Percentile Matching Algorithm) Follow-Up Time Censored at 3- Follow-Up Time Censored at Last Years Follow-Up Untreated Treated[1] Untreated Treated[1] Summary (N=62) (N=62) (N=62) (N=62) Number of deaths (%) 12 (19.4) 5 (8.1) 25 (40.3) 21 (33.9) Mean survival time[2] (95% CI) 2.59 (2.37, 2.81) 2.83 (2.68, 2.98) 5.54 (4.32, 6.75) 8.01 (6.91, 9.10) Difference in mean survival -- 0.24 (-0.03, 0.50) -- 2.47 (0.84, 4.11) time (95% CI) Hazard ratio for risk of death[3] -- 0.30 (0.10, 0.89) -- 0.40 (0.21, 0.77) (95% CI) Source: Review team’s analysis based on ADTTE.xpt dataset. [1] Includes patients in ProLon1 and ProLon2 [2] Based on the area under the survival curves from the beginning of follow-up to the minimum of the largest observed time on each of the two groups [3] Based on a Cox regression model (with treatment as the only covariate) stratified by continent of residency. Note: Treated patients were matched 1:1 to untreated patients (who were alive at the age of the treated patient at the lonafarnib treatment initiation) by variant status (classic/unknown versus nonclassic), sex and continent of residence using a fixed 50th percentile matching algorithm. In the fixed 50th percentile matching algorithm, candidate untreated patients were first sorted by decreasing last known age and the candidate in the 50th percentile was selected as the match. Follow-up time for a matched pair of treated and untreated patients began at the age of the treated patient at lonafarnib initiation. Abbreviations: CI, confidence interval; MST, mean survival time Figure 8. Kaplan-Meier Survival Curves for Follow-Up Time (in Years) Censored at Last Follow-Up

Source: Generated by the review team The Applicant presented the efficacy results shown in Table 17 below in Section 14 of the PI. However, the results reported in this table did not address the key review issues. Additionally, the Agency does not recommend presenting the analysis results for the odds ratio and relative risk in the labeling because these analyses considered patients with unknown survival status as non-deaths.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 17. Survival Analysis Summary, Main Analysis Population

Source: Module 2.5 Section 6.2 6.3.7. Reduced Efficacy Due to Drug Interactions

Issue The Applicant proposed dose adjustment for lonafarnib when moderate CYP3A inducers are coadministered.

Background Clinical drug-drug interaction (DDI) studies showed that lonafarnib was a sensitive substrate of CYP3A. Lonafarnib exposure (as measured by AUCinf) was increased five-fold by ketoconazole (a potent CYP3A4 inhibitor) (study P00393) and was profoundly reduced by 98% by rifampin (a potent inducer for CYPs including CYP3A) (study EIG-LNF-007). Based on these results, the Applicant proposed contraindications for strong and moderate CYP3A inhibitors as well as strong CYP3A inducers. However, for moderate CYP3A inducers, the Applicant proposed increasing the lonafarnib dose by 50%, based on PK simulations for drug-drug interactions as well as a QTc safety threshold.

Assessment It is expected that coadministered moderate CYP3A inducers would decrease the exposure of lonafarnib and may result in a reduction in the therapeutic effect of lonafarnib. However, the Applicant-proposed dose adjustment (i.e., dose increase by 50%) for lonafarnib in the presence of moderate CYP3A inducers is not adequately supported by the available data as assessed below. The Applicant used a noncompartmental PK analysis for lonafarnib dose adjustments by assuming that there was a single metabolism pathway by CYP3A involved in lonafarnib

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) metabolism. The Applicant simulated lonafarnib exposures at steady state in various dose regimens by increasing the magnitude of induction (i.e., increasing clearance by two- to five- fold) corresponding to 50% to 80% decrease in AUC by moderate induction. However, as discussed in Section 7.7.2 for the CYP2C9 issue, multiple CYPs may be involved in the metabolism of lonafarnib, including CYP3A and CYP2C9 as the primary enzymes. If the contribution of the CYP3A pathway (fmcyp3A) decreases after multiple-dose administrations of lonafarnib, the contribution from other metabolism pathways (e.g., CYP2C9) may also change. In addition, lonafarnib is an autoinhibitor of CYP3A, such that the fmcyp3A to the total clearance of lonafarnib is expected to be different between single- and multiple-dose administrations of lonafarnib. Overall, the Applicant’s simplified PK simulations by changing the clearance of lonafarnib did not take into account the autoinhibition of the CYP3A pathway or the potential interplay between fmcyp3A and fmcyp2C9 following multiple dosing. Therefore, the actual effect of a moderate CYP3A inducer on the PK of lonafarnib could not be reliably characterized by the Applicant’s simplified PK simulations.

In the simplif ied PK simulation, the Applicant selected Cmax as the targeting exposure for lonafarnib dose adjustment in the presence of moderate CYP3A inducers (i.e., increasing clearance by two- to five-fold). As Cmax does not linearly scale with increases in clearance, a lonafarnib dose increase of 50% was selected as it would result in lonafarnib Cmax not exceeding the Applicant-identified QTc safety threshold. However, this QTc safety threshold is not valid for lonafarnib monotherapy due to the limitations of the conducted QT study in which the combination of lonafarnib and ritonavir was administered (see more details in Section 7.7.1 for QT issue). Furthermore, saturable absorption of lonafarnib was observed at doses above 200 mg while the PK of lonafarnib was dose proportional from 25 to 200 mg. At doses greater than 200 mg, lonafarnib exposure in systemic circulation will not be increased proportionally to the dose increment. Instead, the lonafarnib-associated gastrointestinal toxicity may become aggravated when the lonafarnib doses are increased to higher than those studied in the pivotal clinical studies.

Conclusion Coadministration of moderate CYP3A inducers will lower lonafarnib exposures and may result in a reduction in the therapeutic effect of lonafarnib. However, the current data are insufficient in supporting the proposed dose adjustment of lonafarnib (i.e., increasing dose by 50%). The team recommended a labeling for contraindication of concomitant medications that are moderate CYP3A inducers. 6.3.8. Bioavailability of Drug Suspension

Issue The clinical data for the proposed lonafarnib suspension by mixing with orange juice or applesauce were not available in this NDA.

Background The Applicant proposed administering lonafarnib with food in patients with HGPS and PL. In the pivotal clinical studies in HGPS and PL, lonafarnib was administered as an intact capsule

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) with food or as a suspension prepared by dissolving the capsule contents in Ora Blends (i.e., Ora Blend SF® and Ora-Plus®) for patients who could not swallow the capsules. The Applicant proposed additional mixing vehicles (i.e., orange juice and applesauce) to prepare lonafarnib suspension. A clinical study for the relative bioavailabilit y of lonafarnib mixed with applesauce and suspended in orange juice compared with lonafarnib intact capsules is ongoing in healthy subjects following a single-dose administration.

Assessment Both high-fat/high-calorie and low-fat/low-calorie meals decreased the exposure of lonafarnib relative to a fasted state and delayed Tmax. Cmax of lonafarnib was decreased by 55% and 25% and AUC’ was decreased by 29% and 21%, following a high-fat/high-calorie and low-fat/low- calorie breakfast, respectively. The efficacy and safety of lonafarnib have been demonstrated in the pivotal clinical studies (ProLon1 and ProLon2) (see Section 6.2.1.4.2 for details). Intact capsules and suspensions were used interchangeably within the same patients in the pivotal studies. In addition, caregivers were informed that taking food with lonafarnib would help reduce potential gastrointestinal AEs associated with lonafarnib, though this directive was not mandated. In ProLon1, where PK data were collected, large PK variability was observed, which might be due to multiple confounding factors such as sex and food. In the bioavailability study (EIG-LNF- 017), the exposures of lonafarnib were decreased with either high-fat/high-calorie or low- fat/low-calorie meals. Following a single oral dose of 75 mg lonafarnib capsules in healthy subjects, the Cmax and AUC’ were decreased by 55% and 25%, respectively, under high-fat/high- calorie fed conditions and by 29% and 21%, respectively, under low-fat/low-calorie fed conditions, compared to fasted conditions. Based on PK data from ProLon1, there was no evidence indicating lonafarnib capsules and Ora Blend suspensions had differences in PK (Figure 9). Similar exposures between the suspension and capsule were suggested at the 150 mg/m2 dose. While the capsule appeared to have higher concentrations than the suspension at the 115 mg/m2 dose, this is likely due to an unbalanced number of patients with lower trough concentrations (at 0 hr) to the suspension treatment group. These PK data further supported the proposal for both capsules and suspensions since the treatment goal for the indicated patients is to improve long-term survival which is to be achieved by dose titration and long-term treatment with 150 mg/m2.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 9. Mean Lonafarnib Concentration-Time Profile by Dose and Formulation at Steady State, Study ProLon1

Capsule 150 mg/m2 (N=7/2M/5F) Capsule 115 mg/m2 (N=5/3M/2F)

Suspension 150 mg/m2 (N=12/5M/7F)

Source: Figure 20 in Module 2.7.2 Summary of Clinical Pharmacology Studies The proposed mixing vehicles were supported by the in vitro study for the compatibility of the lonafarnib capsule content with each of the proposed mixing vehicles for suspension, including orange juice and applesauce that were not tested clinically (see OPQ Review for details). A study in healthy subjects is ongoing for the relative bioavailability of lonafarnib capsule content mixed with applesauce and suspended in orange juice compared with lonafarnib intact capsule.

Conclusion The overall clinical PK and in vitro compatibility data support that mixing with orange juice or applesauce is unlikely to result in a clinically significant impact on the PK of lonafarnib administered with food. The review team issued a postmarketing commitment to the Applicant to complete the ongoing relative bioavailability study to better inform the pharmacokinetics of lonafarnib capsule content suspended in orange juice or mixed with applesauce. 6.3.9. Meeting the Substantial Evidence Standard for Processing-Deficient Progeroid Laminopathies

Issue Meeting the substantial evidence standard for processing-deficient PL.

Background Literature on patients with processing-deficient PL is scant, in part attributable to the rarity of the condition and the heterogeneous disease course. Prevalence of PL is expected at 1 in 25 million people in the United States (Progeria Research Foundation 2020). PL is categorized as either processing-deficient (which accumulates abnormal farnesylated prelamin A protein, similar to the accumulated progerin in HGPS) or processing-proficient (which does not lead to accumulation of abnormal farnesylated prelamin A proteins). Identification of processing- deficient PL patients for timely enrollment into trials is a challenge. PL patients are exceedingly rare and may not experience the early, severe clinical manifestations seen in young HGPS 52 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) patients, due to heterogeneous manifestation of disease. PL patient lifespan may exceed an HGPS patient’s lifespan. The most common processing-deficient PL, resulting from a variant in ZMPSTE24, a metalloprotease that works downstream of farnesyltransferase, leads to diseases that share features of HGPS. Due to the downstream enzyme defect, PL is characterized by an accumulation of progerin-like protein in the nuclear membrane, resulting in a disease course similar to that of HGPS. Two patients with processing-deficient PL are reported in the literature (Shackleton et al. 2005; Denecke et al. 2006), with early clinical features of poor weight gain, transient ischemic attacks, lipodystrophy, and joint problems. While four patients with processing-deficient PL were enrolled in the treatment trials, only one patient was included in the safety review, as the others either were enrolled during the Triple Therapy study (thus unable to be evaluated for lonafarnib effect alone) or did not meet criteria for processing deficiency. Three of the patients with PL have tolerated lonafarnib for over 10 years, according to the Applicant’s white paper (see Figure 37). The single patient with PL included in the safety review was not included in the efficacy analyses as the agreed-upon efficacy analysis focused on HGPS patients only. Adverse events experienced by this single patient with PL ((b) (6) ) were similar to those commonly seen in patients with HGPS and included vomiting, diarrhea, nausea, hypokalemia, anorexia, infection, and mucositis. The Applicant submitted support for a mechanistic rationale for the similarities between PL and HGPS and their responses to lonafarnib, as per prior agreement with the Agency. This included published findings from in vitro studies on fibroblasts with processing-deficient LMNA or ZMPSTE24 variants, which had morphologic abnormalities similar to those seen in HGPS. The publications noted improvements in morphology with lonafarnib treatment. We also reviewed published findings using a mouse PL model that found a mortality benefit and bone improvements with treatment with another farnesyltransferase inhibitor (Fong et al. 2006a).

Assessment Similarities between processing-deficient PL (LMNA, ZMPSTE24) and HGPS were described in the context of overlapping clinical symptoms. Nonclinical studies described similar disease courses due to progerin-like protein accumulation. Case reports of patients with processing- deficient PL have noted that the level of prelamin A expression, which is then farnesylated, in these patients is correlated with disease severity (Fukuchi et al. 2004; Barrowman et al. 2012). The significance of prelamin A expression here, is that this would be the substrate available for farnesylation, which is defective in processing-deficient PL, and consequently contributes to defect nuclear protein buildup. However, processing-proficient PL patients do not accumulate farnesylated prelamin A proteins and would thus not benefit from treatment with lonafarnib. The Applicant presented a mechanistic rationale for the treatment of processing-deficient PL with lonafarnib through fibroblast studies, which showed improved nuclear blebbing in both HGPS and PL fibroblasts after lonafarnib treatment. See Figure 39 in Section 18. A PL mouse model, with ZMPSTE24 deficiency, demonstrated a survival benefit with another farnesyltransferase inhibitor, a drug in the same class as lonafarnib (Fong et al. 2006a). The PL mouse had features of retarded growth, osteoporosis, and a short life span of 4 to 8 months, compared to wild-type mice that lived longer than 24 months. With farnesyltransferase inhibitor treatment, only 1 of 13 PL mice died by 20 weeks, compared to 6 of 14 untreated PL mice. PL

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) mice were not followed long term, as they were sacrified at 20 weeks to evaluate for skeletal abnormalities. The Applicant also submitted cardiovascular data for patients with PL, in line with their original protocol endpoints. As with prior discussion during the Investigational New Drug (IND) stage, the team communicated to the Applicant in the midcycle meeting that cardiovascular endpoints of pulse wave velocity and intima medial thickness were exploratory for PL and HGPS. The lack of natural history data and limited baseline cardiovascular data for HGPS and PL patients in ProLon1 and ProLon2 made interpretation of those endpoints difficult. Additionally, the Applicant pointed out that PL patients have been on lonafarnib for over 10 years (see Figure 36). These patients were not included in the efficacy analyses due to their participation in the Triple Therapy study. However, the Applicant claimed that these cases demonstrate the survival benefit and tolerabilit y of lonafarnib in patients with PL. Patient # (b) (6) is 21 years old and was enrolled in ProLon1, continued lonafarnib through the Triple Therapy study, received lonafarnib monotherapy after Triple Therapy, participated in the Dual Therapy, and is now taking lonafarnib monotherapy again. The two additional PL patients (#(b) (6) and #(b) (6) ) enrolled in the Triple Therapy study, continued on to lonafarnib monotherapy after Triple Therapy, participated in Dual Therapy, and are now on lonafarnib monotherapy again. However, the lifespan for patients with PL is difficult to determine, due to heterogeneity in progeroid symptom manifestations. Lifespans can be as long as 45 years, as demonstrated by a case report about a Japanese patient with atypical HGPS (Fukuchi et al. 2004).

Conclusion There are very few cases of processing-deficient PL in the literature compared to HGPS. Still, experts acknowledge that the two conditions have overlapping phenotypic features, including cardiovascular events, and similar disease mechanisms as they both involve buildup of faulty farnesylated nuclear membrane proteins, progerin in the case of HGPS and progerin-like proteins in the case of processing-deficient PL. There were three PL patients in the lonafarnib trials who are still alive today, and each has been on lonafarnib for over 10 years. See Figure 36 for details. Processing-deficient PL is exceedingly rare and the review team was not able to match treated patients with PL to untreated patients with PL, and recruitment of PL patients for trials remains a challenge due to heterogeneous disease presentation course. We have concluded that the substantial evidence standard for the population of processing- deficient PL is established based on our findings for HGPS (which is scientifically justified by the similar pathophysiology, mechanism of action, and disease manifestations) together with confirmatory evidence from mechanistic studies showing that fibroblasts from HGPS and PL patients have similar corrections of nuclear morphology with lonafarnib exposures comparable to those achieved in vivo. In addition, the mouse PL model showed a survival benefit when treated with another farnesyltransferase inhibitor.

The vital status of the three enrolled processing-deficient PL patients may lend some support to the efficacy of lonafarnib in this patient population, but this is less certain given the disease heterogeneity.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 7. Risk and Risk Management 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data

Lonafarnib produced renal toxicity in a 6-month oral toxicology study in rats, and toxicity in the male reproductive tract in a 1-year oral toxicity study in monkeys. Marked impairment of male fertility with gross changes in testes was observed in a rat fertility study (reviewed in Section 13.1.3.3.1). Risk issues identified from embryo-fetal developmental toxicity studies are described in Sections 8.4 and 13.1.3.3.2. The overall documentation of the nonclinical program to support the safe use of lonafarnib in clinical development and as an approved drug is summarized here. The nonclinical safety profile of lonafarnib was evaluated in cardiovascular safety pharmacology studies in monkeys, repeated dose oral toxicology studies in rats for up to 6 months and in monkeys for up to 1 year, and genetic toxicology studies (Ames, in vitro chromosomal aberration, and in vivo mouse micronucleus assays). The data from these studies are summarized below.

Cardiovascular Safety Pharmacology

Lonafarnib inhibited the hERG potassium current in mouse L-929 cells (IC50 ȝ0 ~33 times the human Cmax for unbound drug). LRQDIDUQLE XS WR ȝ0 KDG QR VLJQLILFDQW HIIHFWV RQ the action potential in isolated Purkinje fibers from dogs. At 50 mg/kg, intravenous lonafarnib had no effect on the QTc interval in guinea pigs. Lonafarnib also had no effects on electrocardiograms (ECGs) in repeated dose toxicity studies in monkeys (up to 40 mg/kg/day for 1 year). The AUC0-24hr at 40 mg/kg/day in monkeys was approximately four times the human 2 2 AUC0-24hr observed with 150 mg/m BID, the highest recommended dose based on mg/m .

General Toxicology The results of the 6-month oral toxicity study in rats indicated that treatment with lonafarnib (at doses of 30 and 60 mg/kg/day) produced renal toxicity, including necrosis and mineralization in the inner medulla and mononuclear cell infiltrates. The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day. AUC0-24hr at 15 mg/kg/day was 2.31 ȝJ·hr/mL in males and 14.1 ȝJ·hr/mL in females, which are 0.06 and 0.36 times the human AUC0-24hr (39.1 ȝJ·hr/mL) 2 observed with 150 mg/m BID, respectively. The AUC0-24hr at 30 mg/kg/day (lowest-observed- adverse-effect level) was 19.0 ȝJ·hr/mL in males and 46.1 ȝJ·hr/mL in females, which are 0.49 and 1.2 times the human AUC0-24hr, respectively. The results of the 1-year oral toxicity study in monkeys indicated that treatment with lonafarnib resulted in histological changes in the male reproductive tract at all doses (10, 20, and 40 mg/kg/day), and in the eye at 40 mg/kg/day. The changes in the male reproductive tract included aspermia in the epididymis and atrophy of the seminiferous tubules (mild to severe in all males at 20 and 40 mg/kg/day), seminal vesicle, and prostate gland. Histopathological changes in the eyes included single cell necrosis of photoreceptor cells in the layer of rods and cones and the outer nuclear layer of retina (one male and one female). The NOAEL was not identified in males due to effects in the reproductive tract; it was also not identified in females due to reduction in body weight which was considered adverse at all doses. The AUC0-24hr at

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 10 mg/kg/day was 25.2 ȝJ·hrP/ LQ PDOHV DQG  ȝJ·hr/mL in females, which are 0.6 and 0.3 2 times the human AUC0-24hr observed with 150 mg/m BID, respectively. The AUC0-24hr at the lowest-observed-adverse-effect level for ocular toxicity (40 mg/kg/day) was 144 ȝJ·hr/mL 2 (mean for males and females), which is 3.7 times the human AUC0-24hr observed with 150 mg/m BID.

Genetic Toxicology Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.

Carcinogenicity The Applicant will be required to conduct a carcinogenicity study postapproval.

Impurities Lonafarnib impurities and degradation products were qualified by QSAR evaluation and repeat- dose toxicology studies, as described in Sections 13.1.3.1 and 13.2. Based on the dosing instructions (subsection 2.1 of labeling), the maximum daily dose of lonafarnib is 300 mg/day (i.e., 150 mg BID administered to patients with a maximum expected BSA of 1 m2 to achieve the recommended maximum dose of 150 mg/m2 BID). Therefore, the qualification threshold is 0.15% for drug substance impurities based on the recommendations in ICH Q3A(R2) (June 2008), and 0.2% for drug product impurities (degradants) based on the recommendations in ICH Q3B(R2) (July 2006).

Compound (b) (4) (b) (4) The Applicant proposed an acceptance criterion for compound at(b) (4) % in the drug product, which exceeds the qualification threshold of 0.2%. Based on the pro ed limit, the maximum (b) (4) (b) (4) daily dose of compound (b) (4) will be mg/day (or mg/m2). Compound (b) (4) was predicted to be negative in the Ames test by QSAR analysis, and thus can be controlled as a nongenotoxic impurity. No toxicities were observed in a 28-day oral toxicity (b) study in rats with compound (4) doses of 0.368, 0.49, or 0.613 mg/kg/day (test article was a combination of three impurities). The high dose of 0.613 mg/kg/day is approximately 3.7 mg/m2/day, which is ~(b) (4) times the maximum potential human dose ((b) (4) mg/m2/day) at the (b) proposed acceptance criterion. Therefore, the proposed acceptance criterion ((4) % in drug product) for compound (b) (4) s considered acceptable, based on the reasonable assurance of safety from the 28-day oral toxicity study in rats, which was conducted in accordance with ICH guidances for safety testing (qualification) of impurities.

(b) (4)

The Applicant proposed an acceptance criterion for (b) (4) at (b) (4) % in the drug substance, which is higher than the qualification threshold of 0.15%. Based on the proposed limit, the (b) (4) maximum daily dose of (b) (4) will be mg/day (or(b) (4) mg/m2). (b) (4) was predicted to be negative in the Ames test by QSAR analysis, and thus can be controlled as a nongenotoxic impurity. No toxicities were observed in a 28-day oral toxicity study in rats with (b) (4) doses of 0.079, 0.105, or 0.131 mg/kg/day (test article was a

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) combination of three impurities). The high dose of 0.131 mg/kg/day is approximately 0.8 mg/m2/day, which is ~(b) (4) times the maximum potential human dose ((b) (4) mg/m2/day) at the (b) proposed acceptance criterion. Therefore, the proposed acceptance criterion ((4) % in drug substance) for (b) (4) is considered acceptable, based on the reasonable assurance of safety from the 28-day oral toxicity study in rats, which was conducted in accordance with ICH guidances for safety testing (qualification) of impurities.

(b) (4)

7KH GUXJ VXEVWDQFH VSHFLILFDWLRQV LQFOXGH DQ DFFHSWDQFH FULWHULRQ RI (b) (4) ppm for (b) (4) At the maximum recommended dose of lonafarnib (150 mg BID or 150 mg/m2 BID in the target patient population), the maximum dose of (b) (4) will be(b) (4) mcg/day. The qualification of (b) (4) at the proposed limit is supported by the EPA oral reference dose of (b) (4) mg/kg/day in humans. Given the small stature of patients with HGPS or PL, a maximum body weight of 50 kg can be assumed. Based on this assumption and the proposed acceptance limit for (b) (4) , the maximum potential dose of (b) (4) will be (b) (4) mcg/kg/day ((b) (4) mcg/day ÷ 50 kg), which is only a small fraction of the oral reference dose ((b) (4) mcg/kg/day). In summary, the proposed DFFHSWDQFH FULWHULRQ RI (b) (4) ppm for (b) (4) in the drug substance is acceptable, based on support from the analysis described above.

Chiral Impurity The Applicant proposed an acceptance limit for the chiral impurity at(b) (4) % in the drug substance, which is higher than the qualification threshold of 0.15%. Based on the proposed (b) (b) 2 limit, the maximum daily dose of chiral impurity will be (4) mg/day (or(4) mg/m ). No toxicities were observed in a 28-day oral toxicity study in rats treated with chiral impurity doses of 1.055, 1.406, or 1.758 mg/kg/day (test article was a combination of three impurities). The high dose of 1.758 mg/kg/day is approximately 10.5 mg/m2/day, which is (b) (4) times the maximum potential (b) 2 human dose ((4) mg/m /day) at the proposed acceptance criterion. Therefore, the proposed acceptance criterion (b) (4) % in drug substance) for the chiral impurity is considered acceptable, based on the reasonable assurance of safety from the 28-day oral toxicity study in rats, which was conducted in accordance with ICH guidances for safety testing (qualification) of impurities. 7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug-Specific Factors

While lonafarnib is a first-in-class drug, it has been studied for oncology and hepatitis D indications prior to its current study for HGPS and PL. Close to 2,000 individuals (healthy volunteers and patients) have received lonafarnib as part of a study. Safety concerns raised from those studies were gastrointestinal side effects (nausea, vomiting, diarrhea, liver enzyme elevation), some of which may lead to increase in serum creatinine, presumably from intravascular volume depletion. At doses higher than those used for HGPS studies (i.e., 180 mg/m2), bone marrow suppression was seen.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 7.3. Potential Safety Concerns Identified Through Postmarket Experience

Not applicable. Lonafarnib has not been approved in the United States or foreign markets. No postmarketing experience is available at this time. 7.4. FDA Approach to the Safety Review The safety evaluation involved the combined population from ProLon1 and ProLon2 (n=63), which received lonafarnib monotherapy. This included the one PL patient who was not part of the efficacy analysis due to the lack of matching comparator. x ProLon1, n=28: a summary of the ProLon1 study design is found in Section 6.2.1. x ProLon2, n=35: patients who were treatment naïve and enrolled during the lonafarnib monotherapy phase: a summary of ProLon2 study design is found in Section 6.2.1. Submitted datasets were of acceptable quality for review and were adequate to support a safety review. The Applicant identified the main adverse reactions (adverse events with likely causality to lonafarnib, hereafter ARs), which were primarily gastrointestinal intolerances (i.e., vomiting, diarrhea, nausea, weight loss). Hypertension, regardless of causality, was underreported as an AE. This was identified through a review of the vital signs dataset and was later reanalyzed by the Applicant. AEs related to dry eye syndrome were also not initially classified by the Applicant as drug related, likely due to limited information available at the time. Reanalysis of adverse events for the safety population by the review team, disregarding investigator classification, found additional commonly experienced AEs. The review team also searched for toxicities in humans taking into account the toxicity findings in animals. 7.4.1. Reviewer’s Approach to the Safety Evaluation: The review team focused on the 63 patients who received lonafarnib monotherapy, though the Applicant included 21 additional patients who were enrolled in the Triple Therapy study (lonafarnib with pravastatin and zolendronate). Triple Therapy patients were not included in our main safety analysis, as they were on additional study medications to lonafarnib. All analyses represent events that occurred in ProLon1 or ProLon2 (treatment-naïve) patients. Clinical trial data were independently analyzed using JMP and Python software. All safety assessments and conclusions are those of the clinical review team unless otherwise specified. Adverse events were coded according to MedDRA version 22.0. Grading of AE severity was done by CTCAE version 4.03 for ProLon1 and version 3.0 for ProLon2. There are no major discrepancies between the two CTCAE versions. The analysis of general safety—assessment of adverse events, laboratory evaluations, vital signs and electrocardiograms—was based on descriptive summaries and review of source data. In lieu of case report forms, which were not used during the trials, the Applicant submitted patient case narratives that we reviewed for death, investigator-determined causal SAEs, and discontinuations. Further evaluation of severe TEAEs was performed by the review team to assess for additional safety concerns.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) While the Applicant emphasized those adverse events that investigators attributed to drug, we also focused on all treatment-emergent adverse events as the trials were open-label, there is inherent subjectivity in attributing an individual event to drug, and in most cases one cannot definitively rule out a potential drug effect in an individual patient. 7.5. Adequacy of Clinical Safety Database

The safety database was adequate for a sufficient safety assessment of lonafarnib for the proposed indication in the context of a very rare disease. The review team did not identify any major data quality or integrity issues that precluded performing a thorough safety review. No major issues were identified with respect to coding of AEs. Review team evaluation of the AEs and our drug-related causality assessment found differences from investigator classification. Adverse events were regrouped to avoid splitting of related AEs that may minimize reporting rates (e.g., abdominal pain and abdominal pain upper) to facilitate identifying safety signals. See Table 33 for full list of re-grouped terms. Table 18 summarizes the lonafarnib exposure for ProLon1 and ProLon2. Table 18. Duration of Exposure, Safety Population, ProLon1 and ProLon2 Variable ProLon1 (N=28) ProLon2 (N=35) Combined (N=63) Duration of exposure (days) Mean (SD) 778 (134) 743 (317) 759 (250) Median (min, max) 809 (121, 892) 756 (8, 1148) 809 (8, 1148) Patients treated, by duration, n (%) <100 days02 (5.7) 2 (3.2) 100–200 days1(3.6) 1 (2.9) 2 (3.2) 200–400 days 0 2 (5.7) 2 (3.2) 400–800 days8 (28.6) 16 (45.7) 24 (38.1) •800 days 19 (67.9) 14 (40.0) 33 (52.4) Source: adex.xpt; Software: Python Abbreviations: N, number of patients in treatment arm; n, number of patients with given treatment duration; SD, standard deviati on The mean duration of exposure for ProLon1 in the table above differs from that in the Applicant’s clinical study report (CSR) due to differences in the calculation method. The Agency calculated the mean duration of exposure based on duration, total drug prescribed, total drug taken, and percent compliance. The Applicant’s calculation is based on analysis accounting for days the drug was not taken. 7.6. Safety Findings and Concerns Based on Review of Clinical Database

Overall Summary: The demonstrated safety profile of lonafarnib in patients with HGPS is acceptable at the indicated doses. Overall, the most commonly observed ARs were gastrointestinal in nature (vomiting, diarrhea, decreased appetite, nausea, abdominal pain), and these findings were anticipated from antecedent oncology studies with lonafarnib. Cerebral ischemic episodes were reported and categorized as ARs, but they are also a complication of HGPS; it is difficult to parse out any lonafarnib-related effect for these few events, but they are unlikely to be related to lonafarnib, which has shown a survival benefit. Mild liver enzyme elevations were seen in one-third of the patients, but at levels allowing for study continuation.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) In addition to the well accepted ARs above, the reviewer’s safety review identified AEs of special interest. Hypertension was present in one-third of the patients, but as expert opinion accepts this to be a part of HGPS disease course, it was likely underreported. See Sections 7.6.1.7.1 and 7.7.3 for details. Ophthalmic ARs were present, as identified in other lonafarnib studies. See Section 7.6.1.7.3 for details. Transient electrolyte abnormalities were reported in one-fifth to one-third of patients with HGPS. See Sections 7.6.1.7.2 and 7.7.6 for details. Transient myelosuppression was seen as a drop in hemoglobin or low white blood cell count, though not as frequently as reported in oncology studies that used higher doses of lonafarnib. See Section 7.6.1.7.4 for details. In the ProLon1 and ProLon2 trials, cardiovascular events were the most common causes of death and serious adverse events (SAEs); this was an expected finding as this patient population experiences strokes, heart attacks, and heart failure. Gastrointestinal intolerance was seen in more than 80% of the patients, but overall rarely resulted in lonafarnib discontinuation. Many patients were medicated with loperamide to mitigate diarrhea. Trial discontinuations were due to guardian withdrawal of the patient. While not the focus of the safety review, it is noteworthy to mention that 84 patients have been on lonafarnib in ProLon1, Triple Therapy Study (most patients rolled over from ProLon1), and ProLon2. Eight of these patients have tolerated lonafarnib at a dosage of at least 115 mg/m2 twice daily for a decade or longer. 7.6.1. Safety Findings and Concerns, ProLon1 and ProLon2 7.6.1.1. Overall Adverse Event Summary, ProLon1 and ProLon2 Table 19 provides a summary of AEs reported during the duration of the trials, 24-30 months for ProLon1 and 3 years for ProLon2. Of note, there were more frequent study visits and closer follow-up in ProLon1; patients in ProLon1 were seen every 4 months for a total of six visits over 2 years; patients in ProLon2 were seen every 6 months over 3 years. A significant proportion of patients in ProLon1 reported high-grade safety events, in contrast to ProLon2. Table 19. Overview of Adverse Events, Safety Population, ProLon1 and ProLon2 ProLon1 ProLon2 Combined Event Category (N=28) (N=35) (N=63) Any AE 28 (100.0) 34 (97.1) 62 (98.4) Grade 3-4 16 (57.1) 12 (34.3) 28 (44.4) Any SAE 12 (42.9) 12 (34.3) 24 (38.1) SAE with fatal outcome 1 (3.6) 4 (11.4) 5 (7.9) AE leading to discontinuation of study drug 0 3 (8.6) 3 (4.8) AE leading to dose modification of study drug 8 (28.6) 14 (40.0) 22 (34.9) AE leading to interruption of study drug 6 (21.4) 13 (37.1) 19 (30.2) AE leading to reduction of study drug 2 (7.1) 2 (5.7) 4 (6.3) AE leading to delay of study drug 00 0 Source: adae.xpt; Software: Python All values are expressed as n (%).Grading Scale: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.03 for Trials 07-01-0007 and v 3.0 for Trials 09-06-0298 Abbreviations: AE, adverseevent; N, number of patients in treatment arm; n, number of patients with at least one event; SAE, serious adverse event

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The number of SAEs in Table 19 differs from the Applicant’s numbers due to a different algorithm for calculating SAEs. The Agency categorized AEs with severity grade of 3 or above together, whereas the Applicant categorized AEs by maximum grade (i.e., 3, 4, 5). 7.6.1.2. Deaths, ProLon1 and ProLon2 Five patients died during enrollment in ProLon1 and ProLon 2 (Table 20). An additional death in ProLon2 was indentified during the Office of Scientific Investigations (OSI) inspection. See Section 6.3.6 for details. In ProLon1, 28 patients received lonafarnib, and one patient died from stroke. In ProLon2, 35 patients received lonafarnib, and four patients died from cardiovascular events. These deaths were assessed by the investigators and the Applicant as related to complications of the underlying disease and not due to exposure to lonafarnib. As noted previously, lonafarnib has demonstrated a survival benefit. Narratives are provided below. Table 20. Deaths, Safety Population, ProLon1 and ProLon2 ProLon1 ProLon2 Combined Preferred Term (N=28) (N=35) (N=63) Any AE leading to death 1 (3.6) 4 (11.4) 5 (7.9) Myocardial infarction 0 2 (5.7) 2 (3.2) Cerebral ischemia 1 (3.6) 0 1 (1.6) Cardiac failure 0 1 (2.9) 1 (1.6) Death[1] 01 (2.9) 1 (1.6) Source: Review team’s analysis of adae.xpt; Software: Python; CDS Scientist, version 5/21/20. All values are expressed as n (%). All medical terms were spelled in American English. [1] Death alone is noninformative. Abbreviations: AE, adverse event; N, number of patients in treatment arm; n, number of patients with adverse event ProLon1 Narrative of Reported Death (1) A 9-year-old female patient with HGPS (patient #(b) (6) ) experienced a fatal stroke on study day 121. She had a history of transient ischemic strokes, stroke, and ongoing chest pain prior to lonafarnib treatment. She was medicated with clopidogrel, propranolol, nitroglycerin, isosorbide mononitrate, and pravastatin. Fourteen days into lonafarnib treatment, she experienced paresthesias on the right side of her body, which were initially thought to be seizures. Neurologic evaluation diagnosed her with a severe (grade 3) stroke, with left-sided cerebral ischemia. This was not deemed related to treatment and was surprisingly considered a non-SAE. After recovering from the stroke, the patient continued on lonafarnib. She had subsequent clinical signs of stroke: tongue numbness between study days 30 and 60, sleepiness for 2 days with difficulty walking for 3 weeks, and inability to write. She continued on lonafarnib during this time. On study day 121, the patient had a severe stroke that warranted emergent surgery; the patient experienced a subsequent stroke on the same day and died. She was initially on lonafarnib 115 mg/m2 (63.5 mg twice daily) through study day 110, and then 150 mg/m2 (80 mg twice daily) 10 days prior to death. Given precedent history of stroke, her death was not assessed to be related to the study drug by the principal investigator. ProLon2 Narratives of Reported Deaths (1) A 14-year-old female with classic HGPS (patient #(b) (6) ) in the Dominican Republic died from myocardial infarction on study day 229. The initial submitted narrative mentioned no prior cardiovascular disease history or medications at baseline. However, upon receiving FDA’s request for additional medical history, the Applicant subsequently clarified that the patient had evidence of structural heart disease with mild mitral 61 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) regurgitation, tricuspid regurgitation, mild left ventricular hypertrophy (LVH), and mild diastolic left ventricular dysfunction. She experienced mild fatigue and chest pain on study days 173 to 180 before being diagnosed with pericarditis, based on a 24-hour Holter monitor study. There are no further details regarding the pericarditis workup. Additionally, the 24-hour Holter study revealed evidence of paroxysmal supraventricular tachycardia, which persisted until her death on study day 229. The cause of death communicated by the patient’s mother to the clinical study investigators, was cardiac arrest. She received lonafarnib 150 mg/m2 (100 mg in the morning, 125 mg in the evening) through study day 229. The pericarditis and myocardial infarction were assessed to be unrelated to lonafarnib by the principal investigator, given the patient’s underlying history of cardiovascular disease and the understanding that a common cause of HGPS- related death is the progression of cardiovascular disease to cardiac failure, myocardial infarction or arrythmias that may be fatal. (2) An 11-year-old male with classic HGPS (patient #(b) (6) ) in Brazil died from myocardial infarction on study day 337. The patient had a history of significant valvular disease that began 1 year prior to starting lonafarnib. At age 6.5 years, there was an ECG finding of nonobstructive asymmetric septal hypertrophy. At age 9.5 years, cardiac echocardiogram findings were hypertrophic cardiomyopathy with asymmetric obstruction, mitral insufficiency and patent foramen ovale. Evaluation during the ProLon2 trial found significant mitral and aortic stenosis, diastolic left ventricular dysfunction, and prior cerebral ischemia by MRI. For these reasons, the patient was on aspirin. The patient presented to the hospital with chest pain on study day 322 and was diagnosed with non-ST segment elevation myocardial infarction (reported as an SAE). After 5 days, he was discharged with aspirin, atenolol, and isosorbide dinitrate. Coronary CT showed multiple coronary artery lesions, and cardiac echocardiogram showed moderate LVH, mild mitral regurgitation, mild aortic stenosis, and new mild aortic regurgitation. The patient was readmitted to the hospital 9 days after discharge for chest pain, dyspnea, fever, and diarrhea. He was diagnosed with a subsequent non-ST segment elevation myocardial infarction and infectious gastroenteritis. After becoming progressively hypotensive, dyspneic, and hypoxic (requiring continuous positive airway pressure (CPAP) and supplemental oxygen), he died the following day. He was treated with lonafarnib 150 mg/m2 (100 mg twice daily). The myocardial infarctions were assessed to be unrelated to lonafarnib treatment by the principal investigator. (3) A 15-year-old male with classic HGPS (patient #(b) (6) ) in India died on study day 510 from heart failure. He had no significant cardiac history prior to enrollment and was not on concomitant medications. There is an additional mention of candidiasis. On study day 510, the patient was hospitalized for vomiting, dehydration, and difficulty breathing, and was diagnosed with sepsis, metabolic acidosis of pH 7.12, and hyponatremia (serum sodium 121 mEq/L). His lonafarnib dosage was initially 150 mg/m2 (100 mg twice daily), but the dose was reduced to 115 mg/m2 then 90 mg/m2 for development of abdominal pain. The heart failure was assessed to be unrelated to the study drug by the principal investigator, although we note that additional information in the narrative suggests that there may have been another or contributing cause of death (sepsis).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) (4) A 9-year-old male with nonclassic HGPS (patient #(b) (6) ) from Mexico died 22 days after completion of ProLon2. He was enrolled in the subsequent study involving lonafarnib. He had a history of severe cardiovascular and valvular heart disease at baseline, and asthma. On study day 1,122 (20 days after completing ProLon2), the patient was admitted to the hospital with severe respiratory distress and chest pain. ECG showed complete AV block. He was found to be hypoxic and was treated for pneumonia. He died 2 days after admission to the hospital from presumed cerebral ischemia due to severe cardiovascular disease. He was on metoprolol and aspirin. He received 1,102 days of lonafarnib at 150 mg/m2 in ProLon2, then was on the same dosage for 22 days in the subsequent study with everolimus. The cause of death was assessed to be unrelated to lonafarnib by the principal investigator. Based on prior studies, lonafarnib’s target organs of toxicity are: x Gastrointestinal (diarrhea, vomiting, nausea, hypokalemia) x Bone marrow (findings of myelosuppression with neutropenia, anemia, low white blood cell count in oncology studies with higher lonafarnib doses) x Renal (electrolyte abnormalities and urinalysis changes in animal studies) x Eye (retinal toxicity that may cause night vision problems and corneal findings that meet constellation of symptoms of dry eye syndrome) x Testicular (azoospermia in animal studies) No past findings from lonafarnib studies suggest cardiac toxicity or cerebrovascular toxicity. Given the HGPS natural history course, in which patients are expected to have strokes by age 8 and death from myocardial infarction or heart failure by age 14, the stroke and cardiovascular events resulting in death are likely progression of underlying disease particularly given that lonafarnib has been show to reduce the overall risk of death.

7.6.1.3. Serious Adverse Events, ProLon1 and ProLon2 A serious adverse event was defined in the conventional manner, as “any untoward medical occurence, that arises at any dose” and: x Results in death x Is life-threatening x Results in persistent or significant disabilit y/ incapacit y x Is a congenital anomaly or birth defect x Is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization, but based upon appropriate medical and scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed in the definition above x Death, regardless of cause, that occurs within 30 days of last dose of study drug There were 18 SAEs in 12 patients in ProLon1 and 16 SAEs in 12 patients in ProLon2 (Table 21). Several SAEs were related to cardiovascular morbidity, a known sequelae of HGPS.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 21. Serious Adverse Events, Safety Population, ProLon1 and ProLon2 ProLon1 ProLon2 Combined Preferred Term (N=28) (N=35) (N=63) Any SAE 12 (42.9) 12 (34.3) 24 (38.1) Cerebral ischemia 4 (14.3) 2 (5.7) 6 (9.5) Hematoma 3 (10.7) 1 (2.9) 4 (6.3) Myocardial infarction 0 3 (8.6) 3 (4.8) Upper respiratory tract infection 1 (3.6) 1 (2.9) 2 (3.2) Pneumonia 0 2 (5.7) 2 (3.2) Abdominal pain 1 (3.6) 01 (1.6) Alanine aminotransferase increased 1 (3.6) 0 1 (1.6) Aspartate aminotransferase increased 1 (3.6) 01 (1.6) Central nervous system hemorrhage 1 (3.6) 0 1 (1.6) Dehydration 1 (3.6) 01 (1.6) Gait disturbance 1 (3.6) 01 (1.6) Infection 1 (3.6) 0 1 (1.6) Peripheral sensory neuropathy 1 (3.6) 01(1.6) Pyrexia 1 (3.6) 01 (1.6) Bleeding time prolonged 0 1 (2.9) 1 (1.6) Cardiac failure 0 1 (2.9) 1 (1.6) Death 0 1 (2.9) 1 (1.6) Iritis 0 1 (2.9) 1 (1.6) Stomatitis 0 1 (2.9) 1 (1.6) Source: adae.xpt; Software: Python All values are expressed as n (%). Abbreviations: N, number of patients in treatment arm; n, number of patients with adverse event; SAE, serious adverse event Of the 34 SAEs in ProLon1 and ProLon2, 6 SAEs in 5 patients in ProLon1 were assessed to be treatment-related by the investigator (Table 22); none of the SAEs in ProLon2 were assessed as treatment-related by the investigator. Table 22. ProLon1 and ProLon2, Serious Adverse Reactionsas Determined by the Investigator Clinical Investigator Patient Adverse Event Determination (b) (6) ALT increased Related AST increased Related Cerebral ischemia Related Fever Related Dehydration Related Cerebral ischemia Related Source: adae.xpt; Software: JMP 15.1.0

Narratives of the five patients (17.9%) in ProLon1 who experienced the 6 SAEs categorized by the investigator as lonafarnib-related are provided below. Of these, the review team considers four SAEs to be serious ARs.

ProLon1 Narratives of SAEs (1) A 10-year-old male with classic HGPS (patient #(b) (6) ), had initial mild rise in ALT on study day 28, then severe elevation of ALT and aspartate aminotransferase (AST) on study day 56. The ALT value was 202 U/L (approximately 6.7 times the upper limit of normal (ULN)) and AST was 324 U/L (8.1 times the ULN). These values were clarified with the Applicant, as the CSR erroneously cited these ALT and AST values with μkat/L units. Criteria for an SAE of transaminitis (elevated ALT and AST) was defined by Common Terminology Criteria for Adverse Events (CTCAE), with grade 2 criteria being 64 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) >3 to 5 times ULN regardless of whether baseline was normal or abnormal (see Section 7.6.1.6). Additional information provided by the Applicant indicated an intercurrent viral illness prior to day 56, when liver enzymes were elevated. As seen in Table 23, the serum bilirubin remained normal at all timepoints while serum ALT remained mildly elevated from Months 8-24. Table 23. Liver Enzyme Levels, Patient # (b) (6) Enzymes Baseline Month 4 Month 8 Month 12 Month 16 Month 20 Month 24 ALT (U/L) 35 30 49 57 54 52 118 AST (U/L) 35 28 36 39 39 35 45 Bilirubin (mg/dL) 0.3 0.2 0.3 0.2 0.2 0.2 0.2 Source: adlb.xpt; Software: JMP 15.1.0 Reference ranges: ALT 3–30U/L; AST 2–40 U/L; bilirubin 0.3–1.2mg/dl. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase The patient was initially on lonafarnib 115 mg/m2 (85 mg twice daily) through study day 110, with dosage increase to 150 mg/m2 (125 mg twice daily) on study day 111. He was deemed to have tolerated therapy generally well, completed ProLon1, and continued into the Triple Therapy study. After approximately 6.5 years into lonafarnib treatment in the Triple Therapy study, the patient died (see Section 16). This SAE of transaminitis was deemed possibly treatment-related by the investigator. (2) A 10-year-old male with classic HGPS (patient (b) (6) ) had cerebral ischemia on study day 544. At the time of the SAE, the patient had transient dizziness followed by right arm weakness and numbness. Symptoms resolved in under less than 1 hour. MRI showed a bilateral lacunar stroke that was more severe on the left side. A week prior to the SAE, the patient had experienced dizziness, weakness, and loss of balance. He had been taking aspirin, carvedilol, and ezetimibe from baseline. He stopped taking aspirin a few weeks prior to the SAE for nosebleeds, before subsequently resuming aspirin. He was treated with lonafarnib 115 mg/m2 (50 mg twice daily) through study day 111; the dosage was then increased to 150 mg/m2 (70 mg twice daily). This was considered to be possibly treatment-related by the principal investigator, as the patient did not have a prior history of transient ischemic attacks or stroke. The patient’s vital status flow chart was provided to the FDA for mortality benefit evaluation. From the Applicant’s update on December 1, 2019, the review team noted that this patient withdrew from the study approximately 4 years after the SAE, and subsequently died approximately 2 years after study withdrawal. See Section 16 for the patient flow chart. It is not possible to exclude the natural history of the disease as the cause of this patient’s SAE. (3) A 4-year-old female with classic HGPS (patient #(b) (6) ) presented to the emergency room on study day 471 with stomach discomfort and was hospitalized for dehydration and hypokalemia. She received lonafarnib 115 mg/m2 (50 mg twice daily) through study day 111, before dosage increase to 150 mg/m2 (75 mg twice daily). While narrative details that explain possible etiologies for dehydration are limited, this event was concurrent with hypokalemia and hypoglycemia. Upon review of the safety dataset, the review team found that the patient had an AR of diarrhea 1 month prior to the SAE. In the context of the constellation of other ARs listed at this time, the dehydration is plausibly related to the patient’s gastrointestinal intolerances of lonafarnib although there is uncertainty as the timing of the resolution of diarrhea relative to the onset of these SAEs is unclear. 65 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) (4) An 8-year-old female with classic HGPS (patient #(b) (6) ) had cerebral ischemia on study day 433, after experiencing discoloration and cold sensation in both hands and right arm and leg weakness. The patient had a history of three prior strokes (occurring in the year prior to enrollment). She was treated with lonafarnib 115 mg/m2 (60 mg twice daily) through study day 113; the dosage was then increased to 150 mg/m2 (80 mg twice daily). On study day 365, as her lonafarnib formulation changed from capsules to suspension, her dosage was decreased to 75 mg twice daily. It is difficult to evaluate for possible cardiovascular factor changes from lonafarnib use, as the expected natural history of patients with HGPS would have ischemic strokes typically by age 8 (Silvera et al. 2013). On the patient vital status flow chart provided to the FDA for mortality benefit evaluation (Section 16), this patient is shown as deceased after receving lonafarnib treatment for close to 11 years. (5) A 5-year-old female with classic HGPS (patient #(b) (6) ) had a viral infection requiring hospitalization with a fever of 105 degrees, vomiting, and diarrhea. Although this event was assessed as treatment-related by the investigator, the review team concludes that this event was likely not related to the study drug.

ProLon1 For ProLon1, Table 24 lists the patient number with the SAE and the investigator categorization; many of these SAEs were deemed to be unrelated to lonafarnib treatment by the investigator. SAEs in ProLon1 that were not assessed to be treatment-related by the investigator were predominantly cardiovascular related events (e.g., cerebral ischemia, CNS hemorrhage). Table 24. ProLon1 SAEs as Determined by the Investigator Patient SAEs Investigator categorization (b) (6) Hematoma[1] Not related ALT increased Related AST increased Related Cerebral ischemia Related Fever Related Dehydration Related Infection Not related Stomach pain Not related Cerebral ischemia Related Upper respiratory tract infection Not related Sensory neuropathy Not related Cerebral ischemia (two events) Not related CNS hemorrhage Not related Hematoma Not related Gait disturbance Not related Cerebral ischemia Not related Hematoma[1] Not related [1]These patients were taking aspirin 40.5mg daily; platelet counts were normal. Source: adae.xpt; Software: JMP 15.1.0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system; SAE, serious adverse event

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) ProLon2 For ProLon2, Table 25 lists the patient number with the SAE and the investigator categorization. The investigator did not categorize any of the 16 SAE in ProLon2 in 12 patients to be related to lonafarnib. SAEs in ProLon2 were primarily cardiovascular events (e.g., myocardial infarction, cerebral ischemia, cardiac failure); other SAEs had insufficient information or incidence to make a determination of causality or had an alternative explanation.

Table 25. ProLon2 SAEs as Determined by the Investigator Clinical Investigator Patient Adverse Event Determination Additional Comments (b) (6) Myocardial infarction Not related Myocardial infarction Not related Mucositis Not related Drug interrupted Myocardial infarction (death) Not related Pneumonia Not related Drug interrupted Death Iritis Not related Cerebral ischemia Not related Drug interrupted Pneumonia Not related Heart failure (death) Not related Hematoma[1] Not related Myocardial infarction Not related URI Not related Cerebral ischemia Not related Drug interrupted Cerebral ischemia Not related PTT increased Not related [1] Platelet counts were not low. Source: adae.xpt; Software: JMP 15.1.0 Abbreviations: PTT, partial thromboplastin time; SAE, serious adverse event; URTI, upper respiratory tract infection Cardiovascular events were the most prevalent SAEs. Table 25 lists pertinent events by patient ID: myocardial infarctions (3), cardiac failure (1), and cerebral ischemias (2). Mucositis was a SAE. In the review team’s opinion, mucositis is something that may plausibly be drug related, as the drug is taken orally and mucositis is an AE that was reported in four ProLon2 patients ( (b) (6) and in one patient in ProLon1 (#(b) (6) ). One of these patients had neutrophil counts below the lower limit of the reference range around the time of the mucositis AE; the remaining three patients do not have available neutrophil measurements around the time of the mucositis AEs. The mucositis AEs were generally mild or moderate, and patients recovered. However, it is difficult to attribute mucositis to the study drug with certainty. Infections and pneumonia were also reported as SAEs and were deemed not to be related to the study drug (available data for these patients do not show neutropenia). Below are additional comments regarding AEs that would not be expected: Iritis (inflammation of iris of eye) was reported as a grade 4 AE (life-threatening in severity) that was deemed to be not related to treatment. Stomatitis is another term used to describe mucositis (see discussion above). Stomatitis (inflammation of the mouth and lips) was categorized as grade 2 (moderate) in severity with resolution and was classified as not related to treatment. Given other reports of mucositis, this event may be possibly related to drug exposure.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The patient with prolonged bleeding time SAE had cerebral ischemia events 1 month before and 9 days after the prolonged bleeding time event was reported. It may be related to therapies given for cerebral ischemia. Severe TEAEs in ProLon1 and ProLon2 The review team additionally evaluated TEAEs from the standpoint of severe grade with CTCAE •3 for any possible other serious adverse reactions, given the high degree of correlation between severe grade TEAEs and categorization as SAEs. In ProLon1, 16 patients had 46 severe TEAEs. In ProLon2, 14 patients had 24 severe TEAEs. The number of patients who reported at least one severe TEAE was higher in ProLon1 than in ProLon2. In ProLon1, this method identified a high number of cardiovascular events. The relatedness of lonafarnib to these individual cardiovascular events cannot be determined, given that cardiovascular events are expected in the natural history of HGPS, although it is noteworthy that lonafarnib reduces overall mortality. Cerebral ischemia was the most prominent severe TEAE, identified in four patients. If the review team includes the one report of CNS hemorrhage in the same category, it would increase the stroke count to five patients (17.8%). Hematoma was reported in three patients (10.7%), but causality assessment is limited. Additional potential serious ARs identified by this approach were: hypokalemia in three patients (10.7%), diarrhea in two patients (7.1%), ALT increase in two patients (7.1%), and abdominal pain in one patient (3.6%). Laboratory analyses are discussed in Section 7.6.1.6. A brief description of a patient in ProLon1 with seven severe TEAEs follows, as some events were not expected and thus merit consideration as to the possibility of being serious adverse reactions. Patient # (b) (6) had a nonclassic HGPS variant, which has higher mortality than with the classic HGPS variant. In addition to the SAEs listed in Table 24 (CNS hemorrhage, hematoma, and gait disturbance), this patient also had low hemoglobin, hypocalcemia, rash, and pain in the extremities. The gait disturbance SAE date was 6 months after commencing lonafarnib treatment. For this patient, the report date was not associated with other AEs that may help contextualize the circumstance. The CNS hemorrhage occurred over a year later. This patient was able to complete the ProLon1 trial, and was part of the Triple Therapy trial for less than 2 years before death. Gait disturbance was only reported in one other patient (#(b) (6) ) with mild severity. For this patient, the event was reported 4 months after starting lonafarnib treatment. The gait disturbance is described as recovered or resolved and not related to treatment. This patient had concomitant AEs of subluxed hip and pain in limb, which may explain the gait disturbance. The low incidence of gait disturbance, with a likely etiology described in one of the patients, makes it less likely to be a treatment-related although it is not possible to rule out other causes (e.g., minor stroke). Looking at ProLon2, the 24 severe TEAEs were primarily cardiovascular events. There were four patients who died from fatal cardiovascular events (myocardial infarction, heart failure, and death without specific cause, but with history of cardiac valve disorder). The severe TEAEs most commonly reported were: strokes (cerebral ischemia) with 4 events in 2 patients (5.7%) and myocardial infarction with 4 events in 3 patients (8.5%). There were two severe TEAEs for diarrhea and two for abdominal pain, which may be concomitant to gastrointestinal intolerance. The following severe TEAEs were each reported once: valve disorder and heart failure.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Additionally, severe TEAEs possibly related to HGPS disease course were also reported: hypertriglyceridemia (2) and hyperglycemia (1). Other severe TEAEs were likely not related to lonafarnib treatment: pneumonia (without leukopenia), (2), hematoma (with normal platelet counts) (1), gastrointestinal hemorrhage (with normal platelet counts) (1), and seizure (1). 7.6.1.4. Dropouts and/or Discontinuations Due to Adverse Events, ProLon1 and ProLon2 There were no discontinuations in ProLon1. In ProLon2, there were six discontinuations reported due to withdrawal by the parent/guardian, primary investigator, or patient(Table 26). Two withdrawals were due to vomiting (categorized under parent/guardian withdrawal), 1 was a guardian withdrawal (circumstantially for gastrointestinal side effects of weight loss and abdominal discomfort), 2 due to noncompliance with the trial, and 1 was an elective withdrawal (patient had self-discontinued lonafarnib for nausea, weakness, weight loss). One withdrawal (#(b) (6) ) was not counted by the review team because the patient completed the trial. Based on the narratives provided by the Applicant, the review team agrees with the reasons for discontinuation. Table 26. Patient Disposition, Safety Population, ProLon1 and ProLon2 ProLon1 ProLon2 Disposition Outcome (N=28) (N=35) Discontinued study 1 (3.6) 10 (28.6) Death 1 (3.6) 4 (11.4) Primary investigator withdrew patient 0 (0.0) 2 (5.7) Withdrawal by parent/guardian 0 (0.0) 3 (8.6) Withdrawal by patient 0 (0.0) 1 (2.9) Source: Review team based on adds.xpt; Software: R All values are expressed as n (%). Abbreviations: N, number of patients in treatment arm; n, number of patients in specified population or group Table 27 lists the AEs leading to study discontinuation in ProLon2, as provided by the Applicant. Two patients (5.7%) discontinued due to vomiting. Table 27. Adverse Events Leading to Discontinuation from ProLon2, Provided by Applicant Relationship to Drug as

(b) (6) AE Leading to Study Discontinuation Determined by Investigator Bloody vomiting preceding hospitalization for pneumonia Guardian withdrawal from trial Vomiting Not related Guardian withdrawal from study After completing ProLon2 and enrolling in the Related lonafarnib + everolimus study, developed elevated ALT and AST, hyperglycemia (fasting glucose 305 mg/dL), and grade 4 severity hypertriglyceridemia (3235 mg/dL) – baseline triglyceride level was 183 mg/dL. Source: Trial 09-6-0298 Clinical Study Report (Eiger BioPharmaceuticals 2020b) [1] Out of abundance of caution, given the AE occurred within 30 days of completing ProLon2 – the Applicant reported as a discontinuation. Given that the patientcompleted the ProLon2 trial, the review team did not consider this a discontinuation. Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) ProLon2 Narratives of Discontinuations (1) Patient #(b) (6) withdrew from the study for vomiting. The patient was treated with lonafarnib 150 mg/m2 (58.5 mg twice daily). The patient had hematemesis (with normal platelet counts one month prior to the event), followed a month later by hospitalization for pneumonia with recurrent vomiting (study day 423). The patient was instructed to stop lonafarnib (specific reason unavailable), but continued on for 3 days with recurrence of vomiting. Lonafarnib was discontinued, and the patient was withdrawn from the study by the parent. While the narrative cannot exclude the possibility of vomiting-related aspiration pneumonia, this was not a reported sequence of events with other patients. (2) Patient #(b) (6) withdrew from the study for vomiting. The patient was treated with lonafarnib 150 mg/m2 (75 mg in the morning, 100 mg in the evening) and had emesis episodes beginning on study day 1 that progressed from once daily to three times per day. On study day 8, he was given ondansetron to mitigate symptoms without relief. The family requested study discontinuation. (3) Patient #(b) (6) completed ProLon2 and was to continue on Dual Therapy with everolimus; however, the patient had elevated liver enzymes, grade 4 hypertriglyceridemia (serum triglycerides 3235 mg/dL), and hyperglycemia (blood glucose 305 mg/dL). The patient was discontinued from Dual Therapy by the study investigator. This patient had tolerated lonafarnib without these AEs for 2 years in ProLon2. The decision to discontinue was made for safety reasons with concern for exacerbating metabolic changes. Everolimus has been associated with hypertriglyceridemia in the literature (Lai et al. 2019; Sari and Ekenel 2019), and while limited, there is literature on dyslipidemia pertaining to HGPS. Other lamin A diseases are known to have hypertriglyceridemia and hyperglycemia (Özen et al. 2020). Although reported as a discontinuation due to an AE that occurred within 30 days of study completion, the review team considered this patient to have completed the study and did not consider this as an on treatment discontinuation. The patient flow chart provided for vital status update (see Section 16) indicates that four additional patients in ProLon2 (patients (b) (6) discontinued from the study: one withdrawal by the patient, one withdrawal by parent/guardian, and two withdrawals by the investigator (see Table 28).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 28. Discontinuations Not Mentioned by Applicant, ProLon2 Drug Related Determination by Patient AEs Investigator (b) (6) Mild nausea Possibly related Diarrhea Possibly related Diarrhea Related Vomiting Related Fatigue Possibly related Dizziness Possibly related Weight loss (died over a year after withdrawal) Probably related Weakness Not related Vomiting Possible related Anorexia Related Fatigue Related Nausea Probably related Abdominal pain (severe) Related Vomiting Related Weight loss Related Flu-like syndrome Not related Anorexia Related Headache Possibly related Vomiting Related Fatigue Not related Source: adae.xpt Software: JMP 15.1.0 Abbreviations: AE, adverse event The associated AEs were generally mild or moderate and resolving. However, these were not included in the Applicant’s Clinical Study Report with temporal relation explanation. No additional information was available. Vomiting was a common AR with lonafarnib and was the most common cause of discontinuation. However, given the lack of therapeutic alternatives for patients with HGPS, few patients discontinued the study if they were able to tolerate the drug over time. 7.6.1.5. Treatment-Emergent Adverse Events, ProLon1 and ProLon2 The frequency and severity of TEAEs was evaluated in a combination of ProLon1 and ProLon2 trial data to assess the general safety profile of lonafarnib (Table 29). The Applicant defined TEAEs as any AE with onset or worsening of a pre-existing condition on or after the administration of study medication through 30 days following the last dose or any event considered drug-related by the investigator through the end of the study. The review team evaluated the safety dataset (n=63 patients) and assessed frequent AEs to be ARs if there was precedent identification of a safety signal (e.g., ocular AE) from other lonafarnib studies, relevant nonclinical findings, or a plausible mechanism of drug-related AE causality. Approximately one-third to one-half of the trial patients reported a serious AR or an AE of CTCAE severity grade 3 or above. Some AEs, like hypertension, were likely overlooked due to expert opinion that they are part of the natural disease course for HGPS. The review team’s decision to add these AEs was supported by the team’s evaluation of the Applicant’s vital signs dataset and time plot trend. See Section 7.6.1.7.1 for details.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The causality assessment is challenged by the comorbid status of patients with HGPS. Because patients with HGPS are prone to cardiovascular events (e.g., cerebral ischemia, myocardial infarction, heart failure), these AEs inevitably have a high report rate, and it is difficult to evaluate lonafarnib for a possible effect on cardiovascular risk factors. However, it is reassuring that, based on the efficacy analyses, lonafarnib reduces the risk of death. Table 29. Overview of TEAEs, ProLon1 and ProLon2 Subgroups ProLon1 ProLon2 SAE/TEAE (N=28) (N=35) Composite Serious adverse events Applicant derived SAE 18 events (12 patients) 16 events (12 patients) &7&$( VHYHULW\ • GHULYHG SAE 46 events (12 patients) 24 events (14 patients) Adverse reactions (TEAEs) Applicant reported 237 (28 patients) 245 (35 patients) 482 (63 patients) AE leading to study drug 02 discontinuation* AE leading to reduction of dose 2 2 Source: adae.xpt Software: Python *The review team did not include AE leading to interruption of the study drug, as there is often limited information to make a determination of this.Also does not include discontinuations due to withdrawal by the guardian or investigator, although it appears that some of those discontinations were due to AEs. Abbreviations: AE, adverse event; SAE, serious adverse event; TEAE, treatment-emergent adverse event

ProLon1 Two patients had ARs leading to lonafarnib dose reductions (see Table 30 for details). Table 30. Details of ProLon1 Dose Reductions Patient AEs Leading to Dose Reduction (b) (6) Diarrhea, Back pain, musculoskeletal pain Abdominal pain and vomiting, depressed mood Source: Trial 07-01-0007 Clinical Study Report Abbreviations: AE, adverse event

ProLon2

Two patients had ARs leading to lonafarnib dose reductions in ProLon2 (see Table 31 for details). Table 31. Details of ProLon2 Dose Reductions Patient AEs Leading to Dose Reduction (b) (6) Month 12, lonafarnib dose reduced for diarrhea, dizziness, vomiting. Patient had been on 150 mg/m2/day Anorexia (decreased appetite), constipation Patient had been on 150 mg/m2/day, and after brief dose reduction, went back to full dose Source: Trial 09-06-0298 Clinical Study Report Abbreviations: AE, adverse event Table 32 summarizes ARs as defined by trial investigators. To maintain the categorization by the Applicant, the review team has not grouped preferred terms that may customarily be categorized together (i.e., abdominal pain, abdominal pain upper). Terms have been spelled with American English spelling.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 32. Adverse Drug Reactions As Assessed by Investigator, Safety Population, ProLon1 and ProLon2 ProLon1 ProLon2 Combined Preferred Term (N=28) (N=35) (N=63) Any treatment-related AE 28 (100.0) 33 (94.3) 61 (96.8) Diarrhea 25 (89.3) 24 (68.6) 49 (77.8) Vomiting 22 (78.6) 32 (91.4) 54 (85.7) Aspartate aminotransferase increased 18 (64.3) 0 18 (28.6) Alanine aminotransferase increased 14 (50.0) 0 14 (22.2) Nausea 12 (42.9) 12 (34.3) 24 (38.1) Fatigue 11 (39.3) 7 (20.0) 18 (28.6) Decreased appetite 10 (35.7) 16 (45.7) 26 (41.3) Weight decreased 8 (28.6) 9 (25.7) 17 (27.0) Abdominal pain 8 (28.6) 7 (20.0) 15 (23.8) Constipation 8 (28.6) 3 (8.6) 11 (17.5) Upper respiratory tract infection 7 (25.0) 0 7 (11.1) Musculoskeletal pain 5 (17.9) 05 (7.9) Pyrexia 5 (17.9) 05 (7.9) Cough 4 (14.3) 0 4 (6.3) Abdominal pain upper 3 (10.7) 4 (11.4) 7 (11.1) Blood bicarbonate decreased 3 (10.7) 0 3 (4.8) Dehydration 3 (10.7) 03 (4.8) Flatulence 3 (10.7) 03(4.8) Hemoglobin decreased 3 (10.7) 0 3 (4.8) Rash 3 (10.7) 03 (4.8) Back pain 2 (7.1) 02 (3.2) Cerebral ischemia 2 (7.1) 0 2 (3.2) Depressed mood 2 (7.1) 02 (3.2) Epistaxis 2 (7.1) 0 2 (3.2) Hypermagnesemia 2 (7.1) 02 (3.2) Hypokalemia 2 (7.1) 02 (3.2) Infection 2 (7.1) 0 2 (3.2) Pain in extremity 2 (7.1) 02 (3.2) Pruritus 2 (7.1) 02 (3.2) Rhinitis 2 (7.1) 0 2 (3.2) Blood creatinine decreased 1 (3.6) 01 (1.6) Chest pain 1 (3.6) 0 1 (1.6) Chills 1 (3.6) 01(1.6) Dry skin 1 (3.6) 01 (1.6) Dyspepsia 1 (3.6) 0 1 (1.6) Gastroenteritis 1 (3.6) 01 (1.6) Hypoalbuminemia 1 (3.6) 01 (1.6) Hyponatremia 1 (3.6) 0 1 (1.6) Influenza 1 (3.6) 01 (1.6) International normalized ratio 1 (3.6) 0 1 (1.6) Laryngeal pain 1 (3.6) 01 (1.6) Nasal congestion 1 (3.6) 01 (1.6) Oral pustule 1 (3.6) 0 1 (1.6) Oropharyngeal pain 1 (3.6) 01 (1.6) Paresthesia 1 (3.6) 01 (1.6) Perirectal abscess 1 (3.6) 0 1 (1.6) Pneumonia 1 (3.6) 01 (1.6) Sinusitis 1 (3.6) 0 1 (1.6) Skin hyperpigmentation 1 (3.6) 01 (1.6) Tooth fracture 1 (3.6) 01 (1.6) White blood cell count decreased 1 (3.6) 0 1 (1.6) 73 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) ProLon1 ProLon2 Combined Preferred Term (N=28) (N=35) (N=63) Unevaluable event 0 7 (20.0) 7 (11.1) Headache 0 2 (5.7) 2 (3.2) Colitis 0 1 (2.9) 1 (1.6) Dizziness 0 1 (2.9) 1 (1.6) Gastritis 0 1 (2.9) 1 (1.6) Lower gastrointestinal hemorrhage01 (2.9) 1 (1.6) Source: adae.xpt; Software: Python All values are expressed as n (%). Abbreviations: AE, adverse event; N, number of patients in treatment arm; n, number of patients with adverse event CDS Scientist, version 5/21/20 The prevalent ARs experienced by the vast majority of patients were gastrointestinal intolerance symptoms (e.g., vomiting, diarrhea, nausea), which was a known drug effect from antecedent oncology studies. Greater than 80 percent of patients experienced diarrhea or vomiting, and liver enzyme elevations were seen in a quarter of the patients. Decreased appetite (described elsewhere as anorexia) and weight loss were prominent ARs, which were also reported in other studies. Electrolyte abnormalities, such as hypokalemia, were observed in tandem with the gastrointestinal intolerance ARs. Common gastrointestinal ARs were further classified by the Applicant, in relation to severity of symptoms. A total of 57 patients experienced vomiting:30 (53%) patients had mild vomiting (defined as no intervention required), 26 (46%) patients had moderate vomiting (defined as outpatient intravenous hydration; medical intervention required), and 1 (2%) patient had severe vomiting (defined as tube feeding, total parental nutrition, or hospitalization indicated). Of the 35 patients who experienced nausea, 34 (97%) patients had mild nausea (defined as loss of appetite without alteration in eating habits) and 1 (3%) patient had moderate nausea (defined as oral intake decreased without significant weight loss, dehydration, or malnutrition). During the first four months of treatment in Study 1, 19 (68%) patients had vomiting and 10 (36%) patients had nausea. By the end of therapy, 4 (14%) patients who were still on lonafarnib required antiemetics or anti-nauseants. A total of 4 patients discontinued lonafarnib, mostly due to nausea or vomiting. Of the 51 patients who experienced diarrhea, the majority of patients (approximately 92%) experienced mild or moderate diarrhea; 38 (75%) patients reported mild diarrhea (defined as an increase of less than 4 stools per day over baseline) and 9 (18%) patients reported moderate diarrhea (defined as an increase of 4 to 6 stools per day over baseline; limit ing instrumental activities of daily living). Four (8%) patients reported severe diarrhea (defined as an increase of seven or more stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care activities of daily living). During the first four months of treatment in Study 1, 23 (82%) patients had diarrhea; by the end of therapy, 3 (11%) patients had diarrhea. Twelve (43%) patients were treated with loperamide. The review team built on the Applicant-provided ARs table by evaluating the AEs based on prevalence and consideration for previously identified ARs, nonclinical findings, and drug relation plausibility. All ARs listed had an incidence greater than 5% (Table 33). Inclusion of ARs, without regard to the clinical investigator’s classification, yields a slightly higher rate of gastrointestinal intolerances, decreased appetite (anorexia), and weight loss.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 33 $GYHUVH 5HDFWLRQV LQ •RI 3DWLHQWV LQ 3UR/RQ DQG 3UR/RQ1 Based on AE Reports Applicant Initially in Safety Dataset Proposed Adverse Reactions (N=63) (N=63) Gastrointestinal disorders Vomiting 57 (90%) 54 (86%) Diarrhea 51 (81%) 49 (78%) Nausea 35 (56%) 24 (38%) Abdominal pain2 30 (48%) 22 (35%) Constipation 14 (22.2%) 11 (18%) Flatulence 4 (6.3%) 3 (5%) General disorders and administration site conditions Fatigue 32 (51%) 18 (29%) Pyrexia 9 (14.2%) 5 (8%) Infections and infestations Infection3 49 (78%) 2 (3%) Upper respiratory tract infection4 32 (51%) 7 (11%) Rhinitis 12 (19%) 2 (3%) Investigations Decreased appetite (anorexia) 33 (53%) 26 (41%) Electrolyte abnormalities5 27 (43%) Hypermagnesemia 19 (30.1%) 2 (3%) Hyperkalemia 13 (20.6%) Hyponatremia 10 (15.8%) Hypercalcemia 9 (14.2%) Hypokalemia 8 (12.6%) 2 (3%)

Weight decreased 23 (37%) 17 (27%) Myelosuppression6 22 (35%) 3 (5%) Decreased hemoglobin 15 (23.8%) Increased aspartate aminotransferase 22 (34.9%) 18 (29%) Decreased blood bicarbonate 21 (33.3%) 3 (5%) Increased alanine aminotransferase 17 (27%) 14 (22%) Dehydration 3 (5%) 3 (5%) Musculoskeletal and connective tissue disorders Musculoskeletal pain7 30 (48%) 9 (14%) Nervous system disorders Headache 23 (37%) 2 (3%) Cerebral ischemia8 7 (11.1%) 2 (3%) Ophthalmic Ocular changes9 15 (24%) Psychiatric disorders Depressed mood 3 (5%) 2 (3%) Respiratory, thoracic and mediastinal disorders Cough 21 (33%) 4 (6%) Epistaxis 13 (21%) 2 (3%) Skin and subcutaneous tissue disorders Rash 7 (11%) 3 (5%) Pruritus 5 (8%) 2 (3%)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Based on AE Reports Applicant Initially in Safety Dataset Proposed Adverse Reactions (N=63) (N=63) Mucositis 5 (8%) Source: adae.xpt Software: JMP 15.1.0 All values are expressed as n (%). 1 Includes one patient with LMNA heterozygous mutation Progeroid Laminopathy. 2 Abdominal pain includes stomach pain and abdominal pain. 3 Infection includes abdominal infection, candidiasis, chicken pox, Clostridium difficile colitis, colitis, croup, dengue fever, fl u syndrome, flu-like symptoms, fungal infection, gastroenteritis, gastrointestinal infection, Helicobacter pylori infection, infection, infection viral, influenza, nail infection, otitis media, parotitis, perirectal abscess, pneumonia, small intestine infection, submand bular lymphadenitis, tonsillitis, viral infection. 4 Upper respiratory infection includes bronchial infection, bronchitis, sinus infection, upper respiratory infection, upper respiratory infection, upper respiratory tract infection, and upper respiratory tract i nfection. 5 Electrolyte abnormalities includes hypermagnesemia, hypokalemia, hyperkalemia, hyponatremia, hypercalcemia, hypokalemia, hyperphosphatemia, hypocalcemia, and hypernatremia. 6 Myelosuppression includes absolute neutrophil count decreased, low total white blood cells, lymphopenia, decreased hemoglobin, and hematocrit low. 7 Musculoskeletal pain includes arthritis, back pain, bone pain, foot pain, intercostal pain, joint pain, knee pain, leg pain, musculoskeletal pain, pain in ankle/extremity/fingers/hip/leg/limb/lower limbs/left arm, shoulder pain, unilateral leg pain. Excludes musculoskeletal pain for abdomen. 8 Cerebral ischemia includes cerebral ischemia, central nervous system hemorrhage, and ischemia cerebrovascular. 9 Ocular changes include visual acuity change, corneal clouding, conjunctivitis, watering eyes, keratitis. Abbreviations: AE, adverse event; ANC, absolute neutrophil count; WBC, white blood cell The Applicant identified electrolyte abnormalities of hypermagnesemia and hypokalemia as ARs. Hypokalemia AEs were associated with vomiting and diarrhea. The review team’s re- evaluation of AE incidences in patients found rates that were higher than what was initially reported. Thus, the review team recommends including other electrolyte abnormalities (hyponatremia, hypercalcemia, and hyperkalemia) as part of the ARs reported (see Sections 7.6.1.7.2 and 7.7.6). Given previously identified ophthalmic safety concerns (decreased visual acuity/night vision loss) with lonafarnib and the prevalence of ophthalmic AEs in ProLon1 and ProLon2 that may be drug related, the review team recommends including ocular AEs as ARs. See Section 7.6.1.7.3 for details. While myelosuppression was acknowledged by the Applicant to be a drug-related AR in precedent oncology studies (at higher lonafarnib doses of 180 mg/m2), it was not expected for patients in ProLon1 and ProLon2 because lower lonafarnib dosages were administered. The prevalence of myelosuppression related AEs was 23.8% in ProLon1 and ProLon2, though generally resolving and possibly attributable to concurrent viral infections. See Section 7.6.1.7.4 for details. The review team agreed with the Applicant’s AR cutoff of •5% for inclusion in the prescribing information as it captured ARs that occurred in as few as three patients in a sample size of just 63 patients. This cutoff was inclusive of ARs identified in the review team’s independent review of all AEs reported. Additionally, underreported ARs (classified as unrelated by the clinical investigator) of ocular ARs and transient electrolyte abnormalities will be included in the product label. 7.6.1.6. Laboratory Abnormalities, ProLon1 and ProLon2 Overall Summary Laboratory evaluation included hematology laboratories (hemoglobin, neutrophil counts, leukocyte counts, platelet counts), liver enzymes, kidney function, and electrolyte trends. The

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) mean values did not fall outside the reference ranges, and no consistent trends were identified. Patients with HGPS have been reported to have normal hematology laboratories, except elevated platelets, and normal liver enzymes (Merideth et al. 2008). Liver enzyme elevation was observed in some trial patients, though not to the extent meeting concern for drug-induced liver injury. However, drug-induced liver injury can’t be definitively ruled out given the small sample size. The review team performed its own analyses to discern the prevalence, severity, and change of liver enzyme levels over trials, focusing on ALT and AST and searching for Hy’s Law cases. The review team’s analysis focused on patients who had ALT elevation at least 3 times the ULN (grade 2) or higher. Renal function remained normal during the trials, but nephrotoxicity is possible based on the animal studies (see Section 7.7.6). Since causality can not be clearly determined for laboratory abnormalities, a Warning and Precaution was included in the product label with a recommendation to periodically monitor electrolytes (Section 7.6.1.7.2), complete blood counts (Section 7.6.1.7.4), and liver enzymes, and manage abnormalities accordingly.

Hematology Laboratories Twenty-two patients had at least one of the following AEs suggestive of myelosuppression: 19 (30.1%) patients had absolute neutrophil count decreased, 11 (17.7%) patients had lymphopenia, 7 (11.3%) patients had white blood cell count decreased, and 15 (23.8%) patients had decreased hemoglobin. AEs experienced by these patients are discussed in Section 7.6.1.7.4. Mild elevation of platelet counts were found in 24 of 28 ProLon1 patients and 26 of 35 ProLon2 patients.

ProLon1 Figure 10 shows a gradual decline in mean hemoglobin values until month 12, before gradual recovery. Mean hemoglobin values did not fall below the lower reference range of normal. We assessed the extent of low outliers of hemoglobin values, focusing on ProLon1 because ProLon1 collected laboratory studies over 6 study visits, whereas ProLon2 is limited to two laboratory values (baseline and trial completion). Four patients (# (b) (6)) had transient dips in hemoglobin and hematocrit, with recovery. Patient #(b) (6) had normal baseline hemoglobin, with a drop at week 52 to 9.1 g/dL (ref range 11.3-13.4) with gradual recovery. Patient #(b) (6) had low baseline hemoglobin 10.6 g/dL (ref range 11.3-13.4), with gradual recovery. Patient #(b) (6) had a drop in hemoglobin from 11.5 g/dL to 9.4-9.8 g/dL (reference range 11.3-13.4) at week 52 and week 68, before recovery. Patient #(b) (6) had a high baseline hemoglobin value, with subsequent gradual drop in hemoglobin to 11.1 g/dL at week 68 (ref range 11.3-13.4), then 7.7 g/dL at week 84, with some recovery at week 104. In summary, while there may be a transient decline in hemoglobin with lonafarnib treatment, most patients remained within the normal range and patients generally had subsequent improvement in hemoglobin while continuing on treatment.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 10. ProLon1 Patients Mean Hemoglobin (g/L)1 Trend Average Measurements Across Analysis Visit Mean Mean 1.15

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1.08 Baseline Month 4 Month 8 Month 12 Month 16 Month 20 Month 24

Analysis Visit ordered by Analysis Visit (N) (ascending) Source: Review team generated from adlb.xpt Software: JMPClinical 7.1.2 1 Reference range: 11.3-13.4 g/dL Similarly, mean neutrophil count and leukocyte counts for ProLon1 patients were trended over study visits and remained within the normal range (See Figure 11 and Figure 12). There are 12 patients in ProLon1 who developed neutrophil counts below the lower limit of normal (see Table 34). Eight of these patients had baseline neutrophil counts below the reference range (b) (6) ). With the exception of two patients with persisting low neutrophil count for the duration of ProLon1 (# (b) (6) neutrophil counts for these eight patients trended upwards. In addition to evaluating patients with neutrophil counts that fell below the lower limit of normal, we also assessed patients who had significant decreases in neutrophil count from baseline. At week 16, there were 3 patients who had a significant drop in neutrophil count: (b) (6) While these patient did not drop to below the lower limit of normal, the percent drop from baseline was 20-30%, usually around week 16 and 32. Neutrophil counts generally recovered over time despite continued lonofarnib treatment. In summary, there is not an apparent signal for neutropenia with lonafarnib. Table 34. ProLon1 Patients With Low Neutrophil Count (109/L) Reference Patient Range No. (109/L) Baseline Month 4 Month 8 Month 12 Month 16 Month 20 Month 24 (b) (6) 2.58-5.95 3.69 3.12 2.97 2.34 2.98 6.16 3.37 2.58-5.95 3.39 2.99 2.62 2.54 2.73 4.22 5.57 2.77-6.34 1.95 1.92 1.29 - 2.56 1.06 1.58 2.77-6.34 2.05 2.61 2.1 2.65 - 2.43 - 2.49-5.96 4.46 4.25 2.34 3.75 2.75 2.07 2.85 2.29-6.36 2.1 4.07 6.23 2.79 3.5 2.61 4.52 2.29-6.36 1.49 1.48 3.07 2.94 3.76 3.59 4.39 2.58-5.95 2.73 3.31 3.74 1.89 12 4.18 - 2.58-5.95 2.31 3.21 3.26 3.72 3.36 3.32 3.15 2.49-5.96 3.35 2.49 1.96 1.61 2.83 2.21 - 2.58-5.95 1.86 3.69 7.14 3.73 5.1 4.51 4.02 2.29-6.36 1.53 3.06 3.03 5.65 4.13 1.44 2.97 3.04-6.06 2.28 2.54 2.64 3.74 4.34 - 4.7 2.58-5.95 4.15 5.92 5.92 - 3.27 2.27 3.74 Source: adlb.xpt Software: JMP 15.1.0

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Leukocytes were similarly studied. Ten patients had leukocyte counts below the reference range (b) (6) some occurring around week 16 and 32, and others were seen at later visits. However, these generally improved while continuing treatment with lonafarnib. Two patients had a significant change from baseline in leukocyte counts, but in both instances there was a high leukocyte count at baseline that then normalized during the trial (b) (6) Figure 11. ProLon1 Patients Mean Neutrophil Count (109/L)1 Trend Average Measurements Across Analysis Visit Mean Mean 1.9

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Analysis Visit ordered by Analysis Visit (N) (ascending) Source: review team generated from adlb.xpt Software: JMPClinical 7.1.2 1 Neutrophil count reference range: 37-77% Figure 12. ProLon1 Patients Mean Leukocyte Counts (109/L)1 Trend Average Measurements Across Analysis Visit Mean Mean 1.55

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Analysis Visit ordered by Analysis Visit (N) (ascending) Source: review team generated from adlb.xpt Software: JMPClinical 7.1.2 1 Leukocyte count reference range: 5.98-9.88 (109/L) Platelet counts generally stayed within normal or above the reference range, though mean platelet values downtrended at month 12, and again at month 24. There were only two patients with platelet values that fell below the normal reference range. Patient (b) (6) dropped to 166 x 10^9/L (reference range 187-376) at week 68, before recovering. Patient (b) (6) dropped to 169 x 10^9/L (reference range 198-371) at week 32 before recovering. Of note, the recoveries occurred while these patients continued on lonafarnib.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 13. ProLon1 Patients Meant Platelet Count (109/L)1 Trend Average Measurements Across Analysis Visit Mean Mean 2.35

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Analysis Visit ordered by Analysis Visit (N) (ascending) Source: review team generated from adlb.xpt Software: JMPClinical 7.1.2 1 Platelet count reference range: 187-376 (10^9/L)

ProLon2 ProLon2 patients only have two laboratory collections, one at baseline and another at week 104/unscheduled visit. ProLon2 patients maintained mean hemoglobin levels above the lower limit of normal, with some increase at end of therapy. No patients developed hemoglobin values below the lower limit of normal. One patient ((b) (6) ) had a low baseline hemoglobin 10.8 g/dl (reference range 11- 12.8) that recovered to 11.6 g.dL while on lonafarnib. There were no patients in ProLon2 who developed platelet counts below the reference range. Figure 14. Mean Hemoglobin (g/L) trend compared to Lower Limit of Normal for ProLon2 Patients Average Measurements Across Analysis Visit Mean 1.17 Mean

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Analysis Visit ordered by Analysis Visit (N) (ascending) Hemoglobin reference range: 11-12.8 g/dL As shown in Figure 15, mean neutrophil counts for ProLon2 patients also remained within the normal range. There was an upward trend at the end of treatment.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 15. Mean Neutrophil Count (109/L) Trend Compared to Lower Limit of Normal for ProLon2 Patients Average Measurements Across Analysis Visit Mean 1.90 Mean

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Analysis Visit ordered by Analysis Visit (N) (ascending) Neutrophil reference range: 2.58-5.95 x 10^9/L In ProLon2, there were 7 ProLon2 patients with low neutrophil counts (b) (6) ), all but one of whom had the low count at baseline. Those with low baseline counts who had follow-up measurements showed increases into the normal range despite continuing on lonafarnib. Table 35. Low Neutrophil Counts in ProLon2 Patients Baseline Neutrophil Follow-Up Neutrophil Patient # Reference Range Count (109/L) Count (109/L) (b) (6) 2.77–6.34 2.27 None 2.49–5.96 2.31 4.7 2.29–6.36 4.13 1.62 2.49–5.96 1.94 5.88 2.49–5.96 2.08 None 2.49–5.96 2.04 3.09 2.49–5.96 1.69 6.1 Source: adlb.xpt Software: JMPClinical 7.1.2 Neutrophil counts for AEs of infection or pnuemonia were evaluated. Similar ly, for hematoma and gastrointestinal hemorrhage, platelet counts were evaluated. Generally there was no correlation between myelosuppressive AE and AEs involving infections. While AE reported dates did not necessarily correspond to available laboratory studies drawn on trial visits, neutrophil count, leukocyte count, hemoglobin, and platelets were trended for the 22 patients with myelosuppression AE. See Section 7.6.1.7.4 for details.

Liver Enzyme Analyses Patients tended to have elevation of liver enzymes at baseline, with some patients developing further elevation as seen in shifts in severity grade. There were no cases of Hy’s Law. However, given the small sample size of patients, we cannot rule out the possibility of drug induced liver injury. The review team performed analyses of shift tables to evaluate the degree of liver enzyme elevation over the course of treatment. In Table 36 to Table 39, liver enzyme elevations were categorized according to CTCAE version 5.0 grades. As shown below, there were some shifts in

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) serum ALT during treatment with lonafarnib in ProLon1 and ProLon2, particularly for some patients with normal ALT at baseline who developed grade 1 or grade 2 ALT increase postbaseline. Pertinent narratives are provided below. Table 36. Incidence of Grade Shifts in ALT (Increased), Safety Population, ProLon1 ALT (μkat/L) Grade 0 Grade 1 [1]Grade 2 Baseline Toxicity Grade (N=19) (N=7) (N=1) Postbaseline max grade 0 13 (68.4) -- Postbaseline max grade 1 5 (26.3) 6 (85.7) - Postbaseline max grade 2 1 (5.3) 1 (14.3) 1 (100) Postbaseline max grade 3 - - - Postbaseline max grade 4 - - - Source: adlb.xpt; Software: R All values are expressed as n (%). [CTCAE Version 5.0] For AST/ALT, grade 1 was defined as >3x ULN if baseline was normal, 1.5-3.0x baseline if baseline was abnormal; Grade 2 defined as >3.0-5.0x ULN if baseline normal, >3.0-5.0x baseline if baseline abnormal; Grade 3 if >5.0-20.0x ULN if baseline normal or abnormal; Grade 4 if >20x ULN of baseline. 1Total count of patients is 27, as one patient could not be assessed similarly for missing baseline value. Abbreviations: ALT, alanine aminotransferase;N, number of patients within the specified baseline toxicity grade subgroup; n, number of patients with abnormality Table 37. Incidence of Grade Shifts in AST (Increased), Safety Population, ProLon1 AST (μkat/L) Grade 0 Grade 1 Baseline Toxicity Grade (N=20) (N=6) Postbaseline max grade 0 8 (40) - Postbaseline max grade 1 12 (60) 6 (100) Postbaseline max grade 2 - - Postbaseline max grade 3 - - Postbaseline max grade 4 - - Source: adlb.xpt; Software: R All values are expressed as n (%). [CTCAE Version 5.0] Abbreviations: AST, aspartate aminotransferase;N, number of patients within the specified baseline toxicity grade subgroup; n, number of patients with abnormality Table 38. Incidence of Grade Shifts in ALT (Increased), Safety Population, ProLon2[1] ALT (μkat/L) Grade 0 Grade 1 Grade 2 Baseline Toxicity Grade (N=17) (N=14) (N=3) Postbaseline max grade 0 11 (64.7) - - Postbaseline max grade 1 5 (29.4) 12 (85.7) - Postbaseline max grade 2 1 (5.9) 1 (7.1) 3 (100) Postbaseline max grade 3 - 1 (7.1) - Postbaseline max grade 4 - - - Source: adlb.xpt; Software: R All values are expressed as n (%). [CTCAE Version 5.0] [1]Patient(b) (6) n ProLon2had missing baseline ALT value, and thus could not be evaluated in the same manner as the other 34 patients. Abbreviations: ALT, alanine aminotransferase;N, number of patients within the specified baseline toxicity grade subgroup; n, number of patients with abnormality

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 39. Incidence of Grade Shifts in AST (Increased), Safety Population, ProLon2 AST (μkat/L) Grade 0 Grade 1 Baseline Toxicity Grade (N=19) (N=15) Postbaseline max grade 0 12 (63.2) - Postbaseline max grade 1 7 (36.8) 15 (100) Postbaseline max grade 2 - - Postbaseline max grade 3 - - Postbaseline max grade 4 - - Source: adlb.xpt; Software: R All values are expressed as n (%). [CTCAE Version 5.0] Abbreviations: AST, aspartate aminotransferase;N, number of patients within the specified baseline toxicity grade subgroup; n, number of patients with abnormality; Hy’s law analysis did not reveal bilirubin and transaminase elevation patterns that would be concerning for drug-induced liver injury. In Figures 16 and 17, a plot of maximum bilirubin to maximum ALT/AST for ProLon1 and ProLon2 is shown. Figure 16. Hy’s Law Analysis of Patients on Lonafarnib, ProLon1

Source: Clinical Data Scientist group Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BILI, bilirubin; ULN, upper limit of normal

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 17. Hy’s Law Analysis of Patients on Lonafarnib Monotherapy, ProLon2

Source: Clinical Data Scientist group Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BILI, bilirubin; ULN, upper limit of normal

Alanine Aminotransferase For this review, the review team used the ULN of ALT provided by the Applicant, which was 30 U/L. Thirty-four (54%) of ProLon1 and ProLon2 patients had ALT above the reference range. The following analyses breakdown ALT by baseline value and trend ALT for patients who had grade 2 or 3 ALT elevation. From the safety dataset, there were limited ALT data points to fully trend the duration of ALT elevation, but they tended to rise after months of lonafarnib treatment.

Patients With ALT

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) (b) (6) Table 40. ALT Progression for Patient With ALT

Patients With ALT>ULN But <3x ULN (Grade 1) at Baseline In ProLon1, 7 of 27 patients had baseline ALT in the grade 1 category. Six patients remained in this category during the study. One patient (#(b) (6) ) progressed to grade 2 at month 24. A review of the AE list for patient #(b) (6) was notable for a series of elevated ALT AEs: mild elevated ALT (July 25, 2007) followed by severe elevated ALT (August 23, 2007). Subsequently, there was another report of elevated ALT (August 17, 2009), which corresponds to month 24 in Table 42. In addition, patient (b) (6) was described in Section 7.6.1.3 for an SAE based on laboratory tests collected outside of the trial, ALT (ALT 202 U/L) and AST (324 U/L), on study day 56 (August 23, 2007); the Applicant clarified that there was a concurrent viral illness at that time.

Table 42. ALT Trend for Patient #(b) (6) With ALT Elevation to Grade 2, ProLon1 Baseline Month 4 Month 8 Month 12 Month 16 Month 20 Month 24 ALT/ULN 5/24/2007 9/18/2007 1/10/2008 5/29/2008 9/15/2008 1/5/2009 8/24/2009 ALT (U/L) 35 30 49 57 54 52 118 ULN 1.2 1 1.6 1.9 1.8 1.7 3.9 Source: adlb.xpt Software: JMP 15.1.0 Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal In ProLon2, 14 of 34 patients had baseline ALT in the grade 1 category. The majority of patients remained in this category during the study. One patient (#(b) (6) ) progressed to grade 2 (Table 43) and had AEs of hypertriglyceridemia and keratitis reported on July 18, 2017. Elevated ALT and hypertriglyceridemia in some instances may suggest drug-related liver dysfunction, but the patient had been on lonafarnib for 3 years, and there is limited information available to make a causal determination.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 43. ALT Progression for Patient #(b) (6) With ALT>ULN But <3x ULN (Grade 1) at Baseline Baseline Unscheduled ALT/ULN 7/21/2014 7/17/2017 ALT (U/L) 44 125 ULN 1.5 4.2 Source: adlb.xpt Software: JMP 15.1.0 Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal

Patients With ALT >3x ULN at Baseline In ProLon1, there was one patient (#(b) (6) ) who had an ALT greater than three to five times the ULN at baseline. This patient’s ALT remained elevated during the trial (Table 45). For patient #(b) (6) , there were no concurrent AEs reported with the baseline ALT elevation. A few weeks later, on August 22, 2007, the patient had cerebral ischemia. The event was associated with ALT and AST elevation a week later.

Table 44. ALT Progression for Patient #(b) (6) With ALT >3x ULN at Baseline Baseline Month 4 ALT/ULN 8/6/2007 11/27/2007 ALT (U/L) 93 60 ULN 3.1 2 Source: adlb.xpt Reference: JMP 15.1.0 Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal

Aspartate Aminotransfe rase Thirty-eight (60.3%) ProLon1 and ProLon2 patients had AST above the reference range while on treatment with lonafarnib: 15 of 28 patients in ProLon1 and 23 of 35 (65.7%) in ProLon2 (Table 46). Table 45. Laboratory Results for AST and ALT, Safety Population, ProLon1 and ProLon2 ProLon1 ProLon2 Combined Laboratory Test (N=28) (N=35) (N=63) ALT (μkat/L) - increased Any grade (>ULN) 10 (35.7) 23 (65.7) 33 (52.4) Grade 3-4 (>5X ULN) 0 (0.0) 1 (2.9) 1 (1.6) AST (μkat/L) - increased Any grade (>ULN) 15 (53.6) 23 (65.7) 38 (60.3) Grade 3-4 (>5X ULN) 0 (0.0) 0 (0.0) 0 (0.0) Source: adae.xpt; Software: R All values are expressed as n (%). [CTCAE Version 5.0] CDS Scientists, version 6/16/20. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; LLN, lower limit of normal; N, number of patients with relevant laboratory data; n, number of patients with abnormality; ULN, upper limit of normal

AST

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) For Patients With AST>ULN But <3x ULN at Baseline In ProLon1, the 6 patients in this category did not progress to a higher grade during the trial, and AST remained in a similar value range as at baseline. In ProLon2, 15 patients had AST greater than the ULN at baseline and remained in this category during the trial. AST trending for ProLon2 was limited by only one or two laboratory collections during the trial, but of these 15 ProLon2 patients, 10 had subsequent AST laboratory study which retained a similar AST value. (5 ProLon2 patients did not have subsequent AST drawn.)

For Patients With AST >3x ULN at Baseline There were no patients who had AST elevation greater than 3 times the ULN at baseline.

Liver Enzyme Elevation Related ARs The Applicant reported ARs of increased ALT in a total of 14 patients (22.2%) from ProLon1 and ProLon2. Eighteen patients (28.6%) had an AR of increased AST. These ARs were reported within the first 8 months of treatment. Evaluation of the AEs dataset was notable for nine patients in ProLon2 with unevaluable events that mentioned “ALT” or “AST.” These were patients (b) (6) . Their liver enzymes tended to be only slightly above the reference range, which is likely the reason for the unevaluable event categorization. For comprehensiveness, the degree of transaminitis in these patients was trended (Table 47). Generally, there were minor changes in ALT or AST seen, except for one patient who had ALT greater than three times the ULN at completion of the trial. No additional information was available. Table 46. Patients With ALT or AST Greater Than ULN and Adverse Event Categorization as Unevaluable, ProLon2 Patient Baseline ALT Week 104 ALT Baseline AST Week 104 AST (b) (6) 16, 28 (unscheduled) - 3, 52 (unscheduled) - 44 125* 40 71 31 41 44 46 36 44 45 51 57 77 99 68 64 63 42 75 37 43 16 36 29 31 29 100 35 53 Source: adlb.xpt Software: JMP 15.1.0 * 3x ULN Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal

Kidney Function Based on the nephrotoxicity concern from nonclinical studies and transient electrolyte abnormalities seen in trial patients, serum creatinine values were evaluated for an increase in value, as a possible sign of nephrotoxicity. Of note, patients with HGPS and PL are small in size and are not expected to have the same muscle mass as healthy children. Therefore, use of the normal reference range for serum creatinine may not be sensitive for detecting abnormal renal

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) function in these patients and increases in serum creatinine within the normal range could still be concerning for loss of renal function. In ProLon1, mean serum creatinine very slightly trended upward from baseline to month 4, but then dropped; with mean values after week 32 remaining below mean baselines values and well below the upper limit of normal. Figure 18. ProLon1 Creatinine Compared to ULN[1] Average Measurements Across Analysis Visit Mean 0.42 Mean

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Analysis Visit ordered by Analysis Visit (N) (ascending) Source: review team derived from adlb.xpt Software: JMPClinical 7.1.2 [1] Creatinine reference range: 26.52-61.88 umol/L, equivalent to 0.3-0.7 mg/dl One patient had a large increase in serum creatinine (#(b) (6) ) to 0.7 mg/dl (reference range 0.3-1) at week 32 from a baseline of <0.2 mg/dl. After week 32, the serum creatinine trended downwards to 0.4 mg/dl and remained stable, while continuing on lonafarnib. ProLon2 creatinine values were collected at baseline and week 104. Creatinine generally trended upward, but not above the upper limit of the reference range. Additionally, creatinine values were studied for any shifts, but none were found (Table 48 and Table 49). A Grade 1 increase is defined as >ULN to 1.5x ULN. Table 47. Incidence of Grade Shifts in Creatinine (Increased), Safety Population, ProLon1 Creatinine (μmol/L) Grade 0 Baseline Toxicity Grade (N=25) Postbaseline max grade 0 25 (100) Postbaseline max grade 1 - Postbaseline max grade 2 - Postbaseline max grade 3 - Postbaseline max grade 4 - Source: adlb.xpt; Software: R All values are expressed as n (%). [CTCAE Version 5.0] Abbreviations: N, number of patients within the specified baseline toxicity grade subgroup; n, number of patients with abnormality

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 48. Incidence of Grade Shifts in Creatinine (Increased), Safety Population, ProLon2 Creatinine (μmol/L) Grade 0 Baseline Toxicity Grade (N=34) Postbaseline max grade 0 34 (100) Postbaseline max grade 1 - Postbaseline max grade 2 - Postbaseline max grade 3 - Postbaseline max grade 4 - Source: adlb.xpt; Software: R All values are expressed as n (%). [CTCAE Version 5.0] Abbreviations: N, number of patients within the specified baseline toxicity grade subgroup; n, number of patients with abnormality

Electrolyte Trends The most commonly reported electrolyte abnormality TEAEs were: hypermagnesemia (19 of 63 patients), hyperkalemia (13 of 63 patients), hyponatremia (10 of 63 patients), hypercalcemia (9 of 63 patients), and hypokalemia (8 of 63 patients). While study visit laboratory values were not correlated with the reported TEAE, they were trended for characterization of electrolytes with lonafarnib treatment.

ProLon1

Magnesium At baseline, the mean magnesium value exceeded the upper limit of the reference range, as depicted in Figure 19 below. The mean magnesium values were in the normal range at all on- treatment visits. Figure 19. Mean magnesium values in ProLon1 patients Compared to ULN Average Measurements Across Analysis Visit Mean Mean 1.04

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Analysis Visit ordered by Analysis Visit (N) (ascending) Source: adlb.xpt Software: JMPClinical 7.1.2 Magnesium reference range: 0.62-0.9 mmol/L Twenty-four ProLon1 patients transiently had above reference range magnesium values (b) (6)

. Elevated magnesium tended to be transient, over 1 or 2 study visits, with resolution on continued lonafarnib treatment.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Potassium Mean potassium laboratory values over time are shown in Figure 20. There appears to be a downward trend of mean potassium values while on treatment with lonafarnib with mean values remaining within the normal range. Figure 20. Mean Potassium Values in ProLon1 Patients Average Measurements Across Analysis Visit Mean Mean 4.15

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Analysis Visit ordered by Analysis Visit (N) (ascending) Source: adlb.xpt Software: JMPClinical 7.1.2 Potassium reference range 3.2-4.5 mmol/L Hyperkalemia was seen in 10 patients (b) (6) ) with potassium 4.52-5.02 mmol/L (reference range 3.2-4.5). These findings tended to be 1-2 visit findings (e.g. week 32, 52), with resolution while continuing treatment with lonafarnib. Hypokalemia was seen in 3 patients (b) (6)) usually at a later visit (week 68, 84), with potassium values ranging 2.71-3.04 mmol/L. Hypokalemia tended to resolve while patients continued on lonfarnib. In hypokalemia AR reporting, concomitant vomiting or diarrhea was often seen.

Sodium Mean serum sodium values in ProLon1 patients are shown over time in the figure below. There appeared to be a downward trend for serum sodium over time with mean values remaining in the normal range. There are individual variabilities, transiently falling below normal and then recovering while on treatment with lonafarnib.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 21. Mean Sodium Values in ProLon1 Patients Average Measurements Across Analysis Visit Mean Mean 138.0

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Analysis Visit ordered by Analysis Visit (N) (ascending) Source: adlb.xpt Software: JMPClinical 7.1.2 Sodium reference range: sodium, reference range is 135-148 mmol/L Eleven ProLon1 patients (b) (6) had mildly low sodium values, with sodium 131-134 mmol/L (reference range 135-148). These tended to occur at visit week 32 or 52 and resolved with continued treatment of lonafarnib. There were no sodium values that exceeded the upper limit of the reference range.

Calcium Mean serum calcium values over time for ProLon1 are shown in the figure below. There was an uptrend seen at week 52, before recovery while continuing on lonafarnib. Figure 22. Mean Calcium Values in ProLon1 Patients Average Measurements Across Analysis Visit Mean 2.58 Mean

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Analysis Visit ordered by Analysis Visit (N) (ascending) Source: adlb.xpt Software: JMPClinical 7.1.2 Calcium reference range: 2-2.625 mmol/L Seven ProLon1 patients had transient hypercalcemia (# (b) (6) ); six of these patients had slightly above reference range values of 2.55-2.63 mmol/L (reference range 2-2.625 mmol/L) or 10.5-11.4 mg/dL (reference range 8-10.5 mg/dL). Two subjects (b) (6)) had hypercalcemia at baseline. All others tended to have hypercalcemic labs between week 32, 52, and 68 visits. One patient ((b) (6) ) has a calcium value of 20.3 mg/dl at week 52, which is driving up the trend in the mean calcium time plot below. Patient (b) (6) did

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) not have other laboratory abnormalities or a report of an AE that could explain the hypercalcemia at the week 52 visit raising the likelihood of a lab error. Table 49. Patient #(b) (6) Calcium Values Over Study Visits Baseline Week 16 Week 32 Week 52 Week 68 Week 84 Week 104 Calcium 10.3 9.7 9.5 20.3 10 9.3 10 (mg/dL) [8-10.5] Albumin 4.4 4.4 4.2 4.6 4.7 4.4 4.8 g/dL [3-4.6] Source: adlb.xpt Software: JMP 7.1.2

ProLon2 As there were few laboratory studies collected in ProLon2,with just one or two values, it was not meaningful to graph time trends.

Magnesium There were 3 ProLon2 patients (# (b) (6) with magnesium levels of 2.1-2.4 mg/dl, which is above the upper limit of the reference range (1.5-2.2), at the followup visit. There were no other magnesium laboratory values for these patients.

Potassium There were 7 ProLon2 patients (# (b) (6) with hyperkalemia, ranging from 4.58-5.46 mmol/L (ref range 3.2-4.5). There were no additional potassium values for these patients to trend. There were no low potassium values.

Sodium Two ProLon2 patients (b) (6) had sodium level below normal reference range, both with sodium 132 mmol/L (135-148). There were no additional sodium levels.

Calcium Calcium values were generally in the normal range, except for one ProLon2 patient (b) (6) with calcium 10.6 mg/dl (8-10.5) at the followup visit. Baseline calcium was 9.4 mg/dl and normal for this patient. 7.6.1.7. Adverse Events of Special Interest, ProLon1 and ProLon2 The purpose of this section is to provide a more detailed discussion regarding adverse events of special interest that were observed in the lonafarnib trials. 7.6.1.7.1. Hypertension and ECG Changes, ProLon1 and ProLon2 Review of the vital signs dataset in addition to the Applicant’s summary of safety identified hypertension as an under-reported adverse event in ProLon1 and ProLon2. Comparing to height- matched normal blood pressure reference ranges, one-third of HGPS patients in the pivotal trial had hypertension. Comparison of survivors to deceased HGPS patients’ blood pressures found a

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) correlation of sustained hypertension or increase in systolic blood pressure and likelihood of death. See Section 7.7.3 for details. As pediatric patients may have high heart rates, the vital signs dataset was evaluated with tolerance of heart rates above 100 beats per minute (bpm). Of note, three patients had heart rates above 140 bpm, but these patients’ heart rates were unrevealing for any persisting tachycardia over their study visits. ECG data were provided in a datasheet format; the review team primarily relied on the Applicant for interpretation of the tracings. ECGs were performed every 4 months in ProLon1 and only at baseline and end of therapy for ProLon2 unless there was a cardiac indication to perform an ECG in the interim. The Applicant reported that there were ECG abnormalities in 30% of the patients at baseline and 19% of patients at the end of therapy. The most common finding was left ventricular hypertrophy (LVH), which is not surprising given that hypertension is accepted as a part of the HGPS disease course and is the leading cause of cardiac remodeling in children. The Applicant noted LVH in 6 (9.5%) patients at baseline and in an additional 7 (11.1%) patients during the trials. At the end of treatment, a total of 5 (7.9%) patients in ProLon1 and ProLon2 (N=63) had LVH. A past publication on LVH in ProLon1, prior to lonafarnib treatment, mentioned that LV mass remained significantly higher than normal despite correction for body mass composition in patients with HGPS. The LV dysfunction was also progressive and the prevalence increased with age in HGPS patients without treatment (Prakash et al. 2018). QTc prolongation was defined as • VHF LQ PDOHV and • sec in females. Forty patients had a • VHF LQFUHDVH LQ 47F IURP EDVHOLQH IRU 47F% RU 47F). The majority of these patients had these QTc interval increases identified on more than one study visit. The Applicant provided QTc prolongation statistics based on Bazett and Fridericia formulas (Table 51 and Table 52). The Bazett formula was rationalized to be the better formula for pediatric patients who may have faster heart rates. There were no reports of lonafarnib discontinuation or dose reduction for QTc prolongation concerns, and no patients had QTcB or QTcF •500 msec. See Section 7.7.1 for a discussion of the completed thorough QT study, which is not adequate to assess the risks of QT prolongation with lonafarnib and Section 22 for a summary of the required postmarketing trial for a new thorough QT study.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 50. Potentially Clinically Significant ECG Findings (QTcB) 1 of 2

Table 51. Potentially Clinically Significant ECG Findings (QTcF) 2 of 2

7.6.1.7.2. Electrolyte Abnormalities The Applicant based the electrolyte AR reporting on investigator-determined causality with inclusion of some instances of hypermagnesemia and hypokalemia. A review of AEs for the 63 patients in the pivotal trials, however, noted many more AEs of electrolyte abnormalities (e.g., hyperkalemia, hyponatremia, or hypercalcemia). Though not temporally correlated in time to the reported electrolyte abnormality AEs, we also reviewed electrolyte laboratory data collected during trial visits to assess for persistence of effects or trends (see Section 7.6.1.6). Hypermagnesemia was reported twice by the investigator to be possibly related to lonafarnib. A review of all AEs noted 19 (30.1%) patients with a hypermagnesemia AE. Typically these were described as mild and resolved.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Hypokalemia was reported twice by the investigator to be possibly related to lonafarnib. A review of all AEs noted 8 (12.6%) patients with a hypokalemia AE. More than half the hypokalemia AEs were temporally associated with vomiting, dehydration, or infection (upper respiratory infection). Additional AEs of electrolyte abnormalities not mentioned in the Applicant’s AR table were hyperkalemia, hyponatremia, and hypercalcemia. Hyperkalemia was reported as an AE in 13 (20.6%) patients. Hyponatremia was reported as an AE in 10 (15.8%) patients. Hypercalcemia was reported as an AE in 9 (12.6%) patients.. There is limited literature on electrolyte abnormalit ies in HGPS. However, changes in the inner nuclear membrane, where progerin inserts, could lead to alterations in calcium signaling through interference of a muscle A-kinase anchoring protein, a scaffold protein for cAMP and calcium signaling (Burke and Stewart 2002). Since causality can not be clearly excluded, a Warning and Precaution for laboratory abnormalities was included in the product label with a recommendation to periodically monitor for changes in electrolytes.

7.6.1.7.3. Ophthalmic Adverse Reactions Safety concerns are additionally informed by other lonafarnib clinical trials. In the Applicant’s hepatitis D trial with lonafarnib, 10% of study patients experienced ophthalmic AEs, which were primarily changes in visual acuity. Review of the ProLon 1 and ProLon2 safety datasets was notable for 15 patients with 17 ophthalmic AEs. Fourteen of these, including keratitis (6), watering eyes (3), visual acuity change (2), corneal clouding (1), conjunctivitis (2), may be consistent with symptoms of dry eye syndrome, and the review team assessed them as likely drug related. These ophthalmic ARs were generally mild/moderate and resolved. The other three ophthalmic AEs included conjunctival hemorrhage, corneal injury, and iritis.

7.6.1.7.4. Myelosuppression Past oncologic studies with high dosages of lonafarnib (>180 mg/m2/day) have identified myelosuppressive side effects. In these studies, lonafarnib was administered at 70, 90, 115, 150, and 200 mg/m2/dose twice daily. Myelosuppression was observed at the 200 mg/m2/dose level (Kieran et al. 2007b). Though the Applicant concluded that myelosuppression was not observed among patients with HPGS in ProLon1 and ProLon2, there were transient dips in hemoglobin, neutrophil count, and lymphopenia reported as AEs. The review team found 15 of 63 (23.8%) patients with TEAEs for decreased hemoglobin. This contrasts with the Applicant’s reported number of 3 (5%), which only included AEs classified by the clinical investigator to be related. In addition, 19 of 63 (30.2%) patients had AEs of low absolute neutrophil count (ANC), lymphopenia, and low total WBC count. The AEs for patients with transient myelosuppression were evaluated by the review team for possible intercurrent events, such as viral infection that may explain the findings. In approximately one-half of the myelosuppressive AEs, there was a temporally related infection (e.g., upper respiratory infection). It is not possible to determine whether low WBCs and neutrophil counts precipitated these infections or resulted from these infections. In addition, in

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) the other half of cases, no explaination for the low counts was identified. See Table 53 for details. Therefore, a possible drug effect can not be excluded. We have also reviewed the laboratory data obtained at clinic visits and, while we cannot exclude an effect of the drug on some laboratory parameters, there do not appear to be clinically significant changes and in many instances the laboratory parameters improve while continuing on lonafarnib (see Section 7.6.1.6). In addition, it is unclear the extent to which these changes in laboratory parameters are attributable to HGPS itself. Since causality can not be clearly excluded, a Warning and Precaution for laboratory abnormalities was included in the product label with a recommendation to periodically monitor for changes in complete blood counts. Table 52. Myelosuppressive AEs by Patient, Any Intercurrent Events Myelosuppressive Intercurrent Events That May Patient Eve nt Count Mye losuppressive AE AE Da te Explain Myelosuppression (b) (6) 10 Low hemoglobin 5/17/2007 No Low ANC 6/7/2007 No Low hemoglobin 6/7/2007 No Low hemoglobin 9/27/2007 No Low hemoglobin 1/17/2008 No Low hemoglobin 2/14/2008 No Low hemoglobin 3/14/2008 No Low hemoglobin 4/10/2008 No Low ANC 5/21/2008 No Low hemoglobin 7/31/2008 No

3 Low total WBC 8/28/2007 Viral infection 8/3/2007 Low ANC 5/21/2008 No Low total WBC 5/21/2008 No

2 Lymphopenia 1/3/2008 Infection 12/5/2007 Thrombocytopenia 9/8/2008 No

4 Low hemoglobin 5/30/2007 No Low ANC 7/20/2007 No Low total WBC 7/20/2007 No Low ANC 8/18/2008 No

11 Low hemoglobin 6/13/2007 URI 6/7/2007 to 9/24/2007 Low hemoglobin 6/20/2007 URI 6/7/2007 to 9/24/2007 Low ANC 6/28/2007 URI 6/7/2007 to 9/24/2007 Low hemoglobin 6/28/2007 URI 6/7/2007 to 9/24/2007 Low total WBC 6/28/2007 URI 6/7/2007 to 9/24/2007 Low hemoglobin 8/1/2007 URI 6/7/2007 to 9/24/2007 Low hemoglobin 8/29/2007 URI 6/7/2007 to 9/24/2007 Thrombocytopenia 1/15/2008 No Low hemoglobin 6/30/2008 No Lymphopenia 9/22/2008 No Low hemoglobin 12/1/2008 URI 10/22/2008 2 Low ANC 6/27/2007 No Low total WBC 8/31/2009 No

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Myelosuppressive Intercurrent Events That May Patient Eve nt Count Mye losuppressive AE AE Da te Explain Myelosuppression (b) (6) 5 Low total WBC 10/23/2007 No Low ANC 11/4/2008 URI 11/3/2008 Lymphopenia 11/4/2008 URI 11/3/2008 Low ANC 2/18/2009 Infection 2/18/2009 Low total WBC 2/18/2009 Infection 2/18/2009 2 Low hemoglobin 8/7/2007 No Low ANC 3/19/2008 Infection 1/24/2008 3 Low hematocrit 7/6/2007 No Low hemoglobin 7/13/2007 No Low ANC 10/9/2007 URI 8/13/2007

1 Lymphopenia 2/21/2008 URI 2/22/2008 2 Low hemoglobin 7/9/2007 No Low ANC 2/2/2009 No

5 Low ANC 7/25/2007 No Lymphopenia 4/2/2008 No Low ANC 6/25/2008 No Low hemoglobin 6/25/2008 No

3 Low hemoglobin 11/15/2007 No Low hemoglobin 4/30/2008 URI 2/12/2008 Low hemoglobin 3/2/2009 URI 2/20/2009

3 Low hemoglobin 8/1/2007 No Low hemoglobin 1/9/2008 No Lymphopenia 4/4/2008 URI 3/3/2008 2 Lymphopenia 11/20/2007 Sinus infection 10/3/2007 Low ANC 3/11/2008 URI 2/18/2008

2 Low hematocrit 8/23/2007 No* Cerebral ischemia AE 8/22/2007 Low hemoglobin 8/23/2007 No* Cerebral ischemia AE 8/22/2007

4 Low hemoglobin 11/25/2008 No Low hemoglobin 3/17/2009 No Lymphopenia 3/17/2009 No Low hemoglobin 8/31/2009 No

1 Lymphopenia 6/20/2008 No 2 Low hemoglobin 2/28/2008 No Lymphopenia 3/16/2009 Infection 3/10/2008

1 Low hemoglobin 8/29/2007 No 3 Low hemoglobin 5/6/2008 Infection 4/14/2008 Lymphopenia 5/6/2008 Infection 4/14/2008 Low hemoglobin 8/21/2008 No

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Myelosuppressive Intercurrent Events That May Patient Eve nt Count Mye losuppressive AE AE Da te Explain Myelosuppression (b) (6) 6 Low hemoglobin 11/14/2007 No Low hemoglobin 4/9/2008 No Low hemoglobin 12/3/2008 Infection 12/1/2008 Low hemoglobin 2/10/2009 Infection 12/1/2008 Low ANC 6/8/2009 No Low total WBC 6/8/2009 No Source: adae.xpt Software: JMP 15.1.0 Abbreviations: AE, adverse event; ANC, absolute neutrophil count; URI, upper respiratory infection; WBC, white blood cell 7.7. Key Review Issues Relevant to Evaluation of Risk 7.7.1. QTc Safety Assessment

Issue The Applicant has not evaluated the effect of lonafarnib monotherapy on QT interval prolongation in the current NDA submission.

Background The Applicant conducted a Thorough QT (TQT) study (EIG-LNF-010, a double-blind, randomized, placebo- and active-control, parallel-group study with nested crossover design in healthy subjects) with lonafarnib in combination with ritonavir at two dose levels for 5 days, lonafarnib 50 mg and ritonavir 100 mg BID, and lonafarnib 100 mg and ritonavir 100 mg BID. Lonafarnib is primarily eliminated by hepatic metabolism (mostly by CYP3A) and its exposure is increased by the concomitant ritonavir that is a strong CYP3A inhibitor. The Applicant predicted the QT effect of lonafarnib monotherapy based on the exposure-response analysis using data from study EIG-LNF-010. There was no TQT study conducted with lonafarnib alone.

Assessment The QT assessment based on study EIG-LNF-010 is inadequate to assess the effect of lonafarnib monotherapy on the QT interval due to the following limitations: x No lonafarnib monotherapy assessed in the TQT study. A lonafarnib alone arm was not included in the study; therefore, the effect of lonafarnib as a monotherapy on the QTc interval cannot be assessed directly. x Uninterpretable exposure-response analysis results. In study EIG-LNF-010, the ritonavir dose remained the same at 100 mg and, based on prior experience with ritonavir, the QT effect by ritonavir at this dose is expected to be minimal. The Applicant’s concentration- QT analysis included both ritonavir and lonafarnib concentrations and suggested a QT shortening effect with higher ritonavir exposures (negative slope) which is contradictory to the prior experience with ritonavir. When ritonavir concentration was not included in the concentration-QTc analysis, the model suggested a statistically significant intercept for lonafarnib, which is not biologically plausible (i.e., no effect would be expected without exposure) and is inconsistent with the primary model assumption that there would be no QT effect of ritonavir at the studied dose level in the combination setting. 98 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Therefore, it is not reasonable to use the model to predict lonafarnib effect in the monotherapy setting. Consequently, the QT safety threshold identified through this model is not acceptable. Refer to the Interdisciplinary Review Team for Cardiac Safety Studies review for more details (FDA 2020). x Potentially inadequate exposures to major metabolites. It is unclear whether the exposures to the major metabolites of lonafarnib (HM17 and HM21) in the completed TQT study with the combination of lonafarnib and ritonavir are adequate to cover the therapeutic exposures of the metabolites in lonafarnib monotherapy. In general, when parent drug exposures at a lower dose are boosted by its metabolic inhibitor to achieve comparable parent drug exposures at a higher dose without the coadministered inhibitor, the exposures of metabolites at the lower dose are lower than those at the higher dose. The sponsor has not provided data regarding the effect of major metabolites (HM17 and HM21) in the hERG assay. Therefore, despite achieving comparable lonafarnib exposures by the inhibitor (ritonavir) boosting, the exposures to the major metabolites in the completed TQT study with the combination of lonafarnib and ritonavir could be lower than those when lonafarnib was administered alone.

Conclusion The completed study EIG-LNF-010 is inadequate to assess the QT prolongation risks for lonafarnib monotherapy. The review team is requesting a postmarketing requirement to conduct a thorough QT/QTc study with lonafarnib alone to evaluate the effect of lonafarnib on the QT interval prolongation. We are requiring a postmarketing thorough QT/QTc study rather than another pre-approval study so as not to delay access to this drug that has shown a survival benefit for a rare, serious condition with no other approved treatments.

7.7.2. Adverse Reactions Due to Drug Interactions

Issue The drug-drug interaction (DDI) potentials of CYP2C9 inhibitors on the PK of lonafarnib were not adequately addressed.

Background The in vitro rhCYP method identified that CYP3A and CYP2C9 were the major enzymes involved in lonafarnib metabolism, with fm contribution of 43% and 32%, respectively (report SN98277). However, the results in human liver microsomes (HLMs) showed that CYP3A was the major metabolic pathway of lonafarnib with fm contribution of 86% and CYP2C9 had only minor contribution.

Assessment The role of the CYP2C9 pathway in lonafarnib metabolism is unclear based on the available data. The Applicant did not adequately address the inconsistent results obtained from in vitro DDI studies using the rhCYP and HLMs methods. The Applicant claimed that the results in HLMs would be more accurate than those in rhCYPs because HLMs reflect liver CYP enzyme abundance in the human liver. However, after taking into account the individual enzyme

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) abundance in the liver by applying the average CYP abundance in HLMs (50 to 96 pmol/mg protein for CYP2C9 and 108 pmol/mg protein for CYP3A4) (Rodrigues 1999; Rowland Yeo et al. 2004; Zhang et al. 2007) to the rhCYP method, the review team recalculated fmCYP2C9 contribution in rhCYPs method to be between 44 and 47%, which is greater than the Applicant’s reported 32%. Nevertheless, both the Applciant’s and the FDA’s calculation suggested fmCYP2C9 greater than 25% based on the rhCYP study. In addition, the boosting effect on lonafarnib exposure by ritonavir cannot exclude the possibility of CYP2C9 contribution to lonafarnib metabolism. The cross-study comparison (studies P00939 and EIG-LNF-007) showed that lonafarnib exposure increased 13-fold with ritonavir 100 mg coadministration. Ritonavir, as a CYP3A4 inhibitor and an inducer of CYP2C9, could increase lonafarnib exposure through CYP3A inhibition while decreasing lonafarnib exposure by CYP2C9 induction. Note that the CYP2C9 induction effect by ritonavir is dose dependent and the induction at 100 mg is weak, which may explain the overall boosting effect of ritonavir by strong CYP3A inhibition. Because ritonavir is a weak CYP2C9 inducer at the 100-mg dose, a significant contribution of CYP2C9 to lonafarnib metabolism cannot be excluded. Furthermore, the CYP2C9 contribution could be higher after multiple doses of lonafarnib than after single doses because lonafarnib is a strong CYP3A inhibitor which will inhibit the CYP3A metabolizing pathway of itself following multiple dose administration. The potential consequence of this strong autoinhibition of CYP3A could be that the effect of a CYP2C9 inhibitor becomes larger and the effect of a CYP3A inhibitor becomes smaller comparing to their effects on the PK of lonafarnib following a single dose administration.

Conclusion Since CYP2C9 could be a major potential enzyme involved in lonafarnib metabolism as aforementioned, lonafarnib exposures could be increased when CYP2C9 inhibitors are coadministered. However, the DDI potential of CYP2C9 inhibitors on the PK of lonafarnib and the evaluation for the associated dose adjustment for lonafarnib have not been adequately addressed. The review team requested the Applicant to conduct a clinical drug interaction study as a postmarketing requirement to evaluate the effect of concomitant administration of CYP2C9 inhibitors on the PK of lonafarnib. 7.7.3. Hypertension and Mortality

Issue Increases in blood pressure have been documented in patients treated with lonafarnib. In clinical trials, the incidence of hypertension was 8.1%. Sustained hypertension or an increase in either systolic blood pressure or mean blood pressure during the trial was associated with death. Survivors tended to have a reduction in blood pressure.

Background Because the study patients were small children, blood pressure readings were evaluated in consideration to height-matched normal reference ranges. With limited reporting in the literature, systemic hypertension is expected to be common in patients with HGPS. In a prior publication with the Boston Children’s Hospital (BCH) ProLon1 data, 13 of 26 (50%) of patients with HGPS were found to be hypertensive after corrections for height and age (Prakash et al. 2018). This

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) does not provide additional insight into hypertension in the natural history of HGPS, as literature describing the prevalence of hypertension in patients with HGPS is limited to those on lonafarnib treatment trials (Gerhard-Herman et al. 2012). Hypertension was observed in one-third of the pivotal study patients, with an 8% incidence rate during the trials. However, reports of this AE were scarce (3 AEs in 63 patients), as hypertension is accepted to be a progression of HGPS by experts. At study enrollment, 24.2% (15/62) of patients had systolic blood pressure above the 95th percentile for gender and height and 27.4% (17/62) had diastolic blood pressure above the 95th percentile. During the trials, 29% (18/62) had hypertension based on systolic blood pressure or diastolic blood pressure measurements above the 95th percentile on 3 or more occasions. An analysis of survivors and deceased patients from ProLon1 and ProLon2 found a correlation between sustained hypertension or an increase in systolic blood pressure and the likelihood of death. Survival status comparison between live and dead patients found no differences in blood pressure at study enrollment. During the trials, however, the survivors’ blood pressure decreased by a mean of 5.5 mm Hg. A comparison of end-of-treatment systolic blood pressure between surviving and deceased patients found a difference of 10 mm Hg. Mean arterial pressure in survivors was also lower by a mean of 4.6 mm Hg. As expected, age at study enrollment also appeared to affect outcomes; the mean age was 5.9 (SD 2.9) years for survivors (n=42) and 9.4 (SD 3.9) years for deceased patients (n=20).

Assessment Although hypertension is thought to be a component of the HGPS disease course, limitat ion exists in understanding lonafarnib’s effect on possibly exacerbating hypertension in HGPS and PL patients. Since there was a finding of both sustained hypertension in non-surviving HGPS patients and 29% had existing hypertension based on blood pressure readings during the pivotal trials, hypertension is included in the product label as an adverse reaction. 7.7.4. Dosing in Hepatic Impairment

Issue Hepatic impairment on the PK of lonafarnib for lonafarnib monotherapy was not assessed.

Background Lonafarnib is extensively metabolized by the liver and predominantly cleared via hepatic means. The Applicant proposed no dose adjustment for patients with hepatic impairment, based on the results obtained from a study in which the combination of lonafarnib and ritonavir was studied in mild and moderate hepatic-impaired subjects (study EIG-LNF-003).

Assessment In study EIG-LNF-003 involving subjects with mild and moderate hepatic impairment following the administration of the combination of lonafarnib and ritonavir, the exposures of lonafarnib were slightly higher than normal (5% and 14% increase in Cmax and AUC, respectively) in patients with moderate impairment but not changed in patients with mild impairment. However, the coadministration of ritonavir in this study complicates the interpretation for the effect of

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) hepatic impairment on PK of lonafarnib if administered alone. Ritonavir is primarily metabolized by CYP3A4 and CYP2D6, inhibiting CYP3A, CYP2D6, and transporters OATP and P-gp, and inducing CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6. With CYP3A and CYP2C9 involved in lonafarnib metabolism and the high protein binding of lonafarnib, coadministration of ritonavir has multiple and complex effects that could impact PK of lonafarnib, such as by CYP3A4 inhibition, CYP2C9 induction, and changes in protein binding. In addition, these interactions could be altered in hepatic impaired conditions compared to the normal hepatic condition. Therefore, the PK results of lonafarnib obtained from study EIG-LNF-003 reflect the overall effects of DDI with ritonavir and hepatic impairment. The effect of hepatic impairment on the PK of lonafarnib when lonafarnib is administered alone is unknown. Progeria patients generally have normal liver function as reported in the literature (Kieran et al. 2007b). There were no conclusive cases of hepatic impairment in the lonafarnib pivotal studies in HGPS and PL patients.

Conclusion Because the effect of hepatic impairment on the PK of lonafarnib monotherapy is unknown, we cannot recommend no dose adjustment for patients with hepatic impairment. Because hepatic impairment is generally not associated with progeria patients, further investigation of PK, efficacy or safety of lonafarnib to inform dosing in patients with hepatic impairment is not considered necessary. 7.7.5. Dosing in Renal Impairment

Issue Renal impairment on the PK of lonafarnib for lonafarnib monotherapy was not assessed.

Background The renal impairment PK study (EIG-LNF-006), with a combination of lonafarnib and ritonavir, showed increased lonafarnib exposures (AUC) of 14% and 80% in patients with moderate and severe impairment, respectively. The effect of renal impairment on the PK of lonafarnib with lonafarnib alone has not been studied.

Assessment The coadministered ritonavir in study EIG-LNF-006 complicates the interpretation of the renal impairment effect on the PK of lonafarnib since ritonavir has multiple DDIs with lonafarnib and its PK also changed with renal function in study EIG-LNF-003. Compared to the matched control patients with normal renal function, ritonavir exposures increased in patients with severe renal impairment but decreased in patients with moderate renal impairment. In addition, the PK results obtained from study EIG-LNF-006 were highly variable, with the coefficient of variance percent of AUCinf approximately 60% in the severe impairment group. This could be due to the small patient sample size, as only four patients were included in the severe impairment group. Therefore, the results from study EIG-LNF-003 with the lonafarnib and ritonavir combination could not accurately estimate the renal impairment effect when lonafarnib alone was administered.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) In general, patients with progeria have normal renal function (Kieran et al. 2007b). Literature has reported that mean urinary creatinine excretion and clearance were normal for patients with HGPS (Merideth et al. 2008). In the patients with HGPS in the pivotal studies, creatinine level ranged from 0.1 to 0.9 mg/dL (reference range 0.3 to 0.7 mg/dl) or 8.8 to 76.9 μMol/L (reference range 26.52 to 88.4 umol/L), which is consistent with the literature findings for normal renal function in patients with HGPS. Importantly, renal clearance of lonafarnib accounts for less than 1% of the dose administered (study P00260). Therefore, clinically meaningful changes in the PK of lonafarnib are not expected in patients with renal impairment.

Conclusion Because the effect of renal impairment on the PK of lonafarnib monotherapy is unknown, we cannot recommend no dose adjustment for patients with renal impairment. Because renal impairment is generally not associated with progeria patients and renal clearance is minimal for lonafarnib, further investigation of PK, efficacy or safety of lonafarnib to inform dosing in patients with renal impairment is not considered necessary. 7.7.6. Nephrotoxicity

Issue There is concern for electrolyte abnormalities and urinalysis changes from nephrotoxicity with lonafarnib, based on animal studies.

Background

Lonafarnib caused nephrotoxicity in rats with clinical chemistry (e.g., hyperphophatemia, hypokalemia, and hypochoridemia) and urinalysis changes at plasma drug exposures approximately equal to those achieved in humans. There was no apparent signal for renal impairment in ProLon1 and ProLon2 but these data are only available for a few years of treatment. See Sections 13.1.3.1 for details.

Assessment The review team determined that the nonclinical findings support concern for potential renal toxicity in humans that we cannot definitely exclude based on the human data.

Conclusion A Warning and Precaution is included in the product label recommending monitoring of renal function at regular intervals during treatment. 7.7.7. Retinal Toxicity

Issue There is concern for decreased visual acuity or night vision loss with lonafarnib, based on animal studies.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Background Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma drug exposures similar to those achieved in humans. Ophthalmic adverse reactions observed in HGPS patients in ProLon1 and ProLon2 involved the cornea. See Sections 7.6.1.7.3 and 13.1.3.1 for details.

Assessment The review team determined that the nonclinical findings support concern for potential retinal toxicity in humans.

Conclusion A Warning and Precaution was included in the product label with a recommendation for ophthalmological evaluations at regular intervals. 7.7.8. Impaired Fertility

Issue There is concern for impaired fertility and testicular toxicity with lonafarnib, based on animal studies.

Background A one-year study in monkeys showed toxicity in the male reproductive tract at plasma drug exposures lower than human dose. Rat studies demonstrated severe impairment of male fertility at 3 times the human plasma drug exposure, and impairment of female fertility at plasma drug exposures approximately equal to the human dose. See Section 13.1.3.1 and 13.1.3.3 for details.

Assessment The review team determined that the nonclinical findings support concern for human fertility issues and testicular toxicity, because male reproductive tract toxicity was seen in monkeys at plasma drug expousures lower than the human dose, while male rats showed dose-dependent impairment of fertility at plasma drug exposures 1.5 times the human dose and higher (severe fertility impairment and gross changes in testes occurred at higher exposures). Impaired fertility in female rats occurred at plasma drug expousures approximately equal to those achieved in humans.

Conclusion A Warning and Precaution recommends counseling regarding the potential for impaired fertility. Although a desire for pregnancy in HGPS patients is rare, we decided to label this concern as a Warning and Precaution because pregnancy may become less rare with improved life expectancy related to lonafarnib use.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 7.7.1. Embryo-Fetal Toxicity

Issue There are no available human data with lonafarnib in pregnancy, but animal reproduction studies demonstrated embryo-fetal toxicity and skeletal malformations at clinically relevant drug exposures.

Background

While there are no available data on lonafarnib use in pregnant women, nonclinical studies showed embryo-fetal toxicity at clinically relevant exposures during organogenesis. In pregnant rats, post-implantation loss (resorptions) was seen at plasma drug exposures approximately equal to that achieved in humans. In pregnant rabbits, skeletal malformations were seen at plasma drug exposures lower than human exposures. See Section 13.1.3.3 for details.

Assessment Concern for a clinically significant risk to the fetus was demonstrated in animal studies. Specifically, nonclinical effects occurred in two species and effects were seen at clinically relevant exposures. A Warning and Precaution for embryo-fetal toxicity that describes the potential risk to a fetus with recommendations to mitigate the risk (i.e., effective contraception) were included in labeling. Although pregnancy in HGPS patients is expected to be rare, we decided to label this concern as a Warning and Precaution because pregnancy may become less rare with improved life expectancy related to lonafarnib use. Additional information was also described in the Pregnancy and Females and Males of Reproductive Potential subsections of labeling (8.1, 8.3). See Section 8.4 for details.

Conclusion A Warning and Precaution for embryo-fetal toxicity recommends that females of reproductive potential avoid pregnancy and use effective contraception during treatment with Zokinvy. 8. Therapeutic Individualization 8.1. Intrinsic Factors

Therapeutic individualization based on intrinsic factors is not necessary.

Renal Impairment or Hepatic Impairment The effect of renal or hepatic impairment on the PK of lonafarnib as monotherapy has not been studied. The effects of hepatic and renal impairment on the PK of single-dose lonafarnib were assessed in studies EIG-LNF-003 and EIG-LNF-006, respectively; however, both studies were conducted with the combination of lonafarnib and ritonavir. The discussions on the related key review issues are included in Sections 7.7.4 and 7.7.5.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Age and Sex Age and sex were found to have an effect on the PK of lonafarnib in healthy adult subjects in study P02673. Following a single dose administration of 100 mg lonafarnib with a standardized meal, the AUCinf and Cmax of lonafarnib were higher (44% and 26%, respectively) in females than in males and were higher (59% and 27%, respectively) in geriatric subjects (greater than 65 years) than in young subjects (18-45 years). Population PK analysis results also indicated that females had 18.6% lower clearance than males. The overall PK differences due to age or sex are not considered clinically significant to support a need of dose adjustment. Additionally, because patients with HGPS and PL do not reach geriatric age, the observed effect of age on PK of lonafarnib in study P02673 is not considered clinically relevant. Body Surface Area (BSA) and Body Weight Population PK analysis results indicated that clearance and volume of distribution of lonafarnib were lower in subjects with lower body weight and BSA. Based on the PK simulations by the review team, at the proposed BSA-based dosing regimens, the lonafarnib exposure (as measured by AUCtau and Cmax at steady-state) were comparable with overlapping distribution across the subgroups by BSA or body weight. See Section 6.1 for the discussion regarding BSA-based dose recommendation. 8.2. Drug Interactions

Based on the assessments of the in vitro DDI findings, clinical DDI studies were conducted to evaluate the effect of drugs on lonafarnib PK (i.e., lonafarnib as a victim) as well as the effect of lonafarnib on the PK of other drugs (i.e., lonafarnib as a perpetrator) in healthy subjects. Note that some of these DDI studies were conducted with a combination of lonafarnib and ritonavir, instead of lonafarnib alone. The lonafarnib-ritonavir combination is a different development program by the Applicant. Ritonavir is known to be mainly metabolized by CYP3A and CYP2D6. Ritonavir is also a strong inhibitor of CYP3A and, to a lesser extent, of CYP2D6, OATP and P-gp and an inducer of CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6.

Effect of Drugs on Lonafarnib PK (Lonafarnib as a Victim) x In study P00393 with single-dose lonafarnib, with coadministration of multiple-dose ketoconazole (a strong CYP3A inhibitor), the Cmax and AUC of lonafarnib significantly increased by approximately 3-fold and 4-fold, respectively, compared to without ketoconazole coadministration. x In study EIG-LNF-007, with the combination of single-dose lonafarnib and ritonavir, coadministration of multiple-dose rifampin (a strong CYP3A inducer) dramatically decreased the Cmax and AUC of lonafarnib by 92% and 98%, respectively, compared to without rifampin coadministration. Based on the above DDI study results, the Applicant proposed a contraindication for strong and moderate CYP3A inhibitors and strong CYP3A inducers. Coadministration with weak CYP3A inhibitors should be avoided, and if unavoidable, the lonafarnib dose should be reduced to the starting dose of 115 mg/m2 with close monitoring for arrhythmias, syncope, and heart palpitations (because the effect of potentially increased lonafarnib exposures on the QT interval is unknown). Dose adjustment was not recommended for weak CYP3A inducers. These

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) proposals are considered reasonable given the significant drug interaction effect on lonafarnib exposure by rifampin and ketoconazole. Since coadministration with moderate CYP3A inducers could result in reduction in the therapeutic effect of lonafarnib, the Applicant proposed increasing the lonafarnib dose by 50%, which was based on PK modeling and simulations in which Cmax not exceeding a QT safety threshold was used as a safety guideline to determine the dose adjustment. However, the submitted data are insufficient in supporting the proposed dose adjustment as discussed in Sections 6.3.7 and 7.7.1 for the related review issues. Therefore, concomitant moderate CYP3A inducers should be contraindicated.

Effect of Lonafarnib on the PK of Other Drugs (Lonafarnib as a Pe rpe trator) The effects of lonafarnib on the PK of a number of drugs that are substrates of relevant CYPs and transporters were assessed in clinical DDI studies as follows. The results are summarized in Table 54. x CYP3A inhibition on midazolam (EIG-LNF-016, group 1) x CYP3A inhibition on loperamide (EIG-LNF-015) x CYP2C19 inhibition on omeprazole (EIG-LNF-017) x P-gp and OATP1B inhibition on fexofenadine (EIG-LNF-016, group 2)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Table 53. Effect of Lonafarnib on Pharmacokinetics of Coadministered Drugs Dose of Dose of LNF Geometric Mean Ratio (90% CI) Coadministered Drug CoadministeredDrug (or LNF + RTV) Cmax AUC0-t AUC0-inf Midazolam (CYP3A substrate) 1×3 mg 100 mg BID × 5 days 2.80 (2.40, 3.28) 7.08 (6.00, 8.37) 7.39 (6.28, 8.70) Loperamide (Antiemetic; metabolized by 1×2 mg 100 mg BID × 5 days 3.14 (2.80, 3.53) 3.95 (3.45, 4.54) 3.99 (3.45, 4.61) CYP3A and substrate of P-gp) Omeprazole (CYP2C19 substrate) 1×40 mg 75 mg BID × 5 days 1.28 (1.01, 1.61) 1.60 (1.34, 1.91) 1.60 (1.32, 1.94) Fexofenadine (P-gp substrate) 1×180 mg 100 mg BID × 5 days 1.21 (0.96, 1.54) 1.24 (1.04, 1.47) 1.24 (1.05, 1.47) Source: Clinical Study Reports for EIG-LNF-016, EIG-LNF-015, EIG-LNF-017 Abbreviations: CI, confidence interval; LNF, lonafarnib; RTV, ritonavir

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

CYP3A Inhibition Lonafarnib is a strong mechanism-based inhibitor of CYP3A. The systemic exposures of midazolam (a sensitive CYP3A substrate) were increased significantly when coadministered with lonafarnib, which may increase the risk of ARs for midazolam, such as extreme sedation or respiratory depression. Therefore, coadministration of lonafarnib with midazolam is contraindicated. As in the case of midazolam, coadministration of lonafarnib could lead to significant increases in the exposures of sensitive CYP3A substrates. HMG-CoA reductase inhibitors (“statins’) are commonly used by patients with HGPS and PL due to their increased risk of cardiovascular events. Therefore, coadministration of lonafarnib with statins that are CYP3A-metabolism dependent, such as lovastatin, simvastatin, and atorvastatin, should be contraindicated due to an increased risk of myopathy including rhabdomyolysis by the significantly increased statin exposures. Coadministration of lonafarnib with other sensitive CYP3A substrates should be avoided and alternatives should be sought unless the benefit outweighs the possible risks. If coadministration is unavoidable, monitoring for ARs and reducing the dosage of the sensitive CYP3A substrate in accordance with its approved product labeling are recommended.

Loperamide Loperamide, a common antidiarrheal over-the-counter product, was used in the pivotal studies to treat the diarrhea associated with lonafarnib in patients with HGPS and PL. In ProLon1, 43% patients used loperamide. In Study EIG-LNF-015 involving healthy subjects, multiple doses of lonafarnib significantly increased loperamide Cmax and AUC by 2-fold and 3-fold, respectively, which is consistent with the understanding that loperamide is primarily metabolized by CYP3A and CYP2C8, and that lonafarnib is a strong inhibitor of CYP3A. The majority of AEs were gastrointestinal events that occurred during administration of lonafarnib, which were reduced in frequency following coadministration of loperamide. PK simulations were conducted at various dose levels and dose intervals using the data from this DDI study with the goal of identifying a loperamide dosing regimen that would keep the loperamide exposure in a safe range when coadministered with lonafarnib. It was predicted that when loperamide 1 mg once daily was administered with lonafarnib 100 mg BID, the mean Cmax and AUC of loperamide would be 4.1-fold and 4.4-fold lower than the exposures for single dose administration of loperamide 16 mg, which is the maximum recommended loperamide daily dose without lonafarnib coadministration (Doser et al. 1995). At loperamide doses 20 to 50 times the maximum recommended daily dose of 16 mg, cases of respiratory depression, torsades de pointes, cardiac arrest, and sudden death have been reportedly associated with loperamide. Therefore, a starting dose of loperamide not to exceed 1 mg once daily is recommended in patients with HGPS and PL taking lonafarnib, with slow increases in the loperamide dosage with caution in accordance with its approved product labeling.

CYP2C19 Inhibition

Lonafarnib is considered a moderate inhibitor of CYP2C19; the systemic exposures Cmax and AUC of omeprazole (a probe substrate of CYP2C19) were increased by 28% and 60%,

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) respectively, when coadministered with lonafarnib. Given the magnitude of exposure increase observed with omeprazole and the potential for further increases related to CYP2C19 polymorphisms in the general population, coadministration of lonafarnib with CYP2C19 substrates should be avoided. If coadministration is unavoidable, ARs should be monitored and the dosage of the CYP2C19 substrate should be reduced in accordance with its approved product labeling.

P-gp and OATP1B Transporter Inhibition

Lonafarnib is considered a weak P-gp and OATP1B inhibitor; the systemic exposures Cmax and AUC of fexofenadine (P-gp and OATP1B substrate) were slightly increased by 21% and 24%, respectively, when fexofenadine was coadministered with lonafarnib. Therefore, when lonafarnib is coadministered with P-gp substrates (e.g., digoxin, dabigatran) with a narrow therapeutic index, monitoring of drug concentrations and ARs are recommended. 8.3. Plans for Pediatric Drug Development

Lonafarnib was granted orphan drug designation on April 18, 2011, for treatment of HGPS and PL. Currently, there are no plans for additional pediatric studies, and lonafarnib is exempt from the Pediatric Research Equity Act (21 U.S.C. 55c). The Applicant has provided sufficient justification and right of reference to INDs that include pediatric patients with HGPS 2 years of age and older and with PL 13 months of age and older who were treated with lonafarnib. As HGPS is an early-onset, progressive disease, lonafarnib will be indicated for pediatric patients 12 months of age and older with a body surface area of 0.39 m2 and above. 8.4. Pregnancy and Lactation

For details see the full review in DARRTS. Date 29 September 2020 – Ref ID 4677713 by: Jean Limpert, MD and Miriam Dinatale DO, Division of Pediatric and Maternal Health.

Animal Data The following nonclinical information (Table 55) was used in support of the indicated labeling sections. Additional details of the nonclinical data are located in Sections 13.1.2 and 13.1.3.3.2 the final labeling is discussed in Section 21.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 54. Nonclinical Data Supporting Labeling on Pregnancy and Lactation Labeling Section Nonclinical Data 8.1 Pregnancy In rats, oral administration of 30 mg/kg/day lonafarnib during organogenesis decreased fetal body weights and number of live fetuses, and increased postimplantation loss (early and late resorptions). In rabbits, oral administration of lonafarnib during organogenesis resulted in maternal toxicity (body weight loss and abortion) at 120 mg/kg/day and skeletal malformations and variations at doses of 10 mg/kg/day or higher. 8.2 Lactation Lonafarnib is excreted in rat milk. Source: Review team

Pregnancy There are no available data on lonafarnib use in pregnant women. In pregnant rats, oral lonafarnib led to embryo-fetal toxicity at exposures that were 1.1 times the human exposure at recommended doses. In pregnant rabbits, oral administration of lonafarnib during embryogenesis produced skeletal malformations and variations at exposures lower than the human exposure. Given that pregnancy is plausible and animal data are of concern, the Division of Pediatric and Maternal Health (DPMH) recommended adding language in Sections 5.5, 8.1, and 17 of the prescribing information to indicate that lonafarnib may cause fetal harm and is not recommended during pregnancy. Due to the disease rarity, delayed sexual maturation, and early death of patients with HGPS and PL, pregnancy in this population would be highly unlikely. There is only one published report detailing a normal pregnancy outcome in a woman with a mild form of HGPS who did not take lonafarnib. Given that pregnancy is highly unlikely in this rare disease population, postmarketing pregnancy safety studies would not be feasible.

Lactation There are no data on the presence of lonafarnib in the milk of humans. Animal data in rats indicate that lonafarnib is excreted into milk. Given that lactation would be highly unlikely in this rare disease population with early death, a postmarketing lactation study would not be feasible.

Females and Males of Reproductive Potential There are no human fertility data with lonafarnib use in females and males of reproductive potential. Animal data in rats suggest lonafarnib may reduce fertility in males and females of reproductive potential. Given this rare disease population with early death, a postmarketing fertility study in humans would not be feasible. Due to the potential for embryo-fetal harm, DPMH recommends adding language in subsection 8.3 and Section 17 of the prescribing information to advise appropriate contraception for females of reproductive potential during treatment with lonafarnib (which should take into account that these patients are at increased risk for myocardial infarction and stroke).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 9. Product Quality

Zokinvy is a farnesyltransferase inhibitor. It is supplied as 50 mg and 75 mg hard gelatin capsules for oral administration. Each capsule contains either 50 mg or 75 mg of lonafarnib as the active ingredient and the following inactive ingredients: croscarmellose sodium, magnesium stearate, poloxamer 188, povidone, and silicon dioxide. The capsule shells contain gelatin, titanium dioxide, and yellow iron oxide; the 75 mg capsule also contains red iron oxide. The drug substance in Zokinvy capsules is lonafarnib. It is a white to off-white powder. It is nonhygroscopic, is practically insoluble in water, and is known to have only one polymorph. Although lonafarnib is a chiral molecule containing one chiral center, in vivo chiral conversion is not expected. Figure 23. Structure of Lonafarnib

Molecular formula: C27H31Br2ClN4O2 Molecular mass: 638.8 g/mol Lonafarnib is manufactured by (b) (4) . The detailed CMC information regarding lonafarnib manufacturing process, in-process controls, control of materials, critical steps, impurities, and intermediates was provided. Its chemical structure was determined by many modern spectroscopic methods as well X-ray crystallography. The identity,

strength, purity, and quality of lonafarnib is controlled by its specification.(b) (4) Based on the stability studies of multiple batches of the drug substance a retest period of months was granted when stored at (b) (4) (b) (4)

The overall control strategy for the drug product’s identity, strength, purity and quality is deemed adequate based on raw material controls, manufacturing process, in-process controls and drug product specification. Zokinvy is a nonsterile drug product. The drug product specification includes a microbial enumeration test for total aerobic microbial count and total combined yeast/molds count per USP <61>and a test for specified micro-organisms Escherichia coli per USP <62>. The acceptance criteria will adhere to USP <1111>for nonsterile products. Microbial limits testing will be performed at release and stability. Based on satisfactory long-term and accelerated stability data of multiple batches of the drug product assuring the identity, strength, purity, and quality, a 48-month of expiration dating period is granted when stored between 20ºC to 25ºC.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The Applicant has provided sufficient CMC information to assure the identity, strength, purity, and quality of the drug product, Zokinvy (lonafarnib) capsules, 50 mg and 75 mg. The Office of Pharmaceutical Manufacturing Assessment has made an “Approval” recommendation for all manufacturing and testing facilities involved in this NDA. The claim for the Categorical Exclusion for the Environmental Assessment is granted. The label/labeling issues have been satisfactorily resolved from the CMC perspective. Therefore, from the Office of Pharmaceutical Quality perspective, this NDA is recommended for “Approval.” 9.1. Device or Combination Product Considerations

Not applicable. 10. Human Subjects Protections/Clinical Site and Other Good Clinical Practice Inspections/Financial Disclosure

Human Subjects Protections The Applicant states the clinical trials were conducted in substantial conformance with ICH good clinical practice requirements and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The phase 2 studies were conducted according to FDA requirements under IND 139923.

Clinical Site Inspections Dr. Monica Kleinman, MD at Boston Children’s Hospital and Dr. Leslie Gordon at The Progeria Research Foundation and Brown University were inspected (refer to Sections 6.3.6 and 20 for details).

Financial Disclosure The Applicant adequately disclosed financial interests/arrangements with clinic investigators as recommended in the guidance “Financial Disclosure by Clinical Investigators” (February 2013) (see Section 21) and by 21 CFR 54.4. None of the investigators for ProLon1 and ProLon2 are employed by the Applicant or disclosed financial interests with the Applicant. In conclusion, the likelihood that trial results were biased based on financial interests is minimal and should not affect the approvability of the application.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 11. Advisory Committee Summary

An advisory committee was not held for this application. It did not raise challenging efficacy or safety issues that needed external input. III. Appendices

12. Summary of Regulatory History

The drug development program for lonafarnib in Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) began under investigational new drug (IND) applications at Dana-Farber Cancer Institute and later transitioned to Boston Children’s Hospital (b) (4)

Orphan drug designation was granted for lonafarnib for the treatment of HGPS and PL on April 18, 2011. On June 25, 2018, Eiger Biopharmaceuticals (Eiger) submitted a pre-IND meeting request (PIND 139923) to the Division of Gastroenterology and Inborn Errors Products to discuss their proposed development plan for the treatment of HGPS and PL. Eiger informed the Division that they had recently reached an agreement with the Progeria Research Foundation (PRF) in which Eiger would partner with PRF on the lonafarnib development program for HGPS and PL. Eiger also expressed their intention to use clinical data collected by PRF to support a commercial IND and subsequent marketing application. Letters of authorization (LOA) were submitted with the meeting request, including an LOA from Merck Sharp & Dohme Corp to cross-reference IND (b) (4) and an LOA from the Boston Children’s Hospital to cross-reference INDs (b) (4). The meeting took place on August 22, 2018. The FDA agreed with the proposed main endpoint of survival for the NDA submission and provided recommendations on the main efficacy analysis, nonclinical, clinical pharmacology, and product quality strategy. Eiger submitted an initial IND for lonafarnib for the treatment of HGPS and PL without a clinical protocol on October 15, 2018. Per the Division’s recommendation, Eiger withdrew and resubmitted IND 139923 on November 2, 2018, along with an expanded access treatment study protocol EIG-EAP-LNF-001 titled: “A Treatment IND (Investigational New Drug) Protocol for Expanded Access Program for the Use of Lonafarnib in Patients with Hutchinson-Gilford progeria syndrome (HGPS) or Progeroid Laminopathy.” The purpose of the protocol was to provide treatment with lonafarnib to patients with HGPS and PL in anticipation of the planned NDA submission and potential commercial availability of the therapy. During the IND review, the FDA had an informal teleconference with Eiger on November 29, 2018, to discuss the Agency’s concerns on the concomitant use of loperamide for the management of lonafarnib- induced diarrhea during the study for the HGPS/PL patient population. Loperamide is contraindicated in patients less than 2 years of age and the proposed doses in the protocol are higher than the doses currently approved and labeled for loperamide. Eiger agreed to submit a protocol amendment within 30 days to address these concerns, including 1) additional justification for loperamide use and dosing, and 2) the risks associated with loperamide in the

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) pediatric patient population in the informed consent document. FDA issued a Study May Proceed letter on November 30, 2018, and reiterated the importance of submitting a protocol amendment within 30 days to address the loperamide dosing concerns. In the letter, the FDA also recommended additional clinical pharmacology studies such as in vivo drug-drug interaction (DDI) and food effect studies for lonafarnib. A breakthrough therapy designation request was included in the initial IND submission on November 2, 2018. On December 12, 2018, a breakthrough therapy designation was granted for lonafarnib for the treatment of HGPS and PL. On January 18, 2019, FDA issued a Written-Response-Only to provide additional guidance regarding the planned clinical pharmacology package to support the NDA submission. On January 31, 2019, Eiger requested a meeting to discuss the proposed format of patient-level data collected from the clinical studies conducted by the Progeria Research Foundation and Boston Children’s Hospital to support the NDA. The FDA issued the preliminary comments on March 13, 2019, providing recommendations on the process for collecting patient narratives/patient case reports in a drug master file to submit these confidential data directly to the FDA. Eiger cancelled the teleconference after they received the preliminary comments. On February 5, 2019, per the Agency’s recommendations, Eiger submitted an in vivo DDI protocol (study EIG-LNF-015) to determine the appropriate loperamide dose titled, “A Phase 1, open-label, single-center, two-period, single-sequence, multidrug-drug interaction study to evaluate the effects of multiple-dose lonafarnib + ritonavir or multiple-dose lonafarnib on the pharmacokinetics (PK) of single-dose loperamide in healthy subjects.” FDA provided feedback in an advice letter on March 4, 2019. In response to the Agency’s comments, Eiger submitted a revised protocol EIG-LNF-015 on March 15, 2019. In addition, Eiger submitted two new clinical pharmacology protocols: 1) Protocol EIG-LNF-016, a study of drug interaction between lonafarnib and midazolam titled “A Phase 1, open-label, single-center, two-period, single-sequence, multidrug-drug interaction study to evaluate the effects of multiple-dose lonafarnib on the pharmacokinetics of single-dose midazolam, a sensitive cytochrome P450-3A substrate, and in parallel, the effects of multiple-dose lonafarnib on the pharmacokinetics of single- dose fexofenadine, a sensitive P-glycoprotein substrate, in healthy subjects,” and 2) Protocol EIG-LNG-017, a food effect study titled “A Phase 1, single-center, open- label, single-sequence, drug-drug interaction study to evaluate the effects of multiple- dose lonafarnib on the pharmacokinetics of single-dose omeprazole, a sensitive CYP2C19 substrate, and in parallel, a single-sequence, three-period crossover, pivotal food-effect evaluation with single-dose lonafarnib and a single-sequence, two-period crossover pivotal food-effect evaluation with single-dose lonafarnib and ritonavir in healthy subjects.” The FDA found that EIG-LNF-015 and EIG-LNF-016 were acceptable but provided comments on EIG-LNG-017 in an advice letter on April 9, 2019. A protocol amendment for EIG-LNG-017 was received on May 30, 2019. On March 25, 2019, the FDA issued a Written-Response-Only guidance regarding the CMC aspects related to the development, validation, and commercialization of lonafarnib.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) On April 2, 2019, Eiger submitted a meeting request to seek the Agency’s input on the proposed statistical analysis plan for the pivotal study. A face-to-face meeting took place on May 29, 2019. The FDA stated concerns on the interpretation of nonrandomized data, selection bias, matching strategy, and missing data. Recommendations on the supportive survival analysis, natural history cohort, and sensitivity analysis for safety and efficacy were provided. The meeting minutes were issued on June 11, 2019. A pre-NDA CMC meeting was requested July 25, 2019, granted August 9, 2019, and took place on September 24, 2019. The meeting minutes were issued on October 22, 2019. Comments were provided on the required CMC components and final reports to support the NDA submission. A pre-NDA clinical/pharmacology/toxicology meeting was requested July 25, 2019, granted July 30, 2019, and took place on October 8, 2019. The meeting minutes were issued on October 10, 2019. Agreement was reached on the timeline, format, and content of clinical components of the planned NDA. Additional recommendations were provided on the proposed key efficacy analyses and clinical and clinical pharmacology datasets. Rolling review designation was requested on November 8, 2019, and granted for the NDA on November 15, 2019. On March 20, 2020, Eiger submitted the remaining items for a new molecular entity NDA for lonafarnib for the treatment of HGPS and PL under the 505(b)(1) of the Food, Drug, and Cosmetics Act. NDA 213969 is a rolling submission that contained three components: x December 12, 2019: Nonclinical Pharmacology and Toxicology (Module 2.4, Module 2.6 and Module 4). x January 31, 2020: Chemistry, Manufacturing and Controls, Quality Overall Summary and sections (Module 2.3 and Module 3). x March 20, 2020: Administrative information, prescribing information (PI) and complete clinical information package (Module 1, Module 2.5, Module 2.7 and Module 5). The Division determined that the review classification for NDA 213969 is priority because lonafarnib is a drug for a serious disease with no approved therapy and, on its face, appeared to be an important advance. The Sponsor’s initial proposed trade name to their IND, Zokinvy, was found unacceptable under IND 139923 on October 8, 2019. The Sponsor submitted (to IND 139923) a proprietary name reconsideration request on October 24, 2019, in which the FDA found the submitted information supportive and the proposed trade name Zokinvy conditionally acceptable on April 20, 2020. The Applicant submitted the proposed trade name, Zokinvy, and it was found conditionally acceptable for NDA 213969 on July 31, 2020. Eiger is also developing lonafarnib for the treatment of hepatitis D under IND (b) (4) in the Division of Antivirals. On September 11, 2020, in response to an information request, Eiger submitted a cross-referenced statement to include the safety data collected from IND(b) (4) to support the review of NDA 213969, particularly study EIG-300 titled, “A Phase 2, Open-Label Pilot Study of the Safety, Tolerabilit y, Pharmacokinetic and Pharmacodynamic Activity of Lonafarnib (EBP-994) Given Orally in Subjects Chronically Infected with HDV.”

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 13. Pharmacology Toxicology: Additional Information and Assessment 13.1. Summary Review of Studies Submitted Under IND 13.1.1. Pharmacology

Primary Pharmacology HGPS and PL are ultra-rare diseases known as progeria and are caused by in either LMNA or ZMPSTE24 genes, which produce an abnormal farnesylated form of prelamin A (progerin) that accumulates in the nuclear envelope, resulting in cellular and structural damage and functional abnormalities. Deletion of ZMPSTE24 results in expression of full-length but unprocessed, permanently farnesylated prelamin A and progeroid phenotypes in mouse models. Treatment of cultured embryonic fibroblasts from progeroid mice with farnesyltransferase inhibitors (FTIs) reverses abnormal nuclear morphology (Toth et al. 2005). Treatment of ZMPSTE24-/- mice with FTIs improves the disease conditions and prolongs survival (Fong et al. 2006a; Fong et al. 2006b). Lonafarnib is a farnesyltransferase inhibitor that blocks post-translational farnesylation of lamin A with an IC50 of 1.9nM for human farnesyl protein transferase, and thus is expected to provide therapeutic benefit for patients with HGPS or PL by preventing the formation of progerin or “progerin-like” proteins. The Applicant conducted in vitro studies with isolated fibroblasts from patients with PL. In one of these studies, fibroblasts were treated with 2μM lonafarnib for 5 days, and the effects on nuclear morphology were evaluated. The results indicated that treatment with lonafarnib significantly reduced the number of aberrant nuclei as compared to the vehicle control (dimethyl sulfoxide [DMSO]). In another study, isolated fibroblasts from PL patients were treated with 2, 5, or 10μM lonafarnib, and then the nuclear morphology of the cultured cells were examined at 24 and 48 hours after the treatment. The results indicated that lonafarnib at all doses significant ly reduced the percentages of deformed nuclei as compared to the vehicle control (DMSO). The testing concentration of 2μM (1.28 μg/mL) was within the mean lonafarnib concentrations ranging from 1.0 to 2.2 μg/mL (mean Cmin to Cmax) that were observed in the pivotal clinical study (ProLon1) following the proposed dosing regimen in HGPS and PL patients.

Secondary Pharmacology Refer to Section 13.2.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 55. Safety Pharmacology Studies Study/Study No. Findings Effect of SCH 66336 on Cloned hERG Lonafarnib inhibited the hERG potassium current in mouse L- Channels Expressed in Mouse L-929 929 cells with IC50 ȝ0 a WLPHV WKH KXPDQ &max for Cells/ Study No. 46366 unbound drug Effect of SCH 66336 on action potential /RQDIDUQLE XS WR ȝ0 KDG QR VLJQLILFDQW HIIHFWV RQ DFWLRQ parameters in dog isolated cardiac potential in isolated Purkinje fibers from dogs Purkinje fibers / #02160 Dose:   DQG ȝ0

Ancillary Pharmacology of SCH 66336: Lonafarnib (50 mg/kg IV) had no effect on QTc interval in Evaluation of Cardiovascular Function in guinea pigs Guinea Pigs / Study No. P6339 Species/strain: Guinea pigs Number/group: 6 males Dose: 50 mg/kg/day Route of administration and dosing frequency: IV, single dose A 52-Week Oral (Gavage) Toxicity and Lonafarnib had no effects on ECGs in the repeated dose Toxicokinetic Study of SCH 66336 in toxicity studies in monkeys (up to 40 mg/kg/ day for 1 year). Cynomolgus Monkeys/ Study No. 96036 Species/strain: Monkeys AUC0-24hr at 40 mg/kg/day ~4 times the human Number/sex/group: 4 AUC0-24hr Dose: 0, 10, 20, and 40 mg/kg/day Route of administration and dosing frequency: Oral / once daily Source: Review team Abbreviations: AUC, area under the concentration-time curve; ECG, electrocardiogram; IC50, concentration inhibiting 50% of activity 13.1.2. ADME/PK

Absorption Single Dose Pharmacokinetic Studies in Rats and Monkeys (SN96557, SN96558, SN00508, SN96559, SN02196)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 56. Single-Dose Pharmacokinetics of Lonafarnib in Rats Study Number SN96557 SN96557 SN96558 SN00508 Species/strain Rat/Sprague Rat/Sprague Pigmented rat/ Pregnant rat/ Dawley Dawley Long Evans Sprague Dawley Sex/number of animals 3M, 3F 3M, 3F 3M, 3F 3F/6 fetuses Feeding condition Fed Fed Fasted Fasted Vehicle/formulation 0.4% w/v MC DMSO 20% w/v 0.4% w/v MC 0.4% w/v HPMC Method of administration Oral IV Oral Oral Dose (mg/kg) 30 5 30 30 Sample Plasma Plasma Plasma Plasma Analyte Lonafarnib Lonafarnib Lonafarnib [14C]-lonafarnib Assay LC-MS/MS LC-MS/MS LC-MS/MS LSS PK parameters Male Female Male Female Male Female Dam Fetus Cmax ȝJP/ 1.66 2.58 2.48 2.58 1.77 2.62 2.65 0.28 AUClast ȝJāKUP/ 9.07 50.6 2.48 6.43 11.4 19.9 29.4 2.3 Tmax (hr)240.0830.0834468 T1/2 (hr) 1.09 1.92 1.54 2.38 N/A N/A N/A N/A CL (mL/hr/kg) 2635 473 2039 767 N/A N/A N/A N/A Vd (mL/kg) N/A N/A 4522 2633 N/A N/A N/A N/A Bioavailability (%) 77.6 167 N/A N/A N/A N/A Source: Review team Abbreviations: DMSO, dimethyl sulfoxide; F, female; HPMC, hydroxypropyl-methylcellulose; IV, intravenous; LC-MS/MS, liquid chromatography with tandem mass spectrometry; LSS, liquid scintillation spectroscopy; M, male; MC, methylcellulose; N/A, not applicable; PK, pharmacokinetics Table 57. Single-Dose Pharmacokinetics of Lonafarnib in Monkeys Study Number SN96559 SN96559 SN02196 SN02196 Species/strain Monkey/ Monkey/ Monkey/ Monkey/ Cynomolgus Cynomolgus Cynomolgus Cynomolgus Sex/number of animals 3M, 3F 3M, 3F 4M, 4F 4M, 4F Feeding condition Fed Fed Fed Fed Vehicle/formulation 0.4% w/v MC DMSO 20% w/v 0.4% w/v HPMC DMSO 20% w/v Method of administration Oral IV Oral IV Dose (mg/kg) 15 5 15 5 Sample Plasma Plasma Plasma Plasma Analyte Lonafarnib Lonafarnib Lonafarnib Lonafarnib Assay LC-MS/MS LC-MS/MS LC-MS/MS LC-MS/MS PK parameters Male Female Male Female Male Female Male Female Cmax ȝJP/ 2.8 2.08 3.57 3.69 2.47 1.54 3.66 3.79 AUClast ȝJāKUP/ 19.915.07.247.5125.614.08.616.95 Tmax (hr) 4 4 0.083 0.083 6 8 0.083 0.083 T1/2 (hr) NC NC 2.38 2.25 3.75 3.36 2.38 1.88 CL (mL/hr/kg) NC NC NC NC 564 858 598 715 Vd (mL/kg) NCNCNCNCNCNCNCNC Bioavailability (%) 91.4 66.4 NC NC 107 58.3 NC Source: Review team Abbreviations: DMSO, dimethyl sulfoxide; F, female; HPMC, hydroxypropyl-methylcellulose; IV, intravenous; LC-MS/MS, liquid chromatography with tandem mass spectrometry; M, male; MC, methylcellulose; NC, not calculated; PK, pharmacokinetics

Distribution Protein binding of [14C]-lonafarnib is ~99.0 to 99.7% in rats, monkeys, and human plasma (#98139, #98276). The liver, adrenal gland, pancreas, bile duct, and kidneys have the highest concentration of radioactivity in rats following a single oral dose of [14C]-lonafarnib (#96558). The liver, small

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) intestine, and eye have the highest concentration of radioactivity in monkeys following a single oral dose of [14C]-lonafarnib (#96559).

Metabolism The most common metabolic pathways across all species (mice, rat, monkey, and human) involve oxidation, dehydrogenation, or both, and a total of 32 metabolites were characterized. No human specific metabolite was detected. The structures of major metabolites are predicted in the following figure. Figure 24. Structure of Lonafarnib Metabolites

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Excretion Excretion of Total Radioactivity Following an x Overall recovery in rats: 99.2-102% in Oral Dose of [14C] Lonafarnib in Rats and feces /<0.5% in urine Monkeys (#96557, #96559) x Overall recovery in monkeys: >98% in feces /<1.62% in urine. Lonafarnib is Transfer of Radioactivity Into Milk Following an excreted in milk following oral Oral Dose of [14C] Lonafarnib in postpartum administration in lactating rats, with a rats (#00499) mean milk to plasma concentration ratio of 1.5 at 12 hours. 13.1.3. Toxicology 13.1.3.1. General Toxicology

A Six-Month Oral (Gavage) Toxicity and Toxicokinetic Study of SCH 66336 in Rats /Study No. 96034 Key Study Findings:

x No observed adverse effect level (NOAEL)=15 mg/kg/day (AUC0-24hr=2 ȝJ·hr/mL in PDOHV DQG  ȝJ·hr/mL in females) due to histopathological changes in kidney at 30 and 60 mg/kg/day. x The lesions included necrosis and mineralization in the inner medulla and mononuclear cell infiltrates in kidney Conducting laboratory and location: (b) (4) GLP compliance: Yes Table 58. Features and Methods, Study 96034 Study Features and Methods Details Dose and frequency of dosing: 0, 15, 30, and 60 mg/kg/day / once daily Route of administration: Oral gavage Formulation/vehicle: 0.4% w/v methylcellulose in water Species/strain: Sprague Dawley rats Number/sex/group: 10 Age: 6 weeks Satellite groups/unique design: Yes Deviation from study protocol affecting None interpretation of results: Source: Review team

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 59. Observations and Results, Study 96034 Parameter Major Findings Mortality None Clinical signs None Body weights Decreased body weight was seen in males (1.6-5.2% at mid-dose; 6.9-14.4% at high dose) from weeks 5 to 27, and in females (4.0- 9.1% at mid-dose; 4.0-11.8% at high dose) from weeks 2 to 27. Body weight was also decreased 2.0-4.3% in low-dose females from weeks 17-27. Only the changes in the mid-dose and in high- dose females were statistically significant. All changes were drug- related, but were adverse only at the mid and high doses. Ophthalmoscopy No ECG Not determined Hematology The following were observed at week 13: x Increased red blood cells (RBCs) (3.5-8.4%) and decreased mean corpuscular volume (MCV, 2.3-4.8%) in mid- and high-dose females and high-dose males; decreased mean corpuscular hemoglobin (MCH; 3.1- 5.7%) in mid- and high-dose females. x Increased platelets (6.4-9.2%) in high-dose males and females. x Decreased white blood cells (WBCs; 25.0%), lymphocytes (29.6%), and eosinophils (50.0%) in high-dose females; increased neutrophils (40.0%) in high-dose males. The following were observed at week 26: x Increased RBCs (5.6-11.8%), hemoglobin (HGB; 2.6- 6.0%), and hematocrit (HCT; 3.7-5.8%) in all treatment groups. x Decreased reticulocytes (32.9-38.5%) in low- and high- dose males. x Decreased eosinophils (50.0-66.7%) in high-dose animals. x Increased prothrombin time (PT; 6.2-8.0%) in mid- and high-dose females. All findings were considered drug-related. The increase in RBCs, HGB, and HCT may be secondary to dehydration/increased urine volumes, which correspond to the kidney histopathology and other clinical chemistry/urinalysis findings. The hematology findings alone were not considered adverse.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Parameter Major Findings Clinical chemistry The following were observed at week 13: x Increased blood urea nitrogen (BUN; 15.4%) in high-dose animals. x Decreased total protein (5.3-7.9%) and albumin (5.5- 9.1%) in all treated females. x Increased total protein (4.5-7.5%) in mid- and high-dose males, increased globulin (15.0%) and decreased A/G ratio (8.7-13.0%) in all treated males. x Increased alkaline phosphatase (ALP; 25.8-69.4%) in mid- and high-dose males and in all treated females. x Increased phosphorus (17.5%) in high-dose females, decreased potassium (8.8%) in mid- and high-dose males, and decreased chloride (2.8-3.6%) in high-dose animals. The following were observed at week 26: x Increased BUN (25.0%) in high-dose males. x Decreased total protein (9.8-11.0%) in mid- and high-dose females, decreased albumin (6.8-16.9%) and A/G ratio (11.5-19.2%) in all treated females; increased globulin (12.5%) in all treated males. x Decreased cholesterol (19.3-27.6%) in all treated females. x Increased ALP (30.9-118%) in mid- and high-dose males and all treated females. x Increased phosphorus (12.2-49.1%) in mid- and high-dose females; increased potassium (25.4%) and decreased chloride (3.0%) in high-dose females. All findings were considered drug related. The increase in BUN corresponds to the urinalysis and kidney histopathology findings. The electrolyte changes may also correspond to the urinalysis findings and may be kidney related. These changes were considered adverse at the mid- and high doses.

Urinalysis The following were observed at week 13: x Increased urine volume (24.0-56.8%) in all treated males and in high-dose females (significant only in high-dose females). x Decreased urine osmolarity (7.3-34.8%) in all treated males and in high-dose females (not statistically significant). x Decreased creatinine (22.7-47.7%) in mid- and high-dose males and in high-dose females. x Increased urinary excretion of calcium (38.4-237%) in all treated males and high-dose females. x Increased urinary excretion of sodium (47.2-127%) in high-dose animals; increased phosphorus (45.4%) and potassium (2.2-fold) in high-dose females; increased chloride (2.5-to 5.6-fold) in high-dose males and in mid- and high-dose females.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Parameter Major Findings The following were observed at week 26: x Increased urine volume (26.2-29.2%) in mid- and high- dose males (not statistically significant). x Decreased urine osmolarity (11.1-22.4%) in mid- and high-dose males (not statistically significant). x Increased urine pH in mid- and high-dose females (7.6-7.9 vs. 7.1 in controls). x Decreased creatinine (21.1-64.6%) in all treated females and mid- and high-dose males. x Increased urinary excretion of calcium (38.1-198%), phosphorus (16.9-57.2%), sodium (53.1-223%), potassium (23.3-70.3%), and chloride (74.0-210%) in mid- and high-dose animals. All findings were considered as drug related. The decreases in creatinine and osmolarity may be related to the increase in urine volume given that creatinine levels are expressed as mg/dL. Similarly, urine electrolyte levels based on mg/dL were generally decreased (likely also related to the increase in urine volume). These changes also corresponded to the histopathology findings in kidneys, and were considered adverse at the mid- and high doses.

Gross pathology None

Organ weights Decreased pituitary (40.5%), uterus (37.9%), and thymus weights (30.1%) were observed in high-dose females only.

Histopathology Minimal to moderate interstitial necrosis of inner medulla in Adequate battery: Yes kidneys in 1 mid-dose female and 1 male/7 females at high dose; minimal to mild mineralization of inner medulla in kidneys in 4 mid- dose females and 1 male/6 females at the high dose; minimal multifocal mononuclear cell infiltrate in kidneys in 1 low-dose female and 1 male/1 female at the high dose; minimal glomerulopathy in 1 high-dose female. Minimal to mild cytoplasmic vacuolation of midzonal hepatocytes in liver in 5 males/1 female at the mid-dose and 8 males/2 females at the high dose; minimal multifocal mononuclear cell infiltrates in liver in 1 male/2 females at the low dose, 2 males/1 female at the mid-dose, and 2 males/1 female at the high dose. Minimal to mild alveolar macrophage accumulation in lungs in 1 male/1 female at the low dose and 6 males/7 females at the high dose (also in 2 males/1 female in controls); minimal mononuclear cell infiltrates in lungs in 2 males/1 female at the high dose. Minimal multifocal single-cell necrosis of acinar cells in pancreas in 4 high-dose males (also in 1 male/1 female in controls); minimal mononuclear cell infiltrates in 2 males/1 female at the high dose. Minimal to mild cytoplasmic vacuolation in parathyroid gland in 3 mid-dose and 9 high-dose females. Minimal to moderate lymphocyte hypocellularity in thymus in 7 high-dose females; minimal to mild increase in mitotic figures in thymus in 2 mid-dose and 11 high-dose females.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Parameter Major Findings The findings in kidney, liver, parathyroid (females only), and thymus (females only) were drug-related, but were considered adverse only at the mid and high doses. The kidney lesions correspond to the clinical chemistry and urinalysis findings described above. The liver findings may correspond to the slight increases in ALP. The thymus findings may correspond to the changes in WBC subsets at week 13, but this is unclear. It is also unclear whether the pancreas and lung findings were drug related or incidental due to their low severity and presence in controls. Toxicokinetics Plasma drug levels were measured at 2, 6, 12, and 24 hours postdose on day 1 and week 26. Toxicokinetic parameters are presented in Table 63 (copied from the study report). Drug exposures were about 2- to 8-fold higher in females than in males, which likely accounts for the increased incidence and severity of toxicities in females compared to males. Source: Review Team Table 60. Toxicokinetic Parameters in Rats

Source: Study Report # 96034

A 52-Week Oral (Gavage) Toxicity and Toxicokinetic Study of SCH 66336 in Cynomolgus Monkeys/ Study No. 96036 Key Study Findings: x Lonafarnib was administered at 10, 20, and 40 mg/kg/day. A NOAEL was not determined in males due to adverse effects in the reproductive tract at all dose levels or in females due to the decrease in body weight that was considered adverse at all dose levels. x Histopathological changes occurred in eyes at the high dose (single cell necrosis of rods and cones). Conducting laboratory and location: (b) (4) GLP compliance: Yes

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 61. Features and Methods, Study 96036 Study Features and Methods Details Dose and frequency of dosing: 0, 10, 20, and 40 mg/kg/day / once daily Route of administration: Oral gavage Formulation/vehicle: 0.4% w/v methylcellulose in water Species/strain: Monkeys Number/sex/group: 4 Age: 3-4.5 years Satellite groups/unique design: None Deviation from study protocol affecting None interpretation of results: Source: Review Team Table 62. Observations and Results, Study 96036 Parameter Major Findings Mortality None

Clinical signs Liquid/mucoid/nonformed feces were observed in high-dose males and all treated females throughout the study. This may correspond to the decreases in body weight and food consumption, and possibly to the histopathology finding in the small intestine. This was considered drug-related but nonadverse. Body weights In males, body weights were decreased relative to controls at the low dose (6.8-12.2%) from week 2 to 36, at the mid-dose (5.6- 14.6%) from week 2 to 42, and at the high dose (8.1-23.4%) from week 2 to 53. The decrease in body weights in males appeared to recover at the low and mid doses within the final weeks of the study, while body weight gain in high-dose males remained stagnant throughout the study. In females, control body weights were up to 7.1% greater than in all treatment groups prior to study initiation. However, body weights at all lonafarnib doses remained stagnant after about week 26, while control body weights continued to rise. Between weeks 42 and 53, female body weights were decreased 12.1-17.6% at all dose levels relative to the control group. None of these changes were statistically significant and the female findings were not entirely dose dependent, but all changes were all considered drug-related and adverse. Ophthalmoscopy None

ECG None

Hematology Total lymphocytes were decreased in high-dose animals (22.2- 64.0%) on weeks 2, 4, 12, 24 and 52, and in mid-dose animals (12.0-42.1%) on weeks 12, 24 and 52. These changes were considered drug related but nonadverse.

Clinical chemistry Cholesterol was decreased in high-dose animals (31.6-55.6%) on weeks 12, 24 and 52, and in mid-dose animals (12.8-38.9%) on week 52. This was considered drug related but nonadverse.

Urinalysis None

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Parameter Major Findings Gross pathology None Organ weights x Increased liver weight (19-29%) in high-dose females and all treated males. x Decreased thymus weight (27-67%) in all treated animals. x Decreased spleen weight (26-37%) in all treated males. x Decreased testis (40-80%) and epididymis weights (28-62%) in all treated males. x Decreased prostate weight (43%) in high-dose males. x Decreased ovary weight (32-33%) in mid- and high-dose females. x Increased adrenal gland weight (23%) in high-dose males. x Increased thyroid weight (23-55%) in all treated males.

Histopathology x Mild to severe seminiferous tubule atrophy in testes in all mid- Adequate battery: Yes and high-dose males. Aspermia in the epididymis in 3 mid- dose and all high-dose males. x Minimal to mild atrophy in prostate gland in 2 high-dose males. Minimal atrophy in seminal vesicles in 2 high-dose males. x Minimal to mild lymphoid atrophy in thymus in all mid-dose and 3 high-dose males. x Minimal single cell necrosis of photoreceptor cells in the layer of rods and cones and the outer nuclear layer of retina (1 male and 1 female in the high dose group). x Minimal to mild decrease in vacuolation of the zona fasciculata in the adrenal glands in all high-dose males. x Minimal histiocyte accumulation in the lamina propria of small intestine in 2 low-dose, 2 mid-dose, and 3 high-dose males, and 4 high-dose females. x Changes observed in the male reproductive tract, thymus, and adrenal gland correspond to the respective organ weight changes. The thymus findings also correspond to the decrease in lymphocytes noted in the hematology data. The small intestine finding may correspond to the decreased body weight and food consumption changes and clinical signs. All findings were considered drug-related, but only the effects observed in male reproductive tract, thymus, and eye were considered adverse. Toxicokinetics Plasma drug levels were measured at 2, 6, 12, and 24 hours postdose on day 1 and weeks 26 and 52. Toxicokinetic parameters are presented in Table 64 (copied from the study report). Source: Review Team

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 63. Toxicokinetic Parameters in Monkey s

Source: Study Report # 96036

General Toxicology: Additional Studies

Three-Month Oral Toxicity Study in Rats / Study No. 96030 A 3-month oral toxicity study of lonafarnib was performed in Sprague Dawley rats at dose levels of 0, 30, 90, and 180 mg/kg/day. Two females in the high-dose group died on weeks 3 and 12 due to emaciation. The major effects included a decrease in white blood cell (WBC) count (mid- and high-dose groups), lymphoid hypocellularity in spleen, thymus, and mesenteric lymph node (mid- and high-dose groups), necrosis and vacuolation in parathyroid (high-dose females), bone marrow hypocellularity (mid- and high-dose females), mineralization in kidneys (mid- and high- dose females), necrosis in pancreas (mid- and high-dose females), and altered spermatogenesis in high-dose males. A NOAEL was identified at 30 mg/kg/day.

Three-Month Oral Toxicity Study in Monkeys / Study No. 96612 A 3-month oral toxicity study of lonafarnib was conducted in cynomolgus monkeys with dose levels of 0, 15, 30, and 60 mg/kg/day. Two males in the high-dose group died on weeks 3 and 9 due to hemorrhage and severe thrombocytopenia. These animals exhibited mild to severe atrophy of lymphoid organs, severe bone marrow hypocellularity, gastrointestinal ulcers, liver necrosis, and degeneration of seminiferous tubules. The surviving animals in the 60 mg/kg/day group exhibited reductions in red blood cells (13%) and white blood cells (28%), increased ALT (70%), and necrosis of retina. Bone marrow and thymus hypocellularity occurred in the 30 and 60 mg/kg/day groups. Increased levels of hepatic P450 levels occurred in all treatment groups. The NOAEL was 15 mg/kg/day. However, the drug was tolerated at 30 mg/kg/day.

Special Toxicology

A Three-Month Electroretinography Study of SCH 66336 in Cynomolgus Monkeys With a Three-Month Postdose Evaluation / Study No. 97263 This study was conducted to evaluate the potential effects of lonafarnib, a farnesyltransferase inhibitor, on retinal function and vision. Rhodopsin kinase, a farnesylated G-protein-coupled receptor kinase, is involved in phototransduction in rod cells. Mortality, clinical signs, body weight, food consumption, hematology, toxicokinetics, direct and indirect ophthalmic exams,

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) electroretinography, and histopathology of ocular tissues were evaluated in cynomolgus monkeys following daily nasogastric gavage doses of 15 or 60 mg/kg/day lonafarnib (3/sex/group). The low-dose animals were treated daily for 92 days and were euthanized after a 3-month recovery period on day 183. The high-dose animals were euthanized after 6 weeks of treatment (day 42) for collection of ocular tissues for histopathology. True concurrent controls were not included, but 4 untreated animals from the testing facility’s colony underwent ophthalmic and electroretinographic evaluation at week 5 and were euthanized on day 42 along with the surviving high-dose animals. One high-dose male was euthanized prematurely on day 18 due to adverse clinical signs (diarrhea, dehydration, skin turgor, and decreased activity), decreased WBCs and platelets, and a 15% decrease in body weight. The death of this animal was considered drug related. In addition, diarrhea, dehydration, and decreased activity were observed in most animals at both doses, and decreased red blood cells, neutrophils, lymphocytes, and platelets were also observed at the high dose. No drug-related changes in ophthalmoscopic parameters or histopathology in the eye were observed. Drug-related decreases in amplitude of the electroretinograms (ERGs) recorded under the scotopic (dark-adapted or low-light, rod-isolating) blue, red, and white conditions were observed at several time points throughout the treatment period in the 15 and 60 mg/kg/day groups, with dose-dependent severity. Drug-related increases in ERG latency were observed dose dependently in both treatment groups under scotopic blue and white conditions, but a decrease in ERG latency was observed under scotopic red conditions. All scotopic ERG changes appeared to return to baseline by the end of the recovery period, with the exception of the decreased ERG amplitude under scotopic blue conditions at 60 mg/kg/day. However, it is unclear whether this was a true lack of recovery given the absence of concurrent controls. No differences in ERG waveforms were observed under photopic (light-adapted or high-light, cone- isolating) conditions. Because differences were observed under scotopic conditions, but not under photopic conditions, it was concluded that a drug-related effect on rod-dependent, low- light vision occurred in this study. Furthermore, the low-dose findings were generally less severe than at the high dose and were not present at the end of the recovery period, suggesting that the low-dose findings were less likely to confer a noticeable change in vision. The changes at the high dose, however, may be sufficient to result in mild night blindness. A NOAEL was not established in this study due to adverse, drug-related findings at both dose levels, and the absence of true concurrent controls. The changes at 15 mg/kg/day, however, were minimal and may be reversible.

Impurity Studies

(b) (4) Compound (b) (4) The Applicant performed a QSAR analysis for compound using Leadscope statistical-based and expert rule-based methods. The QSAR results indicated that compound (b) (4) is predicted to be negative for bacterial mutagenicity.

(b) (4)

(b) (4) was evaluated by the CDER/OTS/OCP/DARS Computational Toxicology Consultation Service for bacterial mutagenicity using QSAR models including Derek Nexus, Leadscope, and CASE Ultra. All these model outputs were reviewed with the use of

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) expert knowledge in order to provide additional supportive evidence on the relevance of any predictions and a rationale to support the final conclusion. Based on the entire weight of evidence, (b) (4) is predicted to be negative for bacterial mutagenicity.

Chiral Impurity The Applicant proposed an acceptance criterion for the chiral impurity at(b) (4) % in drug substance, which is higher than the qualification threshold of 0.15% set by International Council for Harmonisation (ICH) Q3A(R2) (June 2008). Based on the proposed limit, the maximum (b) (b) 2 daily dose of chiral impurity will be(4) mg/day (or(4) mg/m ). No toxicities were observed in a 28- day oral toxicity study in rats treated with chiral impurity doses of 1.055, 1.406, or 1.758 mg/kg/day (test article was lonafarnib containing the chiral impurity). The high dose of 1.758 mg/kg/day is approximately 10.5 mg/m2/day, which is (b) (4) times maximum potential (b) 2 human dose ((4) mg/m /day) at the proposed acceptance criterion. Therefore, the rat toxicology study provides a reasonable assurance of safety for the proposed limit.

Genetic Toxicology Table 64. Genetic Toxicology Study No./ Study Title Key Study Findings Bacterial reverse-mutation /RQDIDUQLE ZDV WHVWHG DW FRQFHQWUDWLRQV XS WR  ȝJSODWH ZLWK S. assay / #97526, #97527 typhimurium strains TA97a, TA98, TA100, TA102, and TA1535, and the GLP compliance: Yes E. coli strain WP2 uvrA in the presence and absence of S9. Lonafarnib Study is valid: Yes did not produce increases in revertants greater than 2-fold, relative to solvent control (dimethyl sulfoxide [DMSO]) in any study. Thus, lonafarnib was not mutagenic. Chromosomal Aberration Lonafarnib was tested at concentrations up to 40 ȝJP/ without S9 and Assay in Human Whole up to  ȝJP/ ZLWK 6 LQ Kuman whole blood lymphocytes. Lonafarnib Blood Lymphocytes / did not increase the incidence of structural chromosome aberrations #96210, #96033 under the conditions tested. Thus, lonafarnib was not clastogenic. GLP compliance: Yes Study is valid: Yes Mouse bone marrow Lonafarnib was tested in mice at doses of 15, 30, 50 (males only), or 60 micronucleus study of SCH (females only) mg/kg/day (intraperitoneal), administered for two days. 66336 / #96049 Lonafarnib was negative for the induction of micronuclei in bone marrow GLP compliance: Yes polychromatic erythrocytes under the conditions tested. Study is valid: Yes Other genetic toxicology None studies Source: Review Team 13.1.3.2. Carcinogenicity As agreed at the pre-IND meeting held on August 22, 2018 (PIND 139923), the Applicant will conduct a carcinogenicity study postapproval.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 13.1.3.3. Reproductive and Developmental Toxicology 13.1.3.3.1. Fertility and Early Embryonic Development

Fertility and Early Embryonic Developmental Toxicity Study of SCH 66336 Administered Orally by Gavage in Male Rats / Study No. 02295 Key Study Findings: x NOAEL=30 mg/kg/day for both male fertility and paternal toxicity x At doses of 90 and 180 mg/kg/day, the following changes were noted in males: decreases in body weight, pathology findings in the testes and epididymis (decreased organ weights and gross findings), and decreased fertility index. Examination of the reproductive tract from untreated females showed changes in multiple reproductive parameters (number of corpora lutea, implantation sites, live fetuses, dams with viable fetuses, pre- and postimplantation loss, and early and late resorptions) Conducting laboratory and location: Schering-Plough Research Institute, Lafayette, NJ GLP compliance: Yes Table 65. Methods of Fertility and Early Embryonic Developmental Study in Male Rats, Study 02295 Parameter Method Details Dose and frequency of dosing: 0, 30, 90, 180 mg/kg/day (once daily) Route of administration: Oral gavage Formulation/vehicle: 0.4% (w/v) aqueous methylcellulose Species/strain: Sprague-Dawley rats Number/group: 25 males Satellite groups: None Study design: Male rats were treated for 10 weeks prior to cohabitation, throughout cohabitation, and up to one day prior to the scheduled termination (up to 90 total doses). Females were not treated and were sacrificed on gestation day (GD) 14 if pregnant. Animals were cohabitated for 14 days or until mating was confirmed. Deviation from study protocol affecting None interpretation of results: Source: Review Team

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 66. Observations and Results, Study 02295 Parameters Major Findings Mortality One control male was euthanized prematurely on day 80 due to a dosing error. Clinical signs Peri-oral substance (tan/red/reddish brown) was observed in 2 low-dose, 5 mid-dose, and 8 high-dose males (also in 1 control). Perinasal substance (red/clear) was observed in 3 high-dose males. Body weights Body weights were decreased at the mid-dose (4.8-6.4%) from day 31 to 87, and at the high dose (7.0-14.4%) from day 3 to 87. Necropsy findings Small testes in 21 high-dose males (also in 1 control), flaccid testes in 14 Cesarean section data high-dose males, and discolored epididymis in 6 high-dose males. The male fertility index was decreased to 68% at the mid-dose and 8% at the high dose, as compared to 92% in controls. In the untreated females mated with the mid- and high-dose males, examination of the reproductive tract showed decreases in the number of corpora lutea, implantation sites, live fetuses, and dams with viable fetuses, and increases in pre-implantation loss. Postimplantation loss and the percent of early and late resorptions per animal were also increased at the high dose. The decreased number of implantation sites was considered secondary to the decreased number of corpora lutea. Source: Review Team

Fertility and Early Embryonic Developmental Toxicity Study of SCH 66336 Administered Orally by Gavage in Female Rats / Study No. 02293 Key Study Findings x NOAEL=10 mg/kg/day for both female fertility and maternal toxicity x At doses of 30 and 60 mg/kg/day, the following changes were noted: decreases in body weight and food consumption, decreases in fertility index, and changes in multiple reproductive parameters (number of corpora lutea, implantation sites, live fetuses, dams with viable fetuses, pre- and postimplantation loss, and early and late resorptions) Conducting laboratory and location: Schering-Plough Research Institute, Lafayette, NJ GLP compliance: Yes

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 67. Methods of Fertility and Early Embryonic Developmental Study in Female Rats, Study 02293 Parameter Method Details Dose and frequency of dosing: 0, 10, 30, 60 mg/kg/day (once daily) Route of administration: Oral gavage Formulation/vehicle: 0.4% (w/v) aqueous methylcellulose Species/strain: Sprague-Dawley rats Number/group: 25 females Satellite groups: None Study design: Female rats were treated for 2 weeks prior to cohabitation, throughout cohabitation, and up to gestation day (GD) 7 (23-28 total doses). Mated females were sacrificed on GD 14, and unmated females were sacrificed 15 days after the end of cohabitation. Males were not treated. Animals were cohabitated for 14 days or until mating was confirmed. Deviation from study protocol None affecting interpretation of results: Source: Review Team Table 68. Observations and Results, Study 02293 Parameters Major Findings Mortality None Clinical signs None Body weights Body weights were decreased 1.9-2.9% at the mid-dose and 3.4-5.1% at the high dose from Days 4 to 14, prior to cohabitation with males. Body weights were also decreased 1.2-2.4% at the mid dose and 2.6-5.5% at the high dose throughout gestation. The high-dose changes were largely attributed to body weight loss in the first week of dosing, which corresponds to decreased food consumption during the same period. Necropsy findings The female fertility index was decreased to 88% at the mid and high Cesarean section data doses, as compared to 100% in controls. Drug-related decreases in the number of corpora lutea, implantation sites, live fetuses, and dams with viable fetuses, and increases in pre- and postimplantation loss and early and late resorptions were observed at the mid and high doses. Source: Review Team 13.1.3.3.2. Embryo-Fetal Development

Embryo-Fetal Developmental Toxicity Study of SCH 66336 Administered Orally by Gavage in Rats / Study No. 02292 Key Study Findings: x Maternal NOAEL •0 mg/kg/day x Fetal NOAEL=15 mg/kg/day x Decreased fetal body weights and gravid uterine weights and changes in reproductive parameters (number of live fetuses, postimplantation loss, and early/late resorptions) were noted at 30 mg/kg/day

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Conducting laboratory and location: Schering-Plough Research Institute, Lafayette, NJ GLP compliance: Yes Table 69. Methods of Oral Embryo-Fetal Developmental Study in Rats, Study 02292 Parameter Method Details Dose and frequency of dosing: 0, 5, 15, 30 mg/kg/day (once daily) Route of administration: Oral gavage Formulation/vehicle: 0.4% (w/v) aqueous methylcellulose Species/strain: Sprague-Dawley rats Number/group: 25 pregnant females Satellite groups: None Study design: Pregnant females were treated from gestation day (GD) 6 to 17 and were sacrificed on GD 21. Deviation from study protocol None affecting interpretation of results: Source: Review Team Table 70. Observations and Results, Study 02292 Parameters Major Findings Mortality None Clinical signs None Body weights Body weights were decreased 3.0-7.0% at the high dose on GD (gestation day) 17 and 21. Similarly, body weight gain was decreased 17.6% from GD 6-17, 27.3% from GD 17-21, and 21.4% from GD 6-21 at the high dose. These changes were attributed entirely to a decrease in gravid uterine weight of 29% at the high dose relative to controls. No differences were observed in maternal body weights when adjusted for gravid uterine weights. Necropsy findings Increases in postimplantation loss and early and late resorptions, and a Cesarean section data decrease in the number of live fetuses were observed at the high dose. In addition, gravid uterine weight was decreased 29% at the high dose, which accounted for the decrease in maternal body weight at this dose. Necropsy findings A slight increase in the incidence of visceral (convoluted/ dilated ureter) Offspring and skeletal variations (lumbar rib) were observed at the high dose. The incidence of these changes were above the historical control incidence, and the generally dose-dependent increases at the mid and high doses suggests these findings are drug-related. In addition, fetal body weight was decreased 13.8% at the high dose. Source: Review Team

Embryo-Fetal Developmental Toxicity Study of SCH 66336 Administered Orally by Gavage in Rabbits / Study No. 96046 Key Study Findings:

x Maternal NOAEL=40 mg/kg/day (AUC0-24hr =85121 ng·hr/mL, Cmax =16645 ng/mL) x The following changes were noted: drug-related mortality, weight loss, decreased food consumption, abortion, and cesarean-section findings (decreases in live fetuses, corpora lutea, implantation sites and gravid uterine weight, and increased postimplantation loss) at the high dose (120 mg/kg/day), and drug related clinical signs at 40 and 120 mg/kg/day 134 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) x Fetal NOAEL was not determined due to the presence of drug-related skeletal variations and malformations at all dose levels Conducting laboratory and location: Schering-Plough Research Institute, Lafayette, NJ GLP compliance: Yes Table 71. Methods of Oral Embryo-Fetal Developmental Study in Rabbits, Study 96046 Parameter Method Details Dose and frequency of dosing: 0, 10, 40, 120 mg/kg/day (once daily) Route of administration: Oral gavage Formulation/vehicle: 0.4% (w/v) aqueous methylcellulose Species/strain: New Zealand White (Hra:[NZW]SPF) rabbits Number/group: 20 pregnant females Satellite groups: None Study design: Females were treated once daily from gestation day (GD) 7 to 19, and were euthanized on GD 29. Deviation from study protocol None affecting interpretation of results: Source: Review Team Table 72. Observations and Results, Study 96046 Parameters Major Findings Mortality Five high-dose females were euthanized prematurely between gestation day (GD) 10 and 21. Four of these animals were euthanized due to weight loss and decreased food consumption. Necropsy revealed the presence of hairballs in the stomach of these animals. The fifth animal was euthanized prematurely on GD 20 following an abortion, which was considered to be drug-related. Clinical signs The following were observed: x Abortion and subsequent euthanasia on GD 20 in one high-dose animal. x Peri-vaginal substance in 1 mid-dose and 2 high-dose animals. x Red material in cage pan in 8 high-dose animals. x Reduced number of fecal pellets in 3 low-dose, 5 mid-dose, and 7 high-dose animals (also 1 control). x Small fecal pellets in 1 low-dose, 2 mid-dose, and 2 high-dose animals. x Loose stool in 5 low-dose, 2 mid-dose, and 7 high-dose animals (also in 1 control) x No stool in 1 high-dose animal. x Discolored urine in 1 low-dose and 5 high-dose animals. All findings were considered drug-related, though only the mid- and high- dose findings were considered adverse.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Parameters Major Findings Body weights Mean body weight gain during the treatment period (GD 7 to GD 19) was decreased at the high dose (-0.01 kg at the high dose vs. 0.12 kg in the controls) in the animals that survived until the scheduled C-section. Body weights were decreased 6-12% in the 5 high-dose animals which were euthanized prematurely. Necropsy findings Hairballs were present in the stomachs of 1 low-dose and 4 high-dose Cesarean section data animals. The following were observed: x Decreased number of live fetuses (63%) and number of dams with live fetuses (53%) at the high dose. x Decreased number of corpora lutea (21%) at the high dose. x Decreased number of implantation sites (20%) at the high dose. x Increased pre-implantation loss (5-fold) at the mid dose. x Increased postimplantation loss (9-fold) at the high dose. x Increased early resorptions (9-fold) at the high dose. x Decreased gravid uterine weight (25%) at the high dose. All high-dose findings were considered drug-related and adverse. The increased preimplantation loss at the mid-dose was considered incidental and unrelated to treatment. Necropsy findings Fetal body weight was decreased 9% at the high dose, which may be Offspring related to the higher incidence of reduced skeletal ossification. Fetal variations and malformations are presented in the tables below. The data shows increases in multiple skeletal variations and malformations, which were above historical background levels (noted with a * in the following tables, copied from the study report). Source: Review Team

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 73. Fetal Variations and Malformations

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Source: Study Report # 96046 Blood was collected from pregnant rabbits in this study for generation of toxicokinetic data, which is shown in the table below. Table 74. TK Parameters From the Rabbit Embryofetal Development Study Dose (mg/kg) AUC0-24hr (ng•hr/mL) Cmax (ng/mL) Tmax (hr) 10 11,728 1869 2.67 40 85,121 16645 3 120 1,020,613 91400 6 Source: Review Team Abbreviations: TK, toxicokinetic 13.1.3.3.3. Prenatal and Postnatal Development

A Pre- and Postnatal Developmental Toxicity and Maternal Function Study of SCH 66336 Administered Orally by Gavage in Rats / Study No. 96047 Key Study Findings: x Maternal NOAEL=10 mg/kg/day due to adverse decreases in body weight and body weight gain at the high dose of 20 mg/kg/day x Developmental NOAEL •0 mg/kg/day Conducting laboratory and location: (b) (4) GLP compliance: Yes

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 75. Methods of Oral Pre- and Postnatal Developmental Study in Rats, Study 96047 Parameter Method Details Dose and frequency of 0, 5, 10, 20 mg/kg/day (once daily) dosing: Route of administration: Oral gavage Formulation/vehicle: 0.4% (w/v) aqueous methylcellulose Species/strain: Sprague-Dawley rats Number/group: 25 pregnant females Satellite groups: None Study design: F0 females were treated once daily from gestational day (GD) 6 to postnatal day (PND) 20. F0 females that delivered were euthanizedon PND 21. F1 animals were weaned at PND 21, at which point all F0 females that delivered were euthanized. On PND 4, 8 F1 animals/litter (~4/sex) were selected for further analysis and the remainder were euthanized. On PND 21, 1 F1 animal/sex/litter (25/sex/group total) were selected for further analysis and the remainder were euthanized. Surviving F1 animals were cohabitated for breeding at approximately PND 85. All remaining F1 males were euthanized after F2 pup delivery. All F0 and F1 females that failed to deliver were euthanized on postmating Day 25. The remaining F1 animals and F2 pups were euthanized on PND 7. Deviation from study None protocol affecting interpretation of results: Source: Review Team

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 76. Observations and Results, Study 96047 Parameters Major Findings Mortality None Clinical signs None Body weights Body weights were decreased by 3.4-4.1% at the high dose on gestation day (GD) 18 and 20. Body weight gain was decreased by 15.1% at the high dose from GD 6 to 20. Necropsy findings None Necropsy findings F1 Generation: Offspring Between birth and postnatal day (PND) 16, pups (litters) that were found dead numbered 7(4), 5(4), 5(5), and 12(8) in the control, low-dose, mid- dose and high-dose groups, respectively. Most of these deaths occurred between birth and PND 4. No findings were observed upon necropsy in these pups. In addition, 3, 1, 5, and 5 pups from the same respective groups were missing and presumed cannibalized. These findings were considered incidental and unrelated to treatment as they were within historical control ranges. Postweaning, one high-dose male was found dead on PND 117. There were no necropsy findings or body weight changes in this animal, and cause of death could not be established. It is unclear if this death was drug-related or incidental. A second high-dose male was euthanized on PND 69 due to a fractured palate. This was considered incidental and unrelated to treatment. Prior to weaning on PND 21, pups (litters) that were considered small in size numbered 8(5), 4(2), 5(5) and 31(20) in the control, low-dose, mid- dose, and high-dose groups, respectively. Despite the apparent increased incidence at the high dose, no differences were observed in body weight, so the significance of this finding is unclear. One control, 2 mid-dose, and 2 high-dose females failed to give birth and were euthanized 25 days postmating. All but 1 of the mid-dose females were nongravid. A second control female had no evidence of mating and was also shown to be nongravid. Additionally, 1 control, 1 low-dose, and 1 high-dose female experienced total litter loss on PNDs 2, 6, and 4, respectively. The litter loss at the low dose was due to drowning (cage was flooded with water). All other deaths were due to unknown causes. Due to the low incidence and lack of dose dependence, all findings were considered incidental and unrelated to treatment. F2 Generation: Between birth and PND 7, pups (litters) that were found dead numbered 18(7), 9(7), 4(4), and 20(6) in the control, low-dose, mid-dose, and high- dose groups, respectively. In addition, 7, 3, 3, and 5 pups from the same respective groups were missing and presumed cannibalized. Due to the lack of dose response and the incidence in controls, all findings were considered incidental and unrelated to treatment. Five pups among 2 litters at the high dose experienced subcutaneous hemorrhage in various areas of the body on PND 0 and 1. It is unclear if this finding was drug- related or incidental. Abnormally positioned kidneys (located more posterior than normal) were observed in 4 pups in a single litter at the high dose. As this finding was observed in only a single litter, it is unclear if this was drug-related or incidental. Source: Review Team 140 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Referenced INDs Nonclinical studies, including safety pharmacology, ADME (absorption, distribution, metabolism, and excretion), repeat-dose toxicology, genetic toxicology, and reproductive and developmental toxicology studies have been reviewed under IND (b) (4) and are summarized in the appropriate sections of this review. 13.2. Individual Reviews of Studies Submitted to the NDA

Secondary Pharmacology Lonafarnib and its metabolite HM21 were screened for off-target activity through functional assays (activation and inhibition) for 51 molecular targets. Lonafarnib and HM21 had low activity at most of the targets, with IC50 or EC50>10μM. Lonafarnib had moderate activity for ȕ1 adrenoceptors and cannabinoid 1 and 2 receptors, with IC50 values of 1.2 to 2.1μM. Metabolite HM21 had moderate activity for ȕ1 adrenoceptors, cannabinoid 2 receptors, and mu-1 opioid receptors, with IC50 values of 3.5 to 4.5μM. Metabolite HM21 had moderate activity for 5-HT1B receptors with EC50 of ~2.2μM.

A 28-Day Repeat Dose Toxicity Study of a Mixture of Lonafarnib Impurities in Sprague Dawley Rats / Study No. 2555-15001 Key Study Findings: x A mixture of three impurities (Compound (b) (4) and chiral impurity) was given by oral gavage to rats for up to 28 days x The NOAEL was identified as the highest tested dose of the impurity mixture, which delivered (b) (4) mg/kg/day Compound(b) (4) mg/kg/day (b) (4) and (b) (4) mg/kg/day chiral impurity Conducting laboratory and location: (b) (4) GLP compliance: Yes Table 77. Features and Methods, Study 2555-15001 Study Features and Methods Details Dose and frequency of dosing: Compound (b) (4) /Chiral Impurity 0/0/0, 0.368/0.079/1.055, 0.49/0.105/1.406, or 0.613/0.131/1.758 mg/kg/day / once daily Route of administration: Oral gavage Formulation/vehicle: 0.4% w/v suspension of methylcellulose in water Species/strain: Sprague Dawley rats Number/sex/group: 10/sex/group Age: 8-9 weeks Satellite groups/unique design: None Deviation from study protocol affecting None interpretation of results: Source: Review Team

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 78. Observations and Results, Study 2555-15001 Parameters Major Findings Mortality None Clinical signs None Body weights None Ophthalmoscopy Not performed ECG Not performed Hematology None Clinical chemistry None Urinalysis None Gross pathology None Organ weights None Histopathology None Adequate battery: Yes Source: Review Team 14. Clinical Pharmacology: Additional Information and Assessment 14.1. In Vitro Studies

Plasma Protein Binding x Study SN98139: Lonafarnib was highly bound to human plasma proteins • WR 99.7%) over the concentration range from 0.5 to 40 μg/mL. x Study SN98276: The extent of binding of [14C]-ORQDIDUQLE  ȝJP/ DQG  ȝJ/mL) to purified serum proteins ranged from 94% to 98% for human serum albumin (2% to 4%), alpha-1-acid glycoprotein (0.1%), and various human serum albumin/alpha-1-acid glycoprotein combinations.

Metabolism (CYP450 Phenotyping) x Study 15EIGEP1: A non-GLP study to evaluate the role of CYP450 enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A) in the metabolism of lonafarnib using two in vitro approaches, i.e., human recombinant CYP450 enzymes (rhCYPs) and liver microsomes with CYP-selective chemical inhibitors. – 3KHQRW\SLQJ E\ WKH UK&<3V PHWKRG VXJJHVWHG WKDW &<3$  ȝ/PLQPJ OLYHU SURWHLQ  FRQWULEXWLRQ DQG &<3&  ȝ/PLQPJ OLYHU SURWHLQ  contribution) are the major isoforms responsible for lonafarnib metabolism with other CYPs contributing to a less extent &<3&  ȝ/PLQPJ OLYHU SURWHLQ  FRQWULEXWLRQ  &<3&  ȝ/PLQPJ OLYHU SURWHLQ  FRQWULEXWLRQ  DQG CYP2E1 (3.0 ȝ/PLQPJ OLYHU SURWHLQ  FRQWULEXWLRQ .

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) – Phenotyping by the human liver microsome method suggested that the metabolism of lonafarnib in human liver microsomes was mainly by CYP3A; although CYP1A2 and CYP2A6 might be also involved.

Inhibition of Cytochrome P450 Enzymes by Lonafarnib x Study CYP1838 R3A: Lonafarnib is a potent CYP3A time-dependent and mechanism- based inhibitor and a moderate inhibitor of CYP2C19. Lonafarnib is considered to possess reversible inhibitor activity for CYP2C8 ([IC50]=19.6±2.99ȝM); however, this concentration is not clinically relavent at the recommended dosing regimens. Lonafarnib is not considered an inhibitor of other tested CYPs (CYP1A2, CYP2B6, CYP2C9, or CYP2D6). Lonafarnib is also not considered a time-dependent inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, or CYP2D6 at any of the six tested concentrations (0.2, 0.5, 2, 5, 20, and 50ȝM).

Induction of Cytochrome P450 Enzymes by Lonafarnib x Study 14EIGEP1_Study 6: Lonafarnib is unlikely to be an inducer of CYP1A2, CYP2B6, and CYP3A4. Lonafarnib did not increase either enzyme activity or mRNA expression of CYP1A2, CYP2B6, and CYP3A (<2-fold versus vehicle control and <20% of positive control) at any of the three tested concentrations (0.674, 6.74, and 20.2ȝM).

Inhibition of Transporters by Lonafarnib x Study 14EIGEP1: Lonafarnib did not significantly inhibit the uptake transporters OATP1B3, OAT1, OAT3, or OCT2 at 12ȝM (34.1%, 11.3%, 0%, and 7.05% inhibition, respectively), but had greater than 50% inhibition of OATP1B1, BCRP, and P-gp (62.5%, 93.9%, and 95.3%, respectively).

x Study CYP1838 R1:The IC50 values for OATP1B1, P-gp, and BCRP were 6.69, 1.45, and 0.740ȝM, respectively. Lonafarnib had no inhibitory activity on BSEP, inhibite d OCT1 with an IC50 of 0.80ȝM, and inhibited MATE1 and MATE2-K with an IC50 of 1.91 and 2.55ȝM, respectively. However, the assessment of [Cmax u]/IC50 ratios indicated that lonafarnib is unlikely to cause a clinical DDI via inhibition of MATE2-K or MATE1 at the recommended 115 mg/m2 and 150 mg/m2 dosages x Study CYP1838 R2: Lonafarnib is not a substrate of OATP1B1, OATP1B3, or BCRP, but is likely a marginal substrate of P-gp. 14.2. In Vivo Studies

Absorption, Distribution, Metabolism, and Excretion of [14C]-Lonafarnib, Study P00260

Description A single-dose, open-label study to characterize the ADME of [14C]-lonafarnib following a single 104 mg (107 ȝCi) oral suspension dose administered under fasted conditions in healthy subjects (N=9). Serial blood and plasma PK samples were collected for up to 10 days, urine PK samples were collected in block intervals from 0 to 8 hours up to 10 days, and fecal samples were collected daily over 10 days (patients 1 to 6) or 28 days (patients 7 to 9).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Results

The plasma Cmax of lonafarnib was observed from 2 to 5 hours postdose. The mean elimination half-life was approximately 3 hours. Lonafarnib was extensively metabolized with 21 metabolites characterized in plasma, urine, and feces. The common pathways included oxidation, dehydrogenation, and combinations of these two processes. The two most predominant metabolites identified were HM17 (by oxidation) and HM21 (by dehydrogenation). No single uncharacterized metabolite represented more than 5% of the dose. All human metabolites were detected in rats or monkeys. The drug-derived radioactivity was primarily excreted via feces with the mean total recovery of 61.6% of the radioactive dose. Radioactivity excreted into the urine was less than 1% of the dose. Total body clearance was 834 mL/min (50 L/h) and renal clearance was negligible (0.03 mL/min).

Effect of Age and Sex on Lonafarnib PK: Study P02673

Description A phase 1, single-dose study to evaluate the effect of age (• \HDUV versus 18 to 45 years) and sex (female versus male) on the PK of lonafarnib (SCH 66336) in 48 healthy adult subjects following a single dose of 100 mg lonafarnib after consuming a standardized meal.

Results The PK parameters are shown in Table 80. Lonafarnib exposure was higher in females versus males and in elderly subjects versus young subjects.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 79. Mean Pharmacokinetic Parameters of Lonafarnib Following Single-Dose Oral Administration of 100 mg Lonafarnib, Study P02673

Source: Table in Study P02673 Study Report synopsis

Hepatic Impairment, Study EIG-LNF-003

Description A phase 1, open-label, parallel-group study that investigated the effects of mild hepatic impairment (Child-Pugh score 5 to 6) and moderate hepatic impairment (Child-Pugh score 7 to 9) on the PK of lonafarnib compared with matched control patients with normal hepatic function. Matching was based on age±10%, BMI±20%, and sex. Single-dose lonafarnib 50 mg was administered in the presence of single dose ritonavir 100 mg under fasted conditions. Serial PK samples were collected for 96 hours. The PK of lonafarnib was not studied in patients with severe hepatic impairment (Child-Pugh score greater than 9). The effect of hepatic impairment on the protein binding of lonafarnib was not studied.

Results

The PK results are summarized in Table 81. The exposure (AUCinf) in subjects with mild and moderate hepatic impariment was 11% lower and 13% higher, respectively, than the matched controls. Administration of lonafarnib was generally well tolerated in this study and no new clinically significant safety signals were observed. The coadministration of ritonavir complicates the interpretation of the effect of hepatic impairment on the PK of lonafarnib. The discussions on the related key review issues are included in Sections 7.7.4.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 80. Summary of Lonafarnib Pharmacokinetic Parameter Following a Single Dose of Lonafarnib (50 mg) and Ritonavir (100 mg) in Patients With Mild and Moderate Hepatic Impairment and Normal Hepaticp Function, Studyy EIG-LNF-003

Source: Table 12 in Study EIG-LNF-003 CSR

Renal Impairment, Study EIG-LNF-006

Description A phase 1, open-label, parallel-group study that investigated the effect of moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2) and severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) on the PK of lonafarnib relative to matched control patients with normal renal function. Matching was based on age ±10%, BMI ±20%, and sex. Single-dose lonafarnib 50 mg was administered in the presence of single dose ritonavir 100 mg under fasted conditions. Serial PK samples were collected for 96 hours.

Results The PK results are summarized in Table 82. There was a trend toward increases in lonafarnib exposures and prolonged elimination half-lives (48% to 55% increase) in patients with moderate or severe renal impairment relative to patients with normal renal function. The coadministration of ritonavir complicates the interpretation of the effect of renal impairment on the PK of lonafarnib. The discussions on the related key review issues are included in Sections 7.7.4 and 7.7.5.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 81. Summary of Lonafarnib Pharmacokinetic Parameter Following a Single Dose of Lonafarnib (50 mg) and Ritonavir (100 mg) in Patients With Severe and Moderate Renal Impairmentp and Normal Renal Function, Study EIG-LNF-006

Source: Table 13 in Study EIG-LNF-006 CSR Abbreviations: GM, geometric mean; GMCV, geometric mean coefficient of variation

Study EIG-LNF-017: Food Effect (Group 2)

Description Study EIG-LNF-017 is an open-label study consisting of three substudies, i.e., a two-period, single-sequence, DDI study for lonafarnib and omeprazole (group 1), a three-period crossover pivotal food-effect study with lonafarnib (group 2), and a two-period crossover food-effect study with lonafarnib and ritonavir combination (group 3) in healthy subjects: x Group 1: single-dose omeprazole 40 mg capsule (a sensitive CYP2C19 substrate) (see Section 14.2.1). x Group 2: single-dose lonafarnib 75 mg with food (high-fat/high-calorie standard breakfast and low-fat/low-calorie breakfast) and without food. x Group 3: single-dose of lonafarnib and ritonavir combination with food (high-fat/high- calorie standard breakfast) and without food. Results from this group were not submitted in this NDA. 147 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) In group 2, in the morning on days 1, 4, and 7 following a minimum 10-hour overnight fasting, subjects received a single dose of lonafarnib 75 mg under a high-fat fed state, low-fat fed state, and fasted state, respectively. Serial PK samples were collected for 48 hours.

Results (Group 2) The PK results are summarized in Table 83. Both high-fat/high-calorie and low-fat/low-calorie meal decreased the exposures of lonafarnib relative to a fasted state, and delayed Tmax.The ratio of Cmax of lonafarnib between fed vs. fasted was 47% and 78% for a high-fat/high-calorie and low-fat/low-calorie breakfast, respectively, and AUC ratios were 74% and 83%, respectively. Table 82. Food Effect on Lonafarnib Following Single-Dose Administration of Lonafarnib 75 mg, Groupp 2, Studyy EIG-LNF-017

Source: Table 22 in Study EIG-LNF-017 CSR Abbreviations: CI, confidence interval; CV, coefficient of variation; GMR, geometric mean ratio; LNF, lonafarnib; LSM, least square mean

Study P00042

Description A randomized, open-label, two-way crossover study in 12 healthy subjects (2 males and 10 females). Each subject received a single dose of lonafarnib 100 mg under fasted conditions and a standardized high-fat breakfast, with a 14-day washout period. Serial PK samples were collected for 48 hours.

Results The PK results are summarized in Table 84. High-fat/high-calorie meal decreased the rate and extent of lonafarnib absorption relative to a fasted state, and delayed Tmax. Cmax and AUC of lonafarnib was decreased by 52% and 23%, respectively.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 83. PK Parameters of Lonafarnib Following Single Dose Administration of Lonafarnib 100 mg in Fed and Fasted Conditions, Study P00042

Source: Table 4 in Study P00042 CSR

Abbreviations: AUC(tf), area under the plasma concentration from time 0 to tine of final quantifiable, CV, coefficient of vari ation; PK, pharmacokinetics 14.2.1. Drug-Drug Interaction Studies CYP3A Drug-Drug Interaction Study (Lonafarnib as a Victim) Lonafarnib is a substrate of CYP3A. The effects of ketoconazole (a potent CYP3A inhibitor; study P00393) and rifampin (a potent CYP inducer; study EIG-LNF-007, group 1) on the PK of lonafarnib were evaluated in healthy subjects. Lonafarnib alone or a combination of lonafarnib and ritonavir was studied. Ritonavir is mainly metabolized by CYP3A and 2D6. Ritonavir is also a strong inhibitor of CYP3A and to a less extent to CYP2D6, OATP, and P-gp, and induces CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6.

Study P00393: Ketoconazole

Description Randomized, open-label, two-way crossover study in 16 healthy subjects (14 females/2 males). Each subject received each of the following two treatments: treatment A (placebo daily on days 1 to 5 and lonafarnib 50 mg capsule on day 5) and treatment B (ketoconazole 200 mg daily on days 1 to 5 and lonafarnib 50 mg capsule on day 5), with a 14-day washout period between the two dosing periods.

Results

The PK results are summarized in Tables 85 and 86.The Cmax and AUC(I) of lonafarnib coadministered with ketoconazole were increased 370% and 525%, respectively.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 84. PK Parameters of Lonafarnib Following Single Dose Administration of Lonafarnib 50 mg With or Without Ketoconazole, Study P00393

Source: Table 4 in Study P00393 CSR Abbreviations: CV, coefficient of variation; PK, pharmacokinetic Table 85. Effect of Ketoconazole on PK of Lonafarnib, Study P00393 Dose of Relative Bioavailability (%)(90% CI) Coadministered Coadministered Dose of Drug Drug Lonafarnib Cmax AUC(tf) AUC(I) Ketoconazole 200 mg QD for 5 50 mg single dose 370 (304-449) 536 (425-677) 525 (418-657) days Source: Table 5 in Study P00393 CSR Abbreviations: CI, confidence interval; PK, pharmacokinetics; QD, once daily

EIG-LNF-007 (Group 1): Rifampin

Description Study EIG-LNF-007 is a phase 1, open-label study consisting of 2 groups in 36 healthy subjects with 18 in each group. x Group 1 (CYP3A induction evaluation): single-sequence, 2-period, DDI study with rifampin (a potent CYP3A inducer) x Group 2 (food effect evaluation): single-sequence study for food-effect (high-fat/high- calorie standard breakfast). See Section for Study EIG-LNF-017: Food Effect (Group 2) In group 1, each patient received a single dose of lonafarnib 50 mg and ritonavir 100 mg on days 1 and 13 following a minimum 10-hour overnight fasting, and rifampin 600 mg daily from days 6 to 13. Serial PK samples were collected for 72 hours.

Results (Group 1) When multiple-dose rifampin was coadministered with single-dose lonafarnib 50 mg and ritonavir 100 mg, the exposures of lonafarnib were dramatically decreased (see Table 87 below). The elimination half-life was shortened from 11 hours to 2 hours. The Cmax and AUC of lonafarnib (coadministered with ritonavir) with rifampin was 8% and 1.9%, respectively, of that without rifampin (see Table 88).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 86. PK Parameters of Lonafarnib Following Single Dose Administration of Lonafarnib 50 mg and Ritonavir 100 mg With or Without Rifampin, Study EIG-LNF-007

Source: Table 13 in Study EIG-LNF-007 CSR Abbreviations: GM, geometric mean; GMCV, geometric mean coefficient of variation; LNF, lonafarn b; PK, pharmacokinetic; RTV, ritonavir Table 87. Effect of Rifampin on PK of Lonafarnib, Study EIG-LNF-007 Dose of Relative Bioavailability (90% CI) Coadministered Coadministered Dose of Drug Drug Lonafarnib Cmax AUC(tf) AUC(I) Rifampin 600 mg QD for 5 50 mg single dose 0.08 0.015 0.019 days (and ritonavir (0.061-0.105) (0.012-0.020) (0.013-0.027) 100 mg single dose) Source: Table 14 in Study EIG-LNF-007 CSR Abbreviations: CI, confidence interval; PK, pharmacokinetics; QD, once daily Effect of Lonafarnib on CYPs and Transporters (Lonafarnib as a Perpe trator) Lonafarnib is a potent time-dependent and mechanism-based inhibitor of CYP3A. Lonafarnib is also an inhibitor of CYP2C8 and CYP2C19 and transporters P-gp, OATP1B1, OATP1B3, and BCRP. The following clinical DDI studies were conducted to evaluate the effects of multiple dose lonafarnib on the PK of substrates (CYPs and transporters) following single-dose administration. x Study EIG-LNF-016: CYP3A inhibition on midazolam; and P-gp and OATP1B inhibition on fexofenadine x Study EIG-LNF-015: CYP3A and P-gp inhibition on single dose loperamide x Study EIG-LNF-017: CYP2C19 inhibition on omeprazole

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Study EIG-LNF-016: Midazolam and Fexofenadine

Description An open-label, two-period, single-sequence, DDI study consisting of two groups of healthy subjects to evaluate the effects of multiple-dose lonafarnib (100 mg lonafarnib BID for 5 days) on the PK of midazolam and fexofenadine x Group 1: midazolam (a sensitive CYP3A substrate) single dose 3 mg oral syrup x Group 2: fexofenadine (a substrate for both P-gp and OATP1B) single dose 180 mg Subjects received a single dose of midazolam (group 1) or fexofenadine (group 2) under fasted conditions on day 1. On day 6 through day 10, subjects received lonafarnib BID. On the morning of day 10, subjects were given the morning dose of lonafarnib in a fasted condition with either a single dose of midazolam (group 1) or fexofenadine (group 2). Serial PK samples were collected up through 72 hours postdose on day 1 and day 10 morning dose.

Results

x Group 1: The Cmax and AUC of midazolam were significantly increased by 180% and 639%, respectively (See Table 89). The elimination T1/2 was increased by approximately 90%.

x Group 2: The Cmax and AUC of fexofenadine were slightly increased by 21% and 24%, respectively (summarized in Table 90). The T1/2 was increased by 9%. Table 88. Effect of Lonafarnib on Midazolam Exposures, Group 1, Study EIG-LNF-016

Source: Table 13 in Study EIG-LNF-016 CSR Abbreviations: CI, confidence interval; CV, coefficient of variation; GMR, geometric mean ratio; LNF, lonafarnib; LSM, least square mean

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 89. Effect of Lonafarnib on Fexofenadine Exposures,p Groupp 2, Study EIG-LNF-016

Source: Table 16 in Study EIG-LNF-016 CSR Abbreviations: CI, confidence interval; CV, coefficient of variation; GMR, geometric mean ratio; LNF, lonafarnib; LSM, least square mean

Study EIG-LNF-015: Loperamide (Antiemetic)

Description A phase 1, two-period, single-sequence study consisting of two groups of healthy subjects to evaluate the effect of multiple-dose lonafarnib on the PK of single-dose loperamide. Loperamide is a common over-the-counter antidiarrheal product. Loperamide is primarily metabolized by CYP3A and CYP2C8 (with CYP2D6 and CYP2B6 playing minor roles) and is a substrate of P- gp. x Group 1: Multiple-dose lonafarnib and ritonavir combination on the PK of single-dose loperamide. Results not submitted in this NDA x Group 2: Multiple-dose lonafarnib 100 mg BID for 5 days on the PK of single-dose loperamide 2 mg in 15 patients In group 2, subjects received a single dose of loperamide under fasted conditions on day 1. On days 6 through 10, subjects received lonafarnib BID. On the morning of day 10, subjects were given the morning dose of lonafarnib under a fasted condition with a single dose of loperamide. The final lonafarnib dose was administered 12 hours later without food. Serial PK samples for loperamide plasma concentrations were collected up through 72 hours postdose on days 1 and 10. In addition, serial PK samples for lonafarnib plasma concentrations were collected up through 12 hours postdose on day 10. Trough lonafarnib PK samples were collected prior to dosing on days 7, 8, 9, and 10.

Results The PK results are summarized in Table 91. Coadministration of multiple-dose lonafarnib 100 mg BID for 5 days increased the exposure of loperamide, with the Cmax and AUC increased by 214% and 299% compared with loperamide administered alone.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 90. PK Parameters of Single-Dose Loperamide With or Without Concomitant Multiple-Dose Lonafarnib, Group 2, Study EIG LNF 015

Source: Table 16 in Study EIG-LNF-015 CSR Abbreviations: CI, confidence interval; CV, coefficient of variation; GMR, geometric mean ratio; LNF, lonafarnib; LSM, least square mean

The T1/2 of lonafarnib following multiple dose administration was 4.22 hours. Steady-state Cmax of 964 ng/mL was reached approximately 4 hours after dosing. Steady-state PK was achieved 3 days after the first dosing.

Study EIG-LNF-017: Omeprazole (Group 1)

Description In group 1 of Study EIG-LNF-017, subjects received a single dose of omeprazole (under fasted conditions on day 1). On days 6 through 10, subjects received lonafarnib BID. On the morning of day 10, subjects were given the morning dose of lonafarnib in a fasted condition with a single dose of omeprazole. The final lonafarnib dose was administered 12 hours later without food. Serial PK samples for omeprazole plasma concentrations were collected up through 48 hours postdose on days 1 and 10 morning dose. Trough lonafarnib PK samples were collected prior to dosing on days 7, 8, 9, and 10. Serial PK samples for lonafarnib plasma concentrations were collected up through 12 hours postdose on day 9.

Results The PK results are summarized in Table 92. Coadministered multiple doses of lonafarnib 75 mg twice daily for 5 days moderately increased omeprazole’s systemic exposures at a single dose 40 mg. The Cmax and AUC of omeprazole were increased by 28% and 60%, respectively Table 91. Effect of Lonafarnib on Omeprazole Exposures, Group 1, Study EIG-LNF-017

Source: Table 17 in Study EIG-LNF-017 CSR Abbreviations: CI, confidence interval; CV, coefficient of variation; GMR, geometric mean ratio; LNF, lonafarnib; LSM, least square mean

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 14.3. Pharmacometrics Review A population pharmacokinetics (PPK) model was developed by the Applicant to characterize the PK of lonafarnib in healthy subjects and patients with HGPS. Intrinsic and extrinsic factors which influence the PK and PK variabilit y of lonafarnib were identified. The final model was used to simulate and evaluate lonafarnib exposures under different dosing regimens. In this review, the FDA pharmacometrics review team validated the Applicant’s PPK model and conducted independent analyses to evaluate the appropriateness of the Applicant’s proposed dosing regimens.

Applicant’s Population PK Analyses Three clinical studies were included in this PPK analysis: patients with HGPS from the ProLon1 study and healthy subjects from the EIG-LNF-015 (group 2) and the EIG-LNF-017 (groups 1 and 2) studies. A total of 1,166 PK observations from 76 subjects (including 28 patients with HGPS from ProLon1 study) were included in the final model estimation. Four continuous covariates (age, weight, height and body surface area [BSA]) and three categorical covariates (sex, formulation, and ethnicity) were evaluated in the PPK analysis. The final PPK model for lonafarnib is a one-compartment model with first order absorption and first order clearance. Covariates were allowed to change over time and were carried forward for imputation in the dataset if needed. The parameter estimates for the final PPK model are shown in Table 93. Table 92. Final Model Parameter Estimates for Lonafarnib PK

Source: Applicant’s population PK report Abbreviations: PK, pharmacokinetics

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) The visual predictive check (VPC) plot for the final model is shown in Figure 25. The goodness- of-fit (GOF) plots are shown in Figure 26. Figure 25. Final Model Visual Predictive Check

Source: Applicant’s population PK report

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 26. Goodness-of-Fit for the Final PPK Model

Source: Review team’s analysis Abbreviations: HGPS, Hutchinson-Gilford progeria syndrome; PPK, population pharmacokinetics Overall, based on the GOF and VPC plots, the Applicant’s population PK analysis is acceptable for describing the PK of lonafarnib in both healthy subjects and patients with HGPS, and for subsequently simulating lonafarnib exposures under different dosing regimens. Based on the Applicant’s final PPK model, the allometric scaling coefficient of body weight (BW) on clearance (CL) was estimated to be 0.748; F (bioavailability) of the suspension was estimated 20% lower than that of the capsule. The Applicant’s final PPK model included the effects of both BW and gender on CL and volume of distribution (V). Thus, the review team evaluated the potential collinearity between BW and gender. As shown in Figure 27 left, in the PPK analysis population, there was no significant correlation between BW and gender. Thus, it is reasonable to include both on CL and V. However, in the review team’s sensitivity analysis, by removing gender effect on CL and V, the objective function value (OFV) only increased by 1.755 compared to the Applicant’s final model. This increase is not considered significant. Other parameter estimates were similar between the two models. Thus, including gender effect on CL and V in addition to BW effect is not necessary.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 27. Correlation of Body Weight and Gender in PPK Analysis Dataset

Source: Review team’s analysis Abbreviation: PPK, population pharmacokinetics During the review, the review team identified a significant difference in PPK model estimated CL between healthy subjects and patients with HGPS (Figure 28, left). This difference is likely due to the significant differences in age and body weight between these two populations (Figure 28, right). Figure 28. Clearance and Body Weight Difference in Healthy Subjects and Patients With HGPS Based on the Applicant’s Final PPK Model

Source: Review team’s analysis Abbreviations: HGPS, Hutchinson-Gilford progeria syndrome; PPK, population pharmacokinetics In the Applicant’s PPK analysis, BW was identified as a more significant covariate compared to body surface area. Thus, BW was included in the final PPK model but not BSA. However, given that the Applicant originally proposed a BSA-based dosing regimen and that BW and BSA are highly correlated (Figure 29), the review team conducted sensitivity analyses by replacing BW with BSA to estimate the effect of BSA on CL and V. The model fitting was comparable to the Applicant’s final PPK model based on OFV and GOF (details refer to the Review Team’s Analyses below).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 29. Correlation Between Body Weight and Body Surface Area in the PPK Analysis Dataset

Source: Review team’s analysis Abbreviations: PPK, population pharmacokinetics In addition, the Applicant’s model did not include the interaction between the interindividual variability (IIV) of CL and V. Thus, the final PPK model’s estimation of IIV% may not be reliable.

Applicant’s Dose Regimen Simulations The Applicant originally proposed a BSA-based dosing regimen and this regimen was tested in ProLon1. However, after identifying BW as a more significant covariate on CL and conducting the simulations of various dose regimens of both a fixed dose (50 or 75 mg BID) and 5 or 7.5 mg/kg BID, the Applicant proposed a new dosing regimen that would provide similar exposure to that in ProLon1: x For patients 5 to less than 10 kg, 5 mg/kg BID x For patients 10 kg and above, 50 mg BID The simulation results are shown in Figure 30. Per the Applicant, this regimen would provide equivalent exposures across the weight range of 5 to 20 kg.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 30. Boxplots of Exposure for 5 mg/kg BID Up to 10 kg and 50 mgBID From 10–20kg

Source: Applicant’s population PK report Abbreviations: BID, twice daily; LNF, lonafarnib; PK, pharmacokinetics The Applicant’s newly proposed dosing regimen was to match the exposure observed in the ProLon1. However, it is unclear whether the BW-based regimen would match the BSA-based dosing regimen that was tested in ProLon1 and demonstrated efficacy. In addition, following each proposed dosing regimen, the trend of expected lonafarnib exposure across the relevant body size range is unknown. Thus, the FDA Review team conducted independent analyses to evaluate the necessity to pursue the alternative dosing regimen other than the originally proposed BSA-based dosing. For details refer to the Review Team’s Analyses below. Review Team’s Analyses To evaluate the appropriateness of the Applicant’s originally proposed BSA-based dosing regimen, the FDA review team conducted independent analyses for PPK modeling and simulation. PPK analyses were performed with NONMEM 7.4, and all modeling and simulation results were processed using R 4.0.0.

Population PK Modeling The review team conducted a sensitivity analysis to include BSA instead of BW on CL and V in the PPK model to evaluate the effect of BSA as below: ș CLi = CLtypical × (BSAi/BSAtypical) In the review team’s analysis, the OFV of the Applicant’s final PPK model is 12849.696, while the OFV of the PPK model in the sensitivity analysis is 12859.821. The model estimates in the review team’s sensitivity analysis are shown in Table 94. The GOF plots are shown in Figure 31. 160 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 93. Parameter Estimates for Review Team's PPK Model in Sensitivity Analysis Parameter Description Value RSE THETA1 KA 0.197 9% THETA2 CL 23.3 17.9% THETA3 V 87 17.1% THETA4 ADD ERR 0 (FIXED) THETA5 PROP ERR 0.442 5.6% THETA6 BSA~CL 1.26 13.7% THETA7 BSA~V 1.26 20.6% THETA8 SEX(F)~CL 20.4 12.3% THETA9 SEX(F)~V 85 14.5% THETA10 F1 suspension 0.77 26.8% THETA11 F1 capsule 1 (FIXED) OMEGA(1,1) IIV CL 41.1% 22.2% OMEGA(2,2) IIV V 27.4% 149.6% OMEGA(3,3) IIV KA 11.3% 25.7% OMEGA(4,4) IIV F1 53.1% 22.5% SIGMA(1,1) RV 1 (FIXED) Source: Review team’s analysis Abbreviations: PPK, population pharmacokinetics; RSE, relative standard error Figure 31. Goodness-of-Fit Plots for Review Team’s PPK Model in Sensitivity Analysis

Source: Review team’s analysis Abbreviations: HGPS, Hutchinson-Gilford progeria syndrome; PPK, population pharmacokinetics Based on both OFV and GOF plots, the model fitting appears comparable between the Applicant’s final PPK model and the review team’s model with BSA’s effect on CL and V.

Simulations for Dosing Regimens Using the Applicant’s final PPK model, the FDA review team conducted PK simulations to compare the following dosing regimens: x Originally proposed BSA-based dosing regimen: 115 mg/m2 and 150 mg/m2 BID x Newly proposed BW-based dosing regimen: 5 mg/kg BID for ”0 kg and 50 mg BID for 10-20 kg) x 5 mg/kg BID regardless of BW 161 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) To maintain reasonable correlation amongst BW, height, BSA, and gender, the virtual patients used for simulation had the same demographic characteristics with the population in ProLon1. The continuous baseline demographic characteristics are summarized in Table 95.The ratio of males to females was 11 to 17. The simulation for each dosing regimen was replicated for 1,000 times. Table 94. Summary of Continuous Baseline Demographic Characteristics for the Population in the Simulations for Dosing Regimens Parameters Age (Years) Body Weight (kg) Height (cm) BSA (m2) Mean (SD) 7.1 (3.2) 10.8 (3.2) 97.0 (13.8) 0.54 (0.12) 25th 4.0 8.6 86.6 0.46 Median 7.5 9.8 94.7 0.51 75th 9.0 12.0 103.6 0.58 Min, max 3.0, 16.0 6.8, 20.9 76.5, 134.3 0.38, 0.88 Source: Review team’s analysis Abbreviations: BSA, body surface area; SD, standard deviation As shown in Figure 32 WKH H[SHFWHG $8&IJ RI ORQDIDUQLE DW VWHDG\ state are consistent across all the body weight tiers (5 to less than 10 kg, 10 to less than 15 kg, and 15 to 20 kg) under each dosing regimen. The Applicant’s newly proposed dosing regimen (5 mg/kg and 50 mg) appears to provide comparable steady-VWDWH $8&IJ FRPSDUHG to the originally proposed starting dose of the BSA-based dosing regimen (115 mg/m2), but it was slightly lower than the high target dose of 150 mg/m2 (after titration). Figure 32. Final PPK Model PUHGLFWHG $8&IJ RI Lonafarnib at Steady-State Across Body Weight Tiers Under Different Dosing Regimens

Source: Review team’s analysis $EEUHYLDWLRQV$8&IJDUHD XQGHUWKH SODVPD FRQFHQWUDWLRQ-time curve for a dosing interval; PPK, population pharmacokinetics To evaluate the potential exposure variation for a wider BSA range compared to that in ProLon1, the FDA review team calculated the predicted AUCIJ at steady-state for patients with a BSA range of 0.25 to 0.9 m2. Given the large IIV% and the uncertainty in the correlation amongst the demographic characteristics in HGPS patient population, only typical values were plotted. This

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) prediction was based on the relationship estimated by the PPK model in the review team’s sensitivity analysis shown below: 1.26 CLtypical =23.3×(BSA/1.76) As shown in Figure 33, the AUCIJ at steady state is expected to be higher in patients with low BSA than in patients with high BSA. For the BSA range of 0.25 to0.9 m2, the AUCIJ for the patient with the lowest BSA is predicted to be approximately 1.4-fold of the patient with the highest BSA for both 115 mg/m2 and 150 mg/m2 dosing regimens. However, since a BSA of at least 0.39 m2 is required for the proposed dosing regimens for lonafarnib capsules due to the limitations of the available strengths, the variation within the recommended BSA range is not considered clinically significant. Thus, no dose adjustment or dose capping for higher BSA would be needed. Figure 33. Predicted Median RI $8&IJ DW Steady-State for Subjects With BSA Range of 0.25–0.9 m2

20 115 mg/m2 150 mg/m2 18

16

14 g*h/mL) ʅ 12

10

8

6 at Steady-State ( Steady-State at ʏ 4 AUC 2 0.2 0.4 0.6 0.8 1 BSA (m2)

Source: Review team’s analysis $EEUHYLDWLRQV$8&IJDUHD XQGHUWKH SODVPD FRQFHQWUDWLRQ-time curve for a dosing interval; BSA, body surface area In summary, the Applicant’s final population PK model was able to reasonably describe the PK of lonafarnib in both healthy subjects and patients with HGPS. Although the effect of body weight on CL was identified to be more significant than that of BSA, the review team’s sensitivity analysis, conducted by replacing BW with BSA, was also adequate to describe the CL change with body size. To evaluate the Applicant’s newly proposed BW-based dosing regimen versus the original proposed BSA-based dosing regimen, the review team conducted a PK simulation and demonstrated that both the BW-based or BSA-based dosing regimen could provide consistent lonafarnib exposure across different body weight tiers in patients with HGPS. However, given that the BSA-based dosing regimens were tested in ProLon1, the FDA review team recommends the originally proposed BSA-based dosing regimens to be the appropriate dose for the target patient population.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 14.4. Bioanalytical Methods

Method SN 97318: For studies 07-01-0007, P00260, P02673, and P00042, lonafarnib concentrations in plasma were determined with the following method. Table 95. Bioanalytical Method Validation and Performance for Determination of Lonafarnib Concentration in Human Plasma Validation Parameter Method Validation Summary[1] Bioanalytical method x The analytical method for lonafarnib in human plasma using HPLC with review summary MS/MS detection met acceptance criteria with respect to specificity, sensitivity, precision, accuracy, linearity, recovery, and dilution integrity, spanning a theoretical concentration range of 5.00 ng/mL to 2500.00 ng/mL (high-range) and 1.00 ng/mL to 500.00 ng/mL (low-range). x Stability evaluations in matrix and solutions met acceptance criteria. x With the validated original method (TM.080.C) for the low range (1.00 ng/mL to 500.00 ng/mL), the method for high-range (5.00 ng/mL to 2500.00 ng/mL) was modified (TM.140.0) and cross-validated.

Method description x Human plasma samples containing the test article (lonafarnib) and internal standard ([13C2][15N]-lonafarnib) were extracted by solid phase extraction. The extracted samples were analyzed by an HPLC equipped with a Finnigan TSQ-7000® Triple Quadrupole Mass Spectrometer. x A high-performance liquid chromatographic tandem mass spectrometric (LC/MS/MS) analytical method

Materials used for x Biological matrix: Human plasma containing sodium heparin as calibration curve & anticoagulant concentration x Analyte: lonafarnib x Internal standard (IS): [13C2][15N]-lonafarnib Calibration curve concentration x 1.00 to 500 ng/mL (low-range), using 1.0 mL of human plasma. x 5.00 to 2500 ng/mL (high-range), using 0.2 mL of human plasma

Validated assay range x 1.00 to 500 ng/mL (low-range), using 1.0 mL of human plasma. x 5.00 to 2500 ng/mL (high-range), using 0.2 mL of human plasma. Material used for QCs & x Biological matrix: Human plasma containing sodium heparin as concentration anticoagulant x Analyte: lonafarnib x Internal standard (IS): [13C2][15N]-lonafarnib QC concentrations: x 3.00, 35.0, 400 and 700 ng/mL, referred to as low, medium, high and dilution QC levels, respectively x 15.0, 175, and 2000 ng/mL and 3750 ng/mL, referred to as low, medium, high and over-range QC levels, respectively

Minimum required Not available dilutions (MRDs)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Validation Parameter Method Validation Summary[1] Source & lot of reagents Lonafarnib: Batch: WDT-51786-12-1 (Schering Plough Research Institute) (LBA) [13C2][15N]-lonafarnib: Batch: 51909-49-3 (Schering Plough Research Institute)

Regression model & Linear regression with 1/x2 weighting (y=mx+b) weighting

Validation Parameters Method Validation Summary[1] Acceptability Calibration curve No. of standard calibrators from LLOQ to 8 Acceptable performance during ULOQ accuracy & precision Cumulative accuracy (%bias) from LLOQ to -1.2 to 1.2% Acceptable ULOQ (Note: %Difference was assessed) Cumulative precision (%CV) from LLOQ to ” Acceptable ULOQ

QCs performance Cumulative accuracy (%bias) in 5QCs -5.5 to -1.3% Acceptable during accuracy & QCs: 15.0, 175, and 2000 ng/mL and precision 3750 ng/mL as dilution QC (10-fold dilution) (Note: 4 QCs were used including one dilution QC) (Note: %Difference was assessed) Interbatch %CV ” Acceptable QCs: 15.0, 175, and 2000 ng/mL and 3750 ng/mL as dilution QC (10-fold dilution) (Note: 4 QCs were used including one dilution QC)

Selectivity & matrix Selectivity was demonstrated Acceptable effect

Interference & Lack of interference in the presence of coadministered drugs. Acceptable specificity No significant interference observed in the 6 blank matrix lots screened

Dilution linearity & hook 3750 ng/mL 10-fold dilution demonstrated Acceptable effect

Bench-top/process Up to 72 hours at ambient temperature in human plasma Acceptable stability Accuracy (% difference): 6.5%, -0.3%, and 1.5% for Low, Medium, and High Stability QC (3, 35 and 400 ng/mL), respectively Precision (%CV): 3.7%, 2.4%, and 1.4% for Low, Medium, and High Stability QC (3, 35 and 400 ng/mL), respectively

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Validation Parameters Method Validation Summary[1] Acceptability Freeze-thaw stability Previously frozen and thawed at ambient temperature, over 3 Acceptable cycles in human plasma Accuracy (% difference): 2.0%, 0, and 0.8% for low, medium, and high stability QC (3, 35 and 400 ng/mL), respectively Precision (%CV): 4.8%, 2.1%, and 1.3% for low, medium, and high stability QC (3, 35 and 400 ng/mL), respectively

Long-term storage Up to 18 months at -70°C nominal in human plasma Acceptable Accuracy (% difference): -3.0%, -3.3% and -6.8%, for Low, Medium, and High Stability QC (3, 35 and 400 ng/mL), respectively Precision (%CV): 1.5%, 1.5%, and 1.8% for low, medium, and high stability QC (3, 35 and 400 ng/mL), respectively

Carry over No significant carry over observed Acceptable Method Performance in Study 07-01-0007[1] Assay passing rate 100% (including incurred sample reanalysis (ISR)) Acceptable

Standard curve Cumulative bias range: -1.60 to 2.00% performance &XPXODWLYH SUHFLVLRQ &9  ”

QC performance Cumulative accuracy (%bias):-1.14 to 2.40% Cumulative precision (%CV): ” Study sample analysis/ Samples stored at -70°C prior to and following sample analysis. stability Demonstrated stability period: 1552 days. All samples were assayed within the demonstrated storage stability period. 80 human plasma samples were successfully analyzed for lonafarnib. Method Performance in Study P02673[2] Assay passing rate Not available Acceptable

Standard curve Cumulative accuracy (%bias): -2.80 to 2.80% Acceptable performance (Note: %Difference was assessed) &XPXODWLYH SUHFLVLRQ &9  ” QC performance Acceptable Cumulative accuracy (%bias): -0.571 to 3.00% (Note: %Difference was assessed) Cumulative SUHFLVLRQ &9  ”

Method reproducibility Incurred sample reanalysis was performed in 8 study Acceptable samples.

Study sample analysis/ All QC samples and study samples were stored in a freezer set to -70°C stability within the time period for which storage stability has been demonstrated for lonafarnib *18 months).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib)

Validation Parameters Method Validation Summary[1] Acceptability Method Performance in Study P00260[3] Assay passing rate Not available Acceptable Acceptable Standard curve Cumulative accuracy (%bias): -2.4 to 2.4% performance (Note: %Difference was assessed) &XPXODWLYH SUHFLVLRQ &9  ”

QC performance Cumulative accuracy (%bias): -6.5 to -0.7% Acceptable (Note: %Difference was assessed) &XPXODWLYH SUHFLVLRQ &9  ” Study sample analysis/ Study and QC samples were stored at -70°C. The stability of lonafarnib in stability human plasma has been determined for 18 months at a nominal temperature of -70°C. Study samples were stored frozen for no more than 4.5 months prior to analysis. Source: [1] Method validation report and Bioanalytical report for study 07-01-0007 (ProLon1); (Schering-Plough Research Institute 2010); [2] Appendix 16.2.3 in the clinical study report for study P02673 (Schering-Plough Research Institute 2004); [3] Appendix for Bioanalyhtical report in the clinical study report for study P00260 (Schering-Plough Research Institute 2002) Abbreviations: CV, coefficient of variation; HPLC, high-performance liquid chromatography; ISR, incurred sample reanalysis; LBA, ligand-binding assay; LLOQ, lower limit of quantification; NJ, New Jersey; QC, quality control; ULOQ, upper limit of quantification 15. Trial Design: Additional Information and Assessment

ProLon1 and ProLon2 trial eligibility and exclusion criteria are listed below in full.

ProLon1

Eligibility Criteria As outlined in the study protocol from Boston Children’s Hospital. x Genetic diagnosis: All patients must have confirmatory variant analysis showing the G608G variant in the lamin A gene. x Clinical diagnosis: Patients with PL, showing clinical signs of progeria but with other confirmed variants in LMNA, will be eligible for therapy. This population will be analyzed separately from those with the classical variants. x Travel: Patients must be willing and able to come to Boston for appropriate studies and examinations approximately once every 4 months. x Patients must have a minimum of 1 year of weight data available, with five data points or more, each separated by 1 month or more and approval by the study team. x Patients must have adequate organ and marrow function as defined by the following parameters: – Blood: absolute phagocyte count (APC) (absolute neutrophil count [ANC] + bands + monocytes = APC) >1,000/μL, platelets >75,000/μl (transfusion independent); hemoglobin >9 g/dL. – Renal: creatinine ”1.5 times normal for age or glomerular filtration rate (GFR) >70 mL/min/1.73 m2.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) – Hepatic: bilirubin ”1.5 times upper limit of normal for age; SGPT (alanine aminotransferase) < 5 times upper limit of normal for age and SGOT (aspartate aminotransferase) <5 times upper limit of normal range for age. – Prothrombin time/partial thromboplastin time (PT/PTT): PT/PTT <120% upper limit of normal OR primary investigator (PI) approval x No overt renal, hepatic, pulmonary disease or immune dysfunction. x Patients taking growth hormone when entering the study must have pretreatment weight measures while on growth hormone. In addition, patients must remain on growth hormone treatment for the duration of the clinical trial. Patients entering the trial not on growth hormone must remain off of growth hormone for the duration of their participation. x Signed informed consent according to institutional guidelines must be obtained and patient must begin therapy within 28 days.

Exclusion Criteria x Patient must not be receiving any other experimental drug therapy. x Patients must not be taking medications that significantly affect the metabolism of lonafarnib at the time they start lonafarnib. x Patients must have no uncontrolled infection. x Patients who have known or suspected hypersensitivity to any of the excipients included in the formulation should not be treated. x Patients must not be pregnant or breast-feeding. Female patients of childbearing potential must have negative serum or urine pregnancy test. Male and female patients of reproductive potential must agree to use a medically accepted form of birth control while on study and up to 10 weeks after treatment. It is permissible for female patients to take oral contraceptives or other hormonal methods while receiving treatment with lonafarnib.

ProLon2

Eligibility Criteria ProLon2 eligibility were modified to include patients with variant in LMNA as well as variants in ZMPSTE24. x Genetic diagnosis: All patients must have confirmatory variant analysis showing variant in the LMNA gene or have ZMPSTE24 variants. x Clinical diagnosis: Patients must display clinical signs of progeria as per the clinical trial team. x Travel: Patients must be willing and able to come to Boston for appropriate studies and examinations at initiation of study and at months 6, 12, 18, between 40 and 52, 60, and potentially 96 on study for group 1 and at initiation of therapy and between months 24 and 36 on study for patient group 2.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) x Patients must have adequate organ and marrow function as defined by the following parameters: – Blood: APC (ANC + bands + monocytes = APC) >1,000/μl, Platelets >75,000/μl (transfusion independent); hemoglobin >9 g/dL. – Renal: creatinine ”1.5 times upper limit of normal for age or GFR >70 mL/min/1.73 m2. – Hepatic: bilirubin ”1.5 times upper limit of normal for age; SGPT (alanine aminotransferase) < 5 times upper limit of normal for age and SGOT (aspartate aminotransferase) <5 times upper limit of normal for age. – PT/PTT: PT/PTT <120% upper limit of normal OR PI approval x No overt renal, hepatic, pulmonary disease or immune dysfunction. x Signed informed consent according to institutional guidelines must be obtained and patient must begin therapy within 28 days.

Exclusion Criteria x Other than the drugs used in this protocol, drugs targeted to treat progeria are excluded. Drugs to treat symptoms of progeria are permitted. x Patients must not be taking medications that significantly affect the metabolism of lonafarnib at the time they start lonafarnib. x Patients must have no uncontrolled infection. x Patients who have known or suspected hypersensitivity to any of the excipients included in the formulation should not be treated. x Patients must not be pregnant or breast-feeding. Female patients of childbearing potential must have negative serum or urine pregnancy test. Male and female patients of reproductive potential must agree to use a medically accepted form of birth control while on study and up to 10 weeks after treatment. It is permissible for female patients to take oral contraceptives or other hormonal methods while receiving treatment with lonafarnib.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 16. Efficacy: Additional Information and Assessment

To aid in understanding of the patient survival status, flow charts were provided for ProLon1 in Figure 34 and for ProLon2 in Figure 35. While subsequent audit found a few discrepancies with the status of patients with HGPS, the figures provide a concise depiction of survival status and participation in lonafarnib related trials. Figure 34. Patient Flow Chart, ProLon1

(b) (6)

Source: Responses to the FDA’s Information Request (Eiger BioPharmaceuticals 2020c) (b) (6) Discrepancy identified on audit: Patient last followup date is 6/6/2018, a difference of +274 days

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figureg 35. Patient Flow Chart, ProLon2

(b) (6)

Source: Responses to the FDA’s Information Request (Eiger BioPharmaceuticals 2020c) (b) (6) Discrepancies identified on audit: Patien last followup date (death date) is(b) (6) , a difference of +970 days;Patient (b) (6) (b) (6) last followup date is 6/13/2018, a differen 19 days;Patient ast followup date is 6/11/2018, a difference of -20 days

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) In addition, four PL patients were enrolled in lonafarnib trials. The patient flow chart in Figure 36 depicts their course of treatment. Patient #(b) (6) , who has a processing-deficient PL, enrolled in ProLon1, and has taken lonafarnib for over 10 years. Patient (b) (6) enrolled in ProLon1 and was subsequently found to not have a processing-deficient PL variant. Two siblings with processing-deficient PL (# (b) (6)) enrolled in Triple Therapy and have taken lonafarnib for over 10 years. Figure 36. Patient Flow Chart, Progeroid Laminopathy

(b) (6)

Source: Applicant’s White Paper (Eiger BioPharmaceuticals 2020a) 16.1. Controlled Substance Consultation

Controlled Substance Staff (CSS) evaluated the abuse potential of lonafarnib. Based on the receptor binding profile, pre-clinical assessment of central nervous system activity, and adverse event profiles in clinical trials, abuse potential is not suspected with lonafarnib. CSS concluded that lonafarnib should not be scheduled under the Controlled Substances Act and that no Drug Abuse and Dependence section is necessary in the drug label.

See the full review in DARRTS (Reissig 2020).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 17. Clinical Safety: Additional Information and Assessment

A sequential flow chart of HGPS and PL patients who received lonafarnib treatment is shown below (Figure 37). Figure 37. Disposition Status, ISS Study Populations

Source: 2.7.4 Summary of Clinical Safety, page 19. Abbreviations: ISS, integrated summary of safety. 18. Mechanism of Action/Drug Resistance: Additional Information and Assessment

Processing steps of lamin A protein and of progerin protein in HGPS and point of lonafarnib activity are depicted in Figure 38.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 38. Post-Translational Processing Pathways Producing Lamin A and Progerin

Source: Figure 1 (Gordon et al. 2018) In vitro studies in fibroblast cells from HGPS and PL patients demonstrate morphologic abnormality in nuclei shape, compared to fibroblasts from healthy subjects. Treatment with lonafarnib demonstrated nuclear morphology improvement in both HGPS and PL fibroblasts (see image below).

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Figure 39. Immunofluorescence Micrographs Showing Improvement of Aberrant Nuclear Morphology in Patients With HGPS and PL (MAD-B)

Source: Applicant’s White Paper: “Progeroid Laminopathies” 19. Other Drug Development Considerations: Additional Information and Assessment

Lonafarnib, an FTI, was initially developed and studied as a treatment for cancer in the 1990s by Schering-Plough (now Merck). FTIs were studied in the 1990s to 2000s as putative treatments for oncologic conditions predicated on activation of protein product through transfarnesylation. Initially, lonafarnib was studied under investigator-initiated trials at Boston Children’s Hospital and The Progeria Research Foundation for the treatment of HGPS and PL under investigational new drug (IND) applications (b) (4) which were reviewed by FDA’s Division of Gastroenterology and Inborn Errors Products. The study design was a single arm, single-center treatment study, as the fatality of the disease did not deem placebo treatment to be ethically acceptable. A contemporaneous external comparator was from a natural history study maintained by The Progeria Research Foundation. With promise of benefit for HGPS, Eiger Biopharmaceuticals bought the licensing rights to lonafarnib in June 2018 and continued the investigational study under IND 139923. Lonafarnib, licensed by Eiger, received rare pediatric disease designation on October 17, 2018 (RPD-2018-

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 189), breakthrough therapy designation on December 12, 2018 for potential treatment for a serious, life-threatening condition with preliminary clinical evidence of improvement in all-cause mortality, and orphan drug designation on July 3, 2019 (DRU-2011-3334). The available data were cumulatively presented in NDA 213969, which received priority review for its potential to impact a rare, fatal disease with no approved therapies. Lonafarnib is additionally under study for the treatment of hepatitis D under INDs (b) (4) in the Division of Antiviral Products. For more detailed regulatory history, see Section 12. 20. Data Integrity-Related Consults (Office of Scientific Investigations, Other Inspections)

ProLon1 (study 07-01-0007) and ProLon2 (group 2 of study 09-06-0298) were originally Boston Children’s Hospital clinical investigator initiated studies. The clinical investigators who maintained records were inspected by the Office of Scientific Investigation: Dr. Monica E. Kleinman at Boston Children’s Hospital who maintained records for ProLon1 and ProLon2 and Dr. Leslie Gordon at Brown University who maintained the natural history cohort records. In addition, the survival status of the natural history study was verified by the Divison of Epidemiology (DEPI). DEPI concluded there was high concordance between the NDA dataset and source documentation. As is typical of an investigator-initiated study at a single center, the investigator provided informal oversight including staff training, study conduct assessment, and source data verification. The inspection found the study conduct and records maintained were adequate to support the proposed indication submitted in the NDA. The study data was maintained as electronic spreadsheet files (Microsoft Excel), which did not have traditional controls to ensure data integrity, but the inspection found that the source records were appropriately maintained and available during the inspection. The date of birth and genetic variant status for study patients were verified in the electronic health record (EHR). Death dates and last follow-up dates were verified with the source documentation for both Boston Children’s Hospital and Progeria Research Foundation. For ProLon1, small discrepancies were identified for the last date of lonafarnib treatment, between source data and data submitted to the Agency (patients (b) (6)). The differences were of only one day in two patients, except for patient #(b) (6) who had a difference greater than a week. For patient(b) (6) , the efficacy analysis focused on the last follow-up data (vital status), not the last day of lonafarnib treatment. The review team concluded that these discrepancies would have minimal effect on the overall conclusions and would not impact the regulatory decision. Table 96. Discrepant Last Lonafarnib Treatment Date for Patients, ProLon1 Data Submitted to Subject Agency Source Records* Discrepancy (b) (6) 7/28/2009 7/29/2009 +1 day 11/7/2009 11/6/2009 -1 day 10/5/2009 11/4/2009 +30 days Source: Clinical Inspection Summary for NDA 213969, dated October 6, 2020. *Dates from patient diaries and provider notes reviewed during inspecti on

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) For ProLon2, there were 14 patients with discrepancies, with most being a difference of a few days. Two discrepancies for patients (b) (6) had a difference greater than a week. In addition, there was an unreported death in patient (b) (6) on April 10, 2019; this patient’s last follow-up date was the ProLon2 completion date, August 13, 2016. Overall, the survival benefit seen is impacted minimally by these findings and would not change our regulatory decision (see Section 6.3.6 for additional details). Overall, the Office of Scientific Investigators concluded that the data submitted by the Applicant for ProLon1, ProLon2, the natural history study, and the follow-up data collected by Dr. Gordon appear reliable in support of the proposed indication submitted in the NDA. 21. Labeling Summary of Considerations and Key Additional Information

See the approved Prescribing Information for the final agreed upon language. A summary of the significant changes made to the Full Prescribing Information from the Applicant’s proposed label submitted on March 20, 2020, is shown below. Highlights and Table of Contents were revised for consistency with the rest of the Prescribing Information. Table 97. Major Prescribing Information Changes PI Section Changes 1 INDICATIONS AND USAGE x Indication was limited to pediatric patients with a body surface area of 0.39 m2 or greater to avoid risk of overdosage with currently available ZOKINVY capsule strengths (refer to Section 6.1 for additional details).

2 DOSAGE AND x Revised the tables of recommended dosage and ADMINISTRATION administration to include BSA range for dosing and removal of exact dosage calculations, as the actual daily dose is rounded to the nearest 25 mg. x For ease of patient use, revised the directions for preparation as a suspension in Ora Blend SF, Ora-Plus or orange juice to quantify the required amount of vehicle in mL. Revised the required amount of applesauce to quantify by teaspoon. x Modified ZOKINVY dosage modifications for drug interactions (refer to Sections 7.7.2 and 8.2 for details): - Revised dosage modifications with weak CYP3A inhibitors. - Removed (b) (4)

- Broadened the recommendations to temporarily discontinue ZOKINVY with parenteral midazolam to midazolam. x Removed renal and hepatic impairment subsections which did not recommend dosage adjustments (refer to Section 7.7.4 and 7.7.5 for details).

4 CONTRAINDICATIONS x Added contraindication for moderate CYP3A inducers (refer to Section 7.7.2 for details). x Broadened the contraindication for orally administered midazolam to midazolam (refer to Section 8.2 for details).

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PI Section Changes 5 WARNINGS AND x Combined applicant’s five proposed W&Ps into one W&P that PRECAUTIONS broadly summarizes the risks related to drug interactions. x Added W&P for laboratory abnormalities, nephrotoxicity, retinal toxicity, impaired fertility, and embryo-fetal toxicity after review of the submitted laboratory data and animal data, and in consultation with the Labeling Policy Team, and to be consistent with the recommendations in the guidance for industry “Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products – Content and Format” (October 2011) (refer to Sections 13.1.3.1 and 13.1.3.3 for details).

6 ADVERSE REACTIONS x Revised adverse reactions in Table 3 to include adverse events RFFXULQJ LQ • RI SDWLHQWV, regardless of investigator determined causality. x Combined electrolyte abnormalities together in Table 3, i.e., hypermagnesemia, hypokalemia, hyperkalemia, hyponatremia, hypercalcemia (refer to Section 7.6.1.7.2 for additional details). x Combined myelosuppression AEs together in Table 3, i.e. absolute neutrophil count decreased, low total white blood cells, lymphopenia, decreased hemoglobin, and hematocrit low (refer to Sections 7.6.1.6 and 7.6.1.7.4 for details) x Added hypertension adverse reactions based on clinical trial data (refer to Sections 7.6.1.7.1 for details). x Added additional detail regarding grading of gastrointetinal adverse reaction and liver enzyme elevations (refer to Sections 7.6.1.5 and 7.6.1.6). x Removed (b) (4) , since the focus of the safety evaluation was on patients treated with ZOKINVY monotherapy in ProLon1 and ProLon2.

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PI Section Changes 7 DRUG INTERACTIONS x Converted drug interaction information into a table for easier readability. x Revised the dosage modification for concomitant CYP3A inhibitors use to contraindicate ZOKINVY use with strong or moderate CYP3A inhibitors. If coadministration with a CYP3A weak inhibitor is unavoidable, instruction to reduce to or continue ZOKINVY at a dosage of 115 mg/m2 was revised. x Revised the dosage modification for concomitant CYP3A moderate inducer use to contraindicate ZOKINVY use with moderate CYP3A inducers. (See Section 6.3.7 for details.) x Added avoid coadministration of ZOKINVY with CYP2C9 inhibitors. A postmarketing trial will be performed to determine the effect of CYP2C9 inhibitors on the PK of lonafarnib. (See Section 7.7.2 for details.) x Revised loperamide coadministration to specify loperamide contraindication in patients less than 2 years of age according to loperamide product labeling as well as the starting maximum daily dosage of loperamide with ZOKINVY. (See Section 8.2 for details.) x Revised oral midazolam contraindication to midazolam contraindication. (See Section 8.2 for details.) 8 USE IN SPECIFIC x Revised Pregnancy subsection with specification that POPULATIONS ZOKINVY may cause embryofetal harm. Added further details on pregnant rat and rabbit study findings relative to equivalents of human exposure dosage. See Section 13.1.3.3 for details.) x Revised Females and Males of Reproductive Potential subsection to advise females of reproductive potential to use effective contraception. x Revised Pediatric Use subsection for consistency with the guidance for industry “Pediatric Information Incorporated Into Human Prescription Drug and Biological Product Labeling” (March 2019), to specify ZOKINVY use is established for patients 12 months of age and older, on the basis of studies in pediatric patients 2 years of age and older. x Removed Renal and Hepatic Impairment subsections because there were no clinically relevant differences in response, safety or recommendations in these populations. (See Sections 7.7.4 and 7.7.5 for details.) x Added Adult Use subsection to specify the basis of approval in adult patients.

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PI Section Changes 12 CLINICAL PHARMACOLOGY x Revised mechanism of action description for clarity. x Removed QT interval section, written based on a lonafarnib and ritonavir study in health volunteers. A postmarketing trial with ZOKINVY will be performed to determine lonafarnib effects on QT. (See Section 7.7.1 for details.) x Converted the pharmacokinetics information into a table for easier readability. x Revised metabolism to mention liver enzymes processing lonafarnib. x Details of studies conducted were removed. x Revised the section for drug interaction studies for easier readability. For the effect of ZOKINVY on other drugs, the studies with the lonafarnib and ritonavir combination were removed.

13 NONCLINICAL TOXICOLOGY x Added specifics regarding impairment of fertility in male rats at near human exposure levels. (See Sections 7.1 and 13.1.3.3 for details.) x Added specifics regarding female rat impaired fertility at near human doses. (See Sections 7.1 and 13.1.3.3.1 for details.) x Added renal toxicity in 6 month study in rats at doses near human exposure. (See Section 7.1 for details.) x Added toxicity in male reproductive tract in 1 year monkey study at doses lower than human exposure. x Added ocular (retinal) toxicity in 1 year monkey study, and adverse effect on rod-dependent, low light vision in a 13 week monkey study.

14 CLINICAL STUDIES x Revised to focus on ZOKINVY monotherapy patients in ProLon1 and ProLon2, with inclusion of body surface area, weight range, and baseline demographics. Removed details on Triple Therapy trial, which was not evaluated, to avoid implying an unapproved use of ZOKINVY [per 21 CFR 201.57(c)(2)(iv)]. x Revised survival benefit table with focus on mean survival time in patients censored at 3 years and at last follow-up date. (See Section 6.3.6 for details.)

17 PATIENT COUNSELING x Reordered topics in order of importance to the patient INFORMATION consistent with the guidance for industry “Patient Counseling Information Section of Labeling for Human Prescription Drug and Biological Products – Content and Format” (December 2014). Dosing instructions and taking a missed dose instruction ordered first. x Added additional adverse reaction counseling topics and re- ordered those existing. Listed drug interactions first, then gastrointestinal adverse reactions. Added hypertension, nephrotoxicity, retinal toxicity, impaired fertility, embro-fetal toxicity risks.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 22. Postmarketing Requirements and Commitments

The following postmarketing requirements (PMRs) were agreed upon with the Applicant and will be issued at the time of approval. PMR 3929-1: A carcinogenicity study in an appropriate species. PMR Schedule Milestones: PMR Schedule Milestones: Final Protocol Submission: 12/2020 Study Completion: 02/2023 Final Report Submission: 02/2024 PMR 3929-2: A clinical trial to assess the effect of concomitant administration of a CYP2C9 inhibitor on the pharmacokinetics of lonafarnib. Design and conduct the trial in accordance with the FDA guidance for industry Clinical Drug Interaction Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020). PMR Schedule Milestones: Draft Protocol Submission: 03/2021 Final Protocol Submission: 09/2021 Study Completion: 06/2022 Interim/Other: none Final Report Submission: 06/2023 PMR 3929-3: A thorough QT/QTc study to evaluate the effect of lonafarnib on QT interval prolongation. Design and conduct the trial in accordance with the ICH E14 guidances for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non- Antiarrhythmic Drugs (October 2012) and E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythimic Drugs-Questions and Answers (R3) (June 2017). PMR Schedule Milestones: Draft Protocol Submission: 03/2021 Final Protocol Submission: 09/2021 Study Completion: 06/2022 Interim/Other: None Final Report Submission: 06/2023 The following postmarketing commitment (PMC) was agreed upon with the Applicant and will be issued at the time of approval. PMC 3929-4:

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Complete the ongoing clinical trial EIG-LNF-019 to determine the relative bioavailability of lonafarnib mixed with applesauce and suspended in orange juice compared with an intact Zokinvy capsule following a single dose administration in healthy subjects. PMC Schedule Milestones: Study Completion: 12/2021 Final Report Submission: 12/2022 23. Financial Disclosure

Table 98. Covered Clinical Studies: BCH 07-01-0007 (ProLon1) and Group 2 of BCH 09-06-0298 (ProLon2) Was a list of clinical investigators provided: Yes ց No տ (Request list from Applicant) Total number of investigators identified: 3 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: Enter text here. Significant payments of other sorts: Enter text here. Proprietary interest in the product tested held by investigator: Enter text here. Significant equity interest held by investigator: Enter text here. Sponsor of covered study: Enter text here. Is an attachment provided with details of the Yes տ No տ (Request details from disclosable financial interests/arrangements: Applicant) Is a description of the steps taken to minimize Yes տ No տ (Request information from potential bias provided: Applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3):0 Is an attachment provided with the reason: Yes տ No տ (Request explanation from Applicant)

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 24. References

Barrowman, J, PA Wiley, SE Hudon-Miller, CA Hrycyna, and S Michaelis, 2012, Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity, Hum Mol Genet, 21(18):4084-4093.

Burke, B and CL Stewart, 2002, Life at the edge: the nuclear envelope and human disease, Nature Reviews Molecular Cell Biology, 3(8):575-585.

Guidance for Industry, Patient Counseling Information Section of Labeling for Human Prescription Drug and Biological Products - Content and Format (December 2014)

Denecke, J, T Brune, T Feldhaus, H Robenek, C Kranz, RJ Auchus, AK Agarwal, and T Marquardt, 2006, A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS, Hum Mutat, 27(6):524-531.

Doser, K, B Meyer, V Nitsche, and P Binkert-Graber, 1995, Bioequivalence evaluation of two different oral formulations of loperamide (Diarex Lactab vs Imodium capsules), International journal of clinical pharmacology and therapeutics, 33(8):431-436.

Eiger BioPharmaceuticals, 2020a, Lonafarnib Module 5.3.5.4: White Paper, \\CDSESUB1\evsprod\nda213969\0003\m5\53-clin-stud-rep\535-rep-effic-safety- stud\progeria\5354-other-stud-rep\wp-pl\pl-white-paper.pdf.

Eiger BioPharmaceuticals, 2020b, Lonafarnib Study 09-06-0298 Clinical Study Report: An Open Label Phase II Trial of Zoledronic Acid, Pravastatin, and Lonafarnib (SCH 66336) for Patients With Hutchinson-Gilford Progeria Syndrome and Progeroid Laminopathies, \\CDSESUB1\evsprod\nda213969\0003\m5\53-clin-stud-rep\535-rep-effic-safety- stud\progeria\5351-stud-rep-contr\09-06-0298\09-06-0298.pdf.

Eiger BioPharmaceuticals, 2020c, Responses to the FDA's Information Request, \\CDSESUB1\evsprod\nda213969\0009\m1\us\111-info-amend\clin-info-response- 20202519.pdf.

FDA, 2020, NDA 213969 - Interdisciplinary Review Team for Cardiac Safety Studies QT Study Review (DARRTS Reference ID: 4628005), https://darrts.fda.gov/darrts/ViewDocument?documentId=090140af80572c07.

Guidance for Clinical Investigators, Industry, and FDA Staff, Financial Disclosure by Clinical Investigators (February 2013)

Fong, LG, D Frost, M Meta, X Qiao, SH Yang, C Coffinier, and SG Young, 2006a, A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria, Science, 311(5767):1621-1623.

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Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Fong, LG, JK Ng, J Lammerding, TA Vickers, M Meta, N Coté, B Gavino, X Qiao, SY Chang, SR Young, SH Yang, CL Stewart, RT Lee, CF Bennett, MO Bergo, and SG Young, 2006b, Prelamin A and lamin A appear to be dispensable in the nuclear lamina, J Clin Invest, 116(3):743-752.

Fukuchi, K, T Katsuya, K Sugimoto, M Kuremura, HD Kim, L Li, and T Ogihara, 2004, LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome, J Med Genet, 41(5):e67.

Gerhard-Herman, M, LB Smoot, N Wake, MW Kieran, ME Kleinman, DT Miller, A Schwartzman, A Giobbie-Hurder, D Neuberg, and LB Gordon, 2012, Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria syndrome, Hypertension, 59(1):92- 97.

Gordon, LB, J Massaro, RB D'Agostino, Sr., SE Campbell, J Brazier, WT Brown, ME Kleinman, MW Kieran, and Progeria Clinical Trials Collaborative, 2014, Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome, Circulation, 130(1):27-34.

Gordon, LB, H Shappell, J Massaro, RB D'Agostino, Sr., J Brazier, SE Campbell, ME Kleinman, and MW Kieran, 2018, Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome, JAMA, 319(16):1687-1695.

Hennekam, RC, 2006, Hutchinson-Gilford progeria syndrome: review of the phenotype, Am J Med Genet A, 140(23):2603-2624.

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Kearns, GL, SM Abdel-Rahman, SW Alander, DL Blowey, JS Leeder, and RE Kauffman, 2003, Developmental Pharmacology — Drug Disposition, Action, and Therapy in Infants and Children, New England Journal of Medicine, 349(12):1157-1167.

Kieran, MW, L Gordon, and M Kleinman, 2007a, New approaches to progeria, Pediatrics, 120(4):834-841.

Kieran, MW, LB Gordon, and ME Kleinman, 2014, The role of the farnesyltransferase inhibitor lonafarnib in the treatment of Progeria, Expert Opinion on Orphan Drugs, 2(1):95-105.

Kieran, MW, RJ Packer, A Onar, SM Blaney, P Phillips, IF Pollack, JR Geyer, S Gururangan, A Banerjee, S Goldman, CD Turner, JB Belasco, A Broniscer, Y Zhu, E Frank, P Kirschmeier, P Statkevich, A Yver, JM Boyett, and LE Kun, 2007b, Phase I and pharmacokinetic study of the

184 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a Pediatric Brain Tumor Consortium Study, J Clin Oncol, 25(21):3137-3143.

Lai, KC, JA Brothers, and JZ Stoller, 2019, Severe hypertriglyceridemia associated with everolimus drug-eluting stent placement in an infant, Cardiol Young, 29(4):541-543.

Guidance for Industry, Pediatric Information Incorporated Into Human Prescription Drug and Biological Products Labeling Good Review Practice (March 2019)

Merideth, MA, LB Gordon, S Clauss, V Sachdev, AC Smith, MB Perry, CC Brewer, C Zalewski, HJ Kim, B Solomon, BP Brooks, LH Gerber, ML Turner, DL Domingo, TC Hart, J Graf, JC Reynolds, A Gropman, JA Yanovski, M Gerhard-Herman, FS Collins, EG Nabel, RO Cannon, 3rd, WA Gahl, and WJ Introne, 2008, Phenotype and course of Hutchinson-Gilford progeria syndrome, N Engl J Med, 358(6):592-604.

Guidance for Industry, Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products - Content and Format (October 2011)

Guidance for Industry, E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (October 2012)

g]HQ 6 % $NÕQFÕ DQG ($ 2UDO  &XUUHQW 'LDJQRVLV 7UHDWPHQW DQG &OLQLFDO &KDOOHQJHV LQ the Management of Lipodystrophy Syndromes in Children and Young People, J Clin Res Pediatr Endocrinol, 12(1):17-28.

Prakash, A, LB Gordon, ME Kleinman, EB Gurary, J Massaro, R D'Agostino, Sr., MW Kieran, M Gerhard-Herman, and L Smoot, 2018, Cardiac Abnormalities in Patients With Hutchinson- Gilford Progeria Syndrome, JAMA Cardiol, 3(4):326-334.

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185 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Schering-Plough Research Institute, 2002, SCH 66336: The Absorption, Metabolism and Excretion of 14C-SCH 66336 Following Oral Administration of 14C-SCH 66336 in Healthy Volunteers (Protocol 00260), \\CDSESUB1\evsprod\nda213969\0003\m5\53-clin-stud-rep\533- rep-human-pk-stud\5331-healthy-subj-pk-init-tol-stud-rep\p00260\p00260.pdf.

Schering-Plough Research Institute, 2004, SCH 66336: Effects of Age and Gender on the Pharmacokinetics of SCH 66336 (Lonafarnib) (Protocol P02673), \\CDSESUB1\evsprod\nda213969\0003\m5\53-clin-stud-rep\533-rep-human-pk-stud\5333- intrin-factor-pk-stud-rep\p02673\p02673.pdf.

Schering-Plough Research Institute, 2010, SCH 66336: Determination of SCH 66336 Concentrations in Human Plasma Samples From Protocol No. 05009 Using a Liquid Chromatographic-Tandem Mass Spectrometric Method \\CDSESUB1\evsprod\nda213969\0003\m5\53-clin-stud-rep\535-rep-effic-safety- stud\progeria\5351-stud-rep-contr\07-01-0007\07-01-0007-e3-16-1-10.pdf.

Shackleton, S, DT Smallwood, P Clayton, LC Wilson, AK Agarwal, A Garg, and RC Trembath, 2005, Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype, J Med Genet, 42(6):e36.

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Toth, JI, SH Yang, X Qiao, AP Beigneux, MH Gelb, CL Moulson, JH Miner, SG Young, and LG Fong, 2005, Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes, PNAS, 102(36):12873.

Upreti, VV and JL Wahlstrom, 2016, Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling, J Clin Pharmacol, 56(3):266-283.

Zhang, H, CD Davis, MW Sinz, and AD Rodrigues, 2007, Cytochrome P450 reaction- phenotyping: an industrial perspective, Expert Opinion on Drug Metabolism & Toxicology, 3(5):667-687.

186 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) 25. Review Team

Table 99. Reviewers of Integrated Assessment Role Names Regulatory Project Manager Jenny Doan, MSN, BSN Chief Program Management Staff Michael White, PhD Nonclinical Reviewer Ke Zhang, PhD Nonclinical Team Leader David Joseph, PhD Office of Clinical Pharmacology Clinical Pharmacology: Xiaohui (Michelle) Li, PhD Reviewer Pharmacometrics: Ruojing Li, PhD; Yuching Yang, PhD

Office of Clinical Pharmacology Clinical Pharmacology: Jie (Jack) Wang, PhD Team Leaders Pharmacometrics: Lian Ma, PhD; Xinyuan Zhang, PhD Clinical Reviewer Mari Suzuki, MD Clinical Team Leader Linda Jeng, MD Statistical Reviewer Solomon Chefo, PhD Statistical Team Leader Yan Wang, PhD Cross-Disciplinary Team Leader Linda Jeng, MD Associate Director of Labeling Debra Beitzell, BSN (Labeling Policy Team, Clinical (Acting) Advisor for Labeling,serving as ADL for this application) Division Director (re gulatory) Pamela Lucarelli Division Director (pharm/tox) Mukesh Summan, PhD Division Director (OCP) Michael Pacanowski, PhD Division Director (OB) Dionne Price, PhD Division Director (clinical) Kathleen M. Donohue, MD Office Dire ctor Hylton Joffe, MD, MMSc OCP, Office of Clinical Pharmacology OB, Office of Biostatistics

187 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 100. Additional Reviewers of Application Office or Discipline Names OPQ Application Team Lead: Hitesh Shroff, PhD Drug Substance Reviewer: Sharon Kelly, PhD Drug Substance TL: Donna Christner, PhD Drug Product Reviewer: Caroline Strasinger, PhD Drug Product TL: Moo-Jhong Rhee, PhD Process and Facilities: Jingbo Xiao, PhD Process and Facilities TL: Yubing Tang PhD Microbiology Reviewer: Jingbo Xiao, PhD Microbiology TL: Yubing Tang, PhD Biopharm Reviewer: Kamrun Nahar, PhD Biopharm TL: Tapash Ghosh, PhD Environmental Analysis: Caroline Strasinger, PhD OPDP Adewale Adeleye, PharmD, MBA, Regulatory Review Officer Susan Redwood, MPH, BSN, RN, Patient Labeling Reviewer Barbara Fuller, PhD, Team Leader OSI Zana Handy Marks, MD, Reviewer Karen Bleich, MD, Team Leader OSE/DEPI Joel Weissfeld, MD, MPH, Reviewer Catherine Callahan, PhD, MA, Team Leader OSE/DMEPA Sherly Abraham, RPh, Reviewer Idalia Rychlik, PharmD, Team Leader OSE/DRISK Courtney Cunningham, PharmD, Reviewer Laura Zendel, PharmD, Team Leader OSE/RPM Su-Lin Sun, PharmD Aleksander Winiarski, PharmD, RPh, Team Leader Division of Pe diatrics and Maternal Health: Jeannie Limpert, MD Maternal Health Maternal Health: Miriam Dinatale, DO, Team Leader Pediatrics: Ramy Abdelrahman, MD Pediatrics: Shetarra Walker, MD, Team Leader RPM: Niquiche Guity, PhD Medical Editors Hyo Sook Song Erica Boehm, PhD Michelle Trybulec Controlled Substance Staff Chad Reissig, PhD Division of Cardiology and Nan Zheng, PhD, Reviewer Nephrology/QT Devi Kozeli, MSc, Regulatory Project Manager Clinical Data Scientists Salman Hosain, PhD Jinzhong Liu, PhD 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 Medication Error Prevention and Analysis DRISK, Division of Risk Management

188 Integrated Review Template, version 2.0 (04/23/2020)

Reference ID: 4705501 NDA 213969 Zokinvy (lonafarnib) Table 101. Signatures of Reviewers See attached signature page.

189 Integrated Review Template, version 2.0 (04/23/2020)

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JENNY N DOAN 11/20/2020 04:28:44 PM

HYLTON V JOFFE 11/20/2020 04:36:48 PM

Reference ID: 4705501 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

PHARMACOLOGY/TOXICOLOGY IND ASSESSMENT AND EVALUATION

Application Number*: 139923 Supporting Document Number/s: 30 CDER Receipt Date: 8/24/2020 Sponsor: Eiger Pharmaceuticals Product: Lonafarnib Pharmacologic Class: Farnesyl transferase inhibitor Indication: Treatment of patients with Hutchinson- Gilford progeria syndrome and progeroid laminopathies Therapeutic area: Inborn Errors of Metabolism Review Division: Division of Gastroenterology and Inborn Errors Products (DGIEP) Reviewer: Jackye Peretz, Ph.D. Supervisor/Team Leader: Adebayo Laniyonu, Ph.D. Division Director: Mukesh Summan, M.D., D.A.B.T. (Acting) Project Manager: Mimi Phan Purpose of Review: Carcinogenicity Review (SPA) SPA-1: 104-Week Rat Carcinogenicity Study Protocol Reviewer Completion Date: October 5, 2020 Template Version: May 23, 2019

Reference ID: 4707101 680825 IND #139923 SPA-1 Reviewer: Jackye Peretz, Ph.D.

TABLE OF CONTENTS EVALUATION OF CARCINOGENICITY PROTOCOL ...... 3 BACKGROUND/REGULATORY HISTORY ...... 3 EXECUTIVE CARCINOGENICITY ASSESSMENT COMMITTEE CONCLUSIONS ...... 3 TESTING FACILITY...... 4 DOSE...... 4 VEHICLE ...... 5 APPROPRIATENESS OF TEST SYSTEM ...... 5 TREATMENT DESIGN ...... 6 IN-LIFE PROCEDURES ...... 6 TOXICOKINETICS...... 6 TERMINAL PROCEDURES...... 7 STATISTICAL METHODS ...... 7 STUDY REPORTS...... 7 SUPPORTING DATA SUMMARIES...... 7 PHARMACOLOGY ...... 8 PK/ADME...... 8 TOXICOLOGY...... 8 GENETIC TOXICOLOGY...... 16

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Reference ID: 4707101 680825 IND #139923 SPA-1 Reviewer: Jackye Peretz, Ph.D.

Evaluation of Carcinogenicity Protocol Background/Regulatory History The Sponsor, Eiger Biopharmaceuticals, is developing lonafarnib (also known as SCH 66336 and EBP994), a tricyclic farnesyl protein transferase inhibitor, for the treatment of patients with Hutchinson-Gilford progeria syndrome (HGPS), progeroid laminopathies (PL), and solid tumors. The Sponsor is also developing lonafarnib co-administered with ritonavir (as a boosting agent for lonafarnib) for the treatment of patients co-infected with hepatitis D and hepatitis B viruses. Neither the solid tumor nor hepatitis virus infection indications will be discussed further.

HGPS and PL are rare multisystemic "premature aging" diseases in which children die of severe hardening of the arteries (atherosclerosis) at an average age of 14.5 years old. HGPS and PL are caused by mutations in genes encoding lamin A (LMNA gene) or proteins affecting the post-translational pathway of lamin A (e.g., Zmpste24). Post- translational processing of prelamin A is required for the protein to be inserted into the lamina. The mutations responsible for HGPS and PL result in abnormal prelamin A proteins (often called progerin and progerin-like proteins) that cannot be processed correctly within the cell and thus retain their farnesyl group. This persistent farnesylation is a key step in the ability of the abnormal proteins to associate with the inner nuclear membrane and cause cellular damage via structural instability and functional abnormalities, leading to disease.

Lonafarnib is in clinical investigation under IND (b) (4)

On 8/24/2020, the Sponsor submitted SDN 30, which included the following: 1. Special Protocol Assessment Request- Carcinogenicity Study 2. Special Protocol Assessment Request- Protocol 1742-20XXX- Appendix A

The objective of the submitted SPA-1 request is to evaluate the carcinogenic potential of lonafarnib when administered daily via oral gavage to Sprague Dawley rats for 104 weeks. The proposed study will be conducted in accordance with OECD Principles of Good Laboratory Practice and with the U.S. Department of Health and Human Services, Food and Drug Administration. To support the dose selection of the carcinogenicity study, the Sponsor submitted data from a 3- and 6-month toxicity studies in rats, as well as data from pharmacokinetic/ADME studies and genotoxicity studies conducted with lonafarnib. These data were presented in the Special Protocol Assessment Request, with links to some of the original studies embedded within the references section.

Executive Carcinogenicity Assessment Committee Conclusions The Committee did not agree with the Sponsor’s proposed doses. The Committee recommended a high dose of 30 mg/kg/day based on MTD in the 3- and 6-month toxicity studies, and recommended mid and low doses of 15 and 8 mg/kg/day, respectively, to

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provide adequate AUC spacing (IND 139923 SPA-1 Special Protocol Agreement; R. Aziz; 10/1/2020).

Testing Facility The carcinogenicity study will take place at (b) (4) . This is a different test facility from where the 3- and 6-month toxicity studies were conducted. The carcinogenicity study may not be acceptable if toxicity is significantly different due to these changes such that dose selection would have been altered.

Table 1: Test Facilities for Toxicology Studies with Lonafarnib Study Testing Facility Safety Evaluation Center, Schering-Plough Research 3-month toxicity in rats Institute (SPRI), Lafayette, NJ 07848, USA (b) (4) 6-month toxicity in rats

104-week carcinogenicity in rats

Dose We do not agree with the Sponsor’s proposed doses of 10, 20, and 40 mg/kg/day for males, and recommend doses of 8, 15, and 30 mg/kg/day for males and females based on the maximum tolerated dose (MTD) of 30 mg/kg/day determined in the 3- and 6-month toxicity studies in rats.

The proposed high dose of 40 mg/kg/day in males and females was selected by the Sponsor because of adverse effects on body weight, food consumption, clinical pathology, and anatomic pathology at doses ≥60 mg/kg/day in the 3- and 6-month toxicity studies in rats. However, 40 mg/kg/day has not been tested in either of these studies and, therefore, should not be the high dose in the 104-week carcinogenicity study.

In the 3-month toxicity study, adult rats were orally administered lonafarnib at 30, 90, or 180 mg/kg/day once daily. A NOAEL was not established due to mortalities at 180 mg/kg/day, histopathological findings in multiple tissues at ≥90 mg/kg/day, lymphoid hypocellularity in the spleen and thymus ≥30 mg/kg/day, and dose-dependently decreased WBC counts (low: -26%; mid: -55%; high: -73%). Decreased body weight gains of >10% controls were observed ≥90 mg/kg/day males and females. The MTD in this study was considered to be 30 mg/kg/day due to the presence but low severity of histopathological findings at 30 mg/kg/day and lack of decreased body weight gains compared to controls.

In the 6-month study, adult rats were orally administered lonafarnib at 15, 30, or 60 mg/kg/day once daily. The NOAEL is 15 mg/kg/day due to clinical pathology changes indicative of liver and/or kidney toxicity and histopathological findings in the kidney, liver,

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parathyroid, and/or thymus at the higher doses. By the end of the study, absolute body weights were decreased ~12% in 60 mg/kg/day males and females compared to controls, but only decreased 2.5% and 8.7% in 30 mg/kg/day males and females. The MTD is considered to be 30 mg/kg/day due to decreased body weight observed at 60 mg/kg/day.

The Sponsor did not provide justification for the proposed mid- (20 mg/kg/day) and low- (10 mg/kg/day) doses. To maintain adequate AUC spacing between dose levels, we recommend that the mid- and low-doses be 15 and 8 mg/kg/day, respectively.

Notably, evidence of sex differences in exposure were observed in the 6-month toxicity study in rats. AUC of lonafarnib in females was 2.4-6.1x higher than in males by Week 26. Although exposure to lonafarnib may be a better basis to set doses for the 104-week carcinogenicity study considering the sex differences in exposure, the Sponsor would not be able to test a dose that produces an AUC of lonafarnib in the animal that is 25x the human AUC of lonafarnib, given the toxicities observed at <10x the MRHD of 150 mg/m2 (14.9 μg*h/mL).

Table 2: TK Summary of 6-Month Study in Rats AUC AUC ratio to 0-12h AUC Ratio (μg*h/mL) MRHD1 Dose F:M Females Males (150 mg/m2) (mg/kg/day) Day Day Day Day 1 Day 1 Day 1 Females Males 176 176 176 15 (NOAEL) 10.9 14.1 1.37 2.31 8.0x 6.1x 0.16x 0.95x 30 31.5 46.1 4.03 19.0 7.8x 2.4x 3.1x 1.3x 60 132 136 30.0 38.5 4.4x 3.5x 9.1x 2.6x 2 1. AUC0-12h of lonafarnib at 150 mg/m after 27 months of administration: 14,900 ng*h/mL (14.9 μg*h/mL) Table 18, Special Protocol Assessment Request- Carcinogenicity Study

Vehicle The vehicle to be used is 0.4% (w/v) aqueous methylcellulose (IND 139923 SPA-1 Advice/Information Request; J. Doan; 9/2/2020). This is the same vehicle used in the 3- and 6-month toxicity studies in rats.

Appropriateness of Test System The rodent model will be Sprague Dawley rats, sourced from (b) (4) The Sprague Dawley rat is an appropriate test system in which to conduct a 104-week oral carcinogenicity study. The animals will be 5-7 weeks old by study initiation. This is the same species and strain used in the 3- and 6-month toxicity studies, though the test system will be supplied from a different location.

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Table 3: Test System Supplier Comparison Study Supplier (b) (4) 3-month toxicity in rats 6-month toxicity in rats 104-week carcinogenicity in rats

Treatment Design Sprague Dawley rats (n=70/sex/group) will be administered lonafarnib via oral gavage once daily for 104 weeks. Satellite groups will be included to evaluate the toxicokinetics of lonafarnib at Week 52 at each dose level (n=5/sex/vehicle; 10/sex/lonafarnib groups). Study stopping criteria were not provided.

Table 4: Study Design Dose Weeks of Volume Conc. Number of Animals Group (mg/kg) Treatment (mL/kg) (mg/mL) Males Females 1 vehicle 104 10 0 70 70 2 10 104 10 1 70 70 3 20 104 10 2 70 70 4 40 104 10 4 70 70 5 TK vehicle 52 10 0 5 5 6 TK 10 52 10 1 10 10 7 TK 20 52 10 2 10 10 8 TK 40 52 10 4 10 10 9 Sentinel NA NA NA 5 5

In-Life Procedures The Sponsor intends to evaluate animals for mortality and moribundity twice daily, and will conduct cageside and detailed clinical physical examinations weekly. Body weights will be recorded weekly from Week 1-14, once every two weeks through Week 28, and then once monthly for the remainder of the study. Food consumption will be quantitatively measured once weekly from Week 1-13, and once monthly for the remainder of the study. At scheduled termination, blood samples will be taken from the main study animals to measure hematology parameters.

Toxicokinetics Blood will be collected from the satellite groups of animals prior to the first dose on Day 1 and during Week 52 at 0.5, 2, 4, 6, 12, and 24 postdose (n=3/sex/group/timepoint). A predose trough sample will be collected from the satellite animals in Week 52 prior to dosing. For the vehicle control satellite group, blood samples will be collected 1 hour postdose on Day 1 and Week 52.

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Terminal Procedures Necropsy, macroscopic evaluations, and histopathological evaluations will be conducted on all animals euthanized at the scheduled termination, euthanized prior to scheduled termination, or found dead. At the time of necropsy, an adequate battery of tissues and organs will be collected for macroscopic and histopathological examinations (see protocol pg. 15-17). Blood and bone marrow smears will be collected but not analyzed unless requested by the pathologist. A formal pathology peer review will be conducted.

Statistical Methods The Sponsor provided statistical methods in the carcinogenicity protocol, but they are not reviewed here.

Study Reports The Sponsor did not discuss their intent to submit SEND datasets.

Supporting Data Summaries

Table 5: Previous Reviews Referenced as Needed Date in IND Reviewer SDN Notes DARRTs (b) (4) Cynthia Anita Bigger 5/13/2011 1 30-Day Safety Meeting Review Summary of reproductive Mark Powley 7/6/2011 6 toxicities for Sponsor meeting • EFD study in rabbits 6/7/2018 53 • Electroretinography study in monkeys • 6-month study in rats David McMillan • 12-month study in monkeys 6/12/2019 6, 37, 84 • FEED study in rats • EFD study in rats • PPND study in rats 2/6/2001 168, 173 Micronucleus assay J. Leighton 12/12/2002 347 Impurities evaluation Summary of toxicity studies D. Gautam 2/11/2009 previously reviewed to support research IND Summarized review by D. 139923 K. Zhang 11/29/2018 5 Gautam

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Pharmacology Summarized from Sponsor’s submissions under NDA 213969. Lonafarnib competitively inhibits human farnesyl protein transferase with an IC50 of 1.9 nM, preventing post-translational addition of the 15-carbon isoprenyl lipid farnesyl onto prelamin (A) and inhibiting the formation of progerin.

Lonafarnib has not been specifically tested in vivo in mouse models of progeria (Zmpste24-deficient mice and C608G LMNA mice). However, other farnesyl transferase inhibitors (FTI) have been shown to ameliorate symptoms of progeria in these mouse models. In male and female Zmpste24-deficient mice, oral administration of the FTI ABT- 100 inhibited protein farnesylation, evidenced by body weight gain, improved grip, reduced rib fractures, and prolonged life span in these mice (Fong et al., 2006). In transgenic C608G LMNA mice, oral administration with the FTI tipifarnib reduced total cholesterol, total protein, and creatinine, increased alkaline phosphatase, and improved cardiovascular disease endpoints, including increasing the abundance of vascular smooth muscle cells (Capell et al., 2008).

PK/ADME Summarized in Nonclinical Review by Cynthia A. Bigger (IND (b) (4) ; 5/13/2011; DAV). Exposure to lonafarnib increased with increasing dose in rats and monkeys, though sex differences in exposure were evident in both species. In rats, exposure to lonafarnib was higher in females than males at all doses. In monkeys, exposure to lonafarnib was higher in males than females at low doses, but not at higher doses. Additionally, accumulation was evident in rats after repeated dosing, but not in monkeys. Differences in absorption and/or elimination mechanisms may exists between male and female animals, as well as between species. Lonafarnib was highly protein bound (>99%) in plasma from rats, monkeys, and humans. Lonafarnib is extensively metabolized in rats, monkeys, and humans by oxidation (CYP3A4 and CYP3A5) and dehydrogenation generally involving structural changes in the pendant piperidine ring region. Two metabolites, SCH 441746 (HM21) and SCH 629153 (HM17), present in humans (15.1% and 13.9% of parent, respectively), rats, and monkeys, were found to pharmacologically active similar to lonafarnib. No unique human metabolites have been identified in vivo. The main route of excretion was identified via the feces; renal excretion was not a major elimination pathway.

Toxicology To support the proposed 104-week carcinogenicity study protocol, the Sponsor submitted 3- and 6-month toxicity studies in rats. The 3-month toxicity study is summarized below, while more details are provided for the 6-month toxicity study. The 6-month toxicity study is considered to be the pivotal study used to determine the acceptability of the proposed doses for the 104-week carcinogenicity study.

In a 3-month oral toxicity study (Study 96030), lonafarnib (coded SCH 66336) was administered to Sprague Dawley rats via oral gavage at 30, 90, and 180 mg/kg/day once

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daily for 3 months. The vehicle was 0.4% (w/v) aqueous methylcellulose. A NOAEL was not established due to mortalities at 180 mg/kg/day, histopathological findings in multiple tissues at ≥90 mg/kg/day, lymphoid hypocellularity in the spleen and thymus ≥30 mg/kg/day, and dose-dependent decreases in WBC counts (low: -26%; mid: -55%; high: -73%). The MTD was considered to be 30 mg/kg/day due to the presence but low severity of histopathological findings at 30 mg/kg/day and decreased body weight gains >10% at ≥90 mg/kg/day compared to controls. Two 180 mg/kg/day females died on Weeks 3 and 12 due to emaciation and with discolored nasal discharge. Body weight gains were decreased 11.0% and 17.5% in 90 mg/kg/day males and females, respectively, and 24.4% and 18.4% in 180 mg/kg/day males and females, respectively, compared to controls. Alkaline phosphatase (ALP) was increased 39.9% in 90 mg/kg/day females, 71% in 180 mg/kg/day males, and 154% in 180 mg/kg/day females compared to controls. Gamma-glutamyl transferase (GGT) was increased 600% in 180 mg/kg/day females compared to controls, but not males. Alanine amino transferase (ALT) was increased 58% in 180 mg/kg/day males and 31-55% in ≥90 mg/kg/day females compared to controls. Increased urine volume with decreased urine osmolality, both correlated with increased water consumption, were observed in ≥90 mg/kg/day males and females compared to controls. Urinary calcium was increased without higher serum calcium concentrations, indicative of a kidney defect in calcium reabsorption and may be correlated with histopathological findings in the kidney. Histopathological findings were observed in the kidney (mineralization, tubular basophilia; ≥90 mg/kg/day), liver (hypertrophy/vacuolation; ≥90 mg/kg/day), parathyroid (cytoplasmic vacuolation with or without single cell necrosis; ≥90 mg/kg/day), spleen (lymphoid hypocellularity; ≥30 mg/kg/day), thymus (lymphoid hypocellularity; ≥30 mg/kg/day), mesenteric lymph nodes (lymphoid hypocellularity; ≥90 mg/kg/day), mandibular lymph nodes (lymphoid hypocellularity; 180 mg/kg/day), ileum (hypocellularity of Peyer’s Patch; 180 mg/kg/day), bone marrow (hypocellularity, increased megakaryocytes; ≥90 mg/kg/day), pancreas (acinar cell vacuolation with single cell necrosis; ≥90 mg/kg/day), testes (aspermia, altered spermatogenesis, spermatogonial debris; 180 mg/kg/day), and epididymides (oligospermia, spermatic debris; ≥90 mg/kg/day).

In a 6-month oral toxicity study (Study SN96034), lonafarnib (coded SCH 66336) was administered to Sprague Dawley rats via oral gavage at 15, 30, and 60 mg/kg/day once daily for 6 months. The vehicle was 0.4% (w/v) aqueous methylcellulose. The NOAEL was considered to be 15 mg/kg/day due to decreased body weights at 60 mg/kg/day, clinical pathology changes indicative of liver and/or kidney toxicity at ≥30 mg/kg/day, and histopathological findings in the kidney, liver, parathyroid, and/or thymus at ≥30 mg/kg/day. No mortalities or adverse clinical signs occurred in this study. Body weights were decreased throughout the duration of the study in 60 mg/kg/day males and females compared to controls, culminating in an approximate 12% decrease in absolute body weight at 60 mg/kg/day compared to controls prior to scheduled termination (listed as Week 27). Decreased body weights were not correlated with decreased food consumption.

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Table 6: Body Weight Changes- 6 months Dose Body Weight (g) by Week BW (mg/kg/day) 1 8 15 22 27 % change Males 0 216 461 540 597 589 - 15 217 458 530 585 577 -2.0% 30 216 451 518 569 574 -2.5% 60 216 423 475 515 520 -11.7% Females 0 162 259 288 320 322 - 15 163 258 287 314 308 -4.3% 30 162 243 271 294 294 -8.7% 60 162 239 263 288 284 -11.8%

Effects on hematology parameters include decreased white blood cells (-18%), decreased lymphocytes (-24%) and decreased eosinophils (-100%), as well as increased red blood cells (+12%) in 60 mg/kg/day females compared to controls. These factors were unaffected in males (Table 7). The only hematological effect in males was decreased reticulocytes (-33%, -39%) at ≥30 mg/kg/day compared to controls.

Table 7: Hematology Parameters- 6 Months

Hematology Week 26 Dose Parameter Unit % % (mg/kg/day) Males Females Week 26 change change 0 8.25 - 7.74 - Red Blood Cell 15 8.71 6% 8.20 6% 106/μL Counts 30 8.71 6% 8.30 7% 60 8.81 7% 8.65 12% 0 161 - - - 15 108 -33% - - Reticulocytes 103/μL 30 147 -9% - - 60 99 -39% - - 0--4.9- 15 - - 4.4 -10% White Blood Cells 103/μL 30 - - 4.7 -4% 60 - - 4.0 -18% 0--3.7- 15 - - 3.4 -8% 103/μL 30 - - 3.6 -3% Lymphocytes 60 - - 2.8 -24% 0--76 15% - - 75 30 --77

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Hematology Week 26 Dose Parameter Unit % % (mg/kg/day) Males Females Week 26 change change 60 - - 69 0 0.2 - 0.2 - 15 0.1 -50% 0.1 -50% 103/μL 30 0.1 -50% 0.1 -50% 60 0.1 -50% 0.0 -100% Eosinophils 02-3 15 2 0% 2 % 30 2 0% 2 60 1 -50% 1

Serum chemistry evidence of liver and/or kidney toxicity was observed mainly in females at 30 and/or 60 mg/kg/day (Table 8). Increased blood urea nitrogen (60 mg/kg/day; 117%), ALP (dose dependent; 59-119%), GGT (30 and 60 mg/kg/day; 50%, 800%), potassium (60 mg/kg/day; 25%), and inorganic phosphate (60 mg/kg/day; 49%), as well as decreased total protein (60 mg/kg/day; -11%) and albumin (60 mg/kg/day; -17%) compared to controls. These changes were not associated with changes in organ weights (Table 10). but were correlated with increased urine volumes and altered urine electrolyte levels (Table 9), as well as histopathological findings in the kidney and liver in females at 60 mg/kg/day (Table 11). Increased blood urea nitrogen was observed in 60 mg/kg/day males and increased alkaline phosphatase was observed at all doses in males compared to controls, but the magnitudes of change were much less than in females and only correlated with minimal to mild hepatocellular vacuolation.

Table 8: Clinical Chemistry Parameters- 6 Months

Clin Chemistry Week 26 Dose Parameter Unit % % (mg/kg/day) Males Females Week 26 change change 012-12- Blood Urea 15 13 8% 13 8% mg/dL Nitrogen 30 12 0% 14 17% 60 15 25% 26 117% 0--8.2- 15 - - 7.9 -4% Total protein g/dL 30 - - 7.4 -10% 60 - - 7.3 -11% 0--5.9- Albumin 15g/dL - - 5.5 -7% 30 - - 5 -15%

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Clin Chemistry Week 26 Dose Parameter Unit % % (mg/kg/day) Males Females Week 26 change change 60 - - 4.9 -17% 0--0.8- 15 - - 0.8 0% Creatinine mg/dL 30 - - 0.7 -13% 60 - - 1.9 138% 068-27- Alkaline 15 79 16% 43 59% IU/L phosphatase 30 89 31% 50 85% 60 100 47% 59 119% 0--2- 15 - - 2 0% GGT IU/L 30 - - 3 50% 60 - - 18 800% 0--5.5- 15 - - 5.8 5% Potassium mmol/L 30 - - 5.8 5% 60 - - 6.9 25% 0--5.7- Inorganic 15 - - 6.1 7% mg/dL Phosphate 30 - - 6.4 12% 60 - - 8.5 49%

Increased urine volume with decreased urinary osmolality were observed in ≥30 mg/kg/day males and ≥15 mg/kg/day females compared to controls. Increased urinary pH was observed in ≥30 mg/kg/day compared to controls. In general, dose-dependent alterations in urine electrolytes were observed in lonafarnib-treated males and females compared to controls.

Table 9: Urinalysis Parameters- 6 Months

Urinalysis Week 26 Dose Parameter Unit % % (mg/kg/day) Males Females Week 26 change change 016.4-11.6- 15 13.5 -18% 20.5 77% Urine Volume mL 30 20.7 26% 15.0 29% 60 21.2 29% 24.1 108% 0 1077 - 1183 - Urine Osmolality mOsm/kg 15 1234 15% 836 -29%

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Urinalysis Week 26 Dose Parameter Unit % % (mg/kg/day) Males Females Week 26 change change 30 957 -11% 825 -30% 60 835 -22% 579 -51% 0 7.9 - 7.1 - 15 7.9 0% 7.6 7% pH pH 30 8.1 3% 7.9 11% 60 8.2 4% 7.8 10% 0 130.2 - 111.3 - 15 145.6 12% 70.6 -37% Creatinine mg/dL 30 102.7 -21% 59.8 -46% 60 77.6 -40% 39.4 -65% 05.8-19.9- 15 8.0 38% 17.1 -14% Calcium, urinary mg/dL 30 9.0 55% 16.1 -19% 60 10.4 79% 9.8 -51% 0 0.79 - 1.58 - 15 0.95 20% 1.81 15% Calcium, excreted mg 30 1.51 91% 1.90 20% 60 2.02 156% 1.96 24% 0 1.28 - 4.52 - Calcium, by body 15 1.55 21% 5.65 25% mg/kg weight 30 2.57 101% 6.24 38% 60 3.81 198% 6.70 48% 0 157 - 174 - 15 170 8% 122 -30% Phosphorus, urinary mg/dL 30 124 -21% 113 -35% 60 98 -38% 83 -52% 0 - - 12.10 - 15 - - 12.21 1% Phosphorus, excreted mg 30 - - 12.74 5% 60 --16.2835% 0 30.39 - 35.10 - Phosphorus, by body 15 29.95 -1% 38.33 9% mg/kg weight 30 35.55 17% 41.80 19% 60 36.62 21% 55.17 57% 021-29- 15 25 19% 25 -14% Sodium, urinary mmol/L 30 25 19% 29 0% 60 35 67% 32 10% Sodium, excreted 0 mmol 0.31 - 0.22 -

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Urinalysis Week 26 Dose Parameter Unit % % (mg/kg/day) Males Females Week 26 change change 15 0.27 -13% 0.29 32% 30 0.44 42% 0.35 59% 60 0.73 135% 0.61 177% 0 0.49 - 0.64 - Sodium, by body 15 0.44 -10% 0.89 39% mmol/kg weight 30 0.75 53% 1.16 81% 60 1.36 178% 2.07 223% 0 145 - 158 - 15 155 7% 108 -32% Potassium, urinary mmol/L 30 120 -17% 102 -35% 60 108 -26% 75 -53% 0 1.74 - 0.97 - 15 1.66 -5% 1.02 5% Potassium, excreted mmol 30 2.05 18% 1.12 15% 60 2.13 22% 1.43 47% 0 2.83 - 2.83 - Potassium, by body 15 2.74 -3% 3.18 12% mmol/kg weight 30 3.49 23% 3.67 30% 60 4.01 42% 4.82 70% 049-61- 15 67 37% 55 -10% Chloride, urinary mmol/L 30 62 27% 64 5% 60 74 51% 58 -5% 0 0.65 - 0.42 - 15 0.74 14% 0.56 33% Chloride, excreted mmol 30 1.06 63% 0.69 64% 60 1.49 129% 1.12 167% 0 1.04 - 1.22 - Chloride, by body 15 1.22 17% 1.74 43% mmol/kg weight 30 1.81 74% 2.29 88% 60 2.81 170% 3.78 210%

Relative pituitary, uterus, and thymus weights were decreased in 60 mg/kg/day females compared to controls at Week 26. Decreased thymus weight was correlated with histopathological findings of minimal to moderate cortical lymphocyte hypocellularity in 60 mg/kg/day females. No histopathological correlates were observed in the pituitary or uterus, and no treatment-related changes in organ weights were observed in males.

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Table 10: Organ Weight Changes- 6 Months Week 26 Dose Histopath. Test Unit % (mg/kg/day) Females Correlates? change 0 Rel. BW 0.0073 Pituitary No 60 Rel. BW 0.0050 -31.5% 0 Rel. BW 0.3142 Uterus No 60 Rel. BW 0.2242 -28.6% 0 Rel. BW 0.0468 Thymus Yes 60 Rel. BW 0.0388 -17.1%

Histopathological findings of minimal to mild hepatocellular vacuolation were observed in 30 mg/kg/day males and females and may be due to increased enzyme production in the liver. No other histopathological findings could be attributed to treatment with lonafarnib in males. However, in females, additional histopathological findings include minimal to mild interstitial mineralization and minimal to moderate necrosis of the kidney at ≥30 mg/kg/day, minimal to mild chief cell vacuolation of the parathyroid at ≥30 mg/kg/day, minimal to mild mitotic figures in the thymus at ≥30 mg/kg/day and minimal to moderate cortical lymphocyte hypocellularity in the thymus at 60 mg/kg/day.

Table 11: Histopathological Changes with Lonafarnib Dose (mg/kg/day) n=15/sex/dose Finding Males Females 0 15 30 60 0 15 30 60 Kidney Inner medulla/interstitial mineralization minimal ---1--44 mild ------2

Inner medulla/interstitial necrosis minimal ------11 mild ---1---4 moderate ------2

Liver Hepatocellular vacuolation minimal --57--12 mild ---1----

Parathyroid Chief cell vacuolation minimal ------38 mild ------1

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Reference ID: 4707101 680825 IND #139923 SPA-1 Reviewer: Jackye Peretz, Ph.D.

Dose (mg/kg/day) n=15/sex/dose Finding Males Females 0 15 30 60 0 15 30 60 Thymus Cortical lymphocyte hypocellularity minimal ------5 mild ------1 moderate ------2

Mitotic figures minimal ------28 mild ------3

In females, on Day 1 and during Week 26, AUC of lonafarnib increased supraproportionally to dose across the dose range. In males, AUC of lonafarnib increased supraproportionally to dose on Day 1 at all doses, and between 15 and 30 mg/kg/day during Week 26. However, between 30 and 60 mg/kg/day, AUC of lonafarnib increased proportionally to dose. Accumulation was observed between Day 1 and Week 26 at 15 and 30 mg/kg/day in males and females, but not at the high dose. Evidence of sex differences in exposure were observed, though independent of dose. AUC of lonafarnib in females was 4.4-8.0x higher than in males on Day 1, and 2.4-6.1x higher by Week 26.

Table 12: TK Summary with Lonafarnib AUC AUC ratio to 0-12h AUC Ratio (μg*h/mL) MRHD1 Dose F:M Females Males (150 mg/m2) (mg/kg/day) Day Day Day Day 1 Day 1 Day 1 Females Males 176 176 176 15 10.9 14.1 1.37 2.31 8.0x 6.1x 0.16x 0.95x 30 31.5 46.1 4.03 19.0 7.8x 2.4x 3.1x 1.3x 60 132 136 30.0 38.5 4.4x 3.5x 9.1x 2.6x 2 1. AUC0-12h of lonafarnib at 150 mg/m after 27 months of administration: 14,900 ng*h/mL (14.9 μg*h/mL) Table 18, Special Protocol Assessment Request- Carcinogenicity Study

Genetic Toxicology Summarized in Nonclinical Review by Cynthia A. Bigger (IND (b) (4) ; 5/13/2011; DAV). Lonafarnib was negative in a standard battery of in vitro and in vivo genotoxicity studies.

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Reference ID: 4707101 680825 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/ ------

JACKYE R PERETZ 10/05/2020 11:09:39 AM

ADEBAYO A LANIYONU 10/05/2020 11:13:58 AM

Reference ID: 4707101 680825 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research Office of New Drugs/Office of Cardiology, Hematology, Endocrinology and Nephrology Division of Cardiology and Nephrology (DCN)

Date: June 22, 2020

From: Shetarra Walker MD, MSCR, Clinical Reviewer

Through: Fred Senatore MD, PhD, FACC, DCN Team Leader Norman Stockbridge, MD, PhD, DCN Division Director

To: Mari Suzuki, MD, Medical Reviewer, DRDMG

Subject: Consult Request: NDA 213969/Lonafarnib capsules for oral use (dosage strengths: 50mg and 75 mg)-- Provide input on limitations of cardiovascular endpoint data to support labeling an indication for a limited number of patients with processing deficient progeroid laminopathy (PL)

This memo responds to your request for our input on the Sponsor’s (Eiger) intent to rely on cardiovascular endpoint data to support labeling an indication for a limited number of patients with PL treated with lonafarnib. DCN was previously consulted twice, in 2014 and 2018, to provide input on this development program. To address this consult, we reviewed prior DCN consults, white paper on progeroid laminopathies provided by Eigar, clinical response to an Information Request (IR) dated 28 May 2020, and pertinent efficacy data included in the new drug application (NDA) submission.

Conclusion and Recommendations DRDMG requested that DCN provide input on limitations of carotid-femoral pulse wave velocity (PWVcf) and carotid echodensity endpoints to provide supportive evidence for an indication in patients with PL. We acknowledge PL is an ultra-rare syndrome of which Eigar has provided data for four patients. In the PWVcf data provided for PL patients, we note there is lack of baseline PWVcf data in three out of the four PL patients for comparison, inconsistent data in HGPS patients showing a treatment effect on PWVcf; and, in patients with reduction in PWVcf, results are mostly marginal with unclear clinical significance.

The carotid echodensity data are not interpretable because it is unclear how a reduction in echodensity, measured in pixels, translates to a clinically meaningful benefit or outcome. Eigar interchanges carotid wall thickness with echodensity, which is confusing because each parameter may yield a different interpretation. In addition, Eigar has not provided data showing an association between a mortality benefit and changes in PWVcf or carotid echodensity. Therefore, we conclude that the PWVcf and carotid echodensity data are inadequate to support a labeling claim (b) (4)

In addition, we recommend that Eigar provide analyses of the CIMT data with linear measurements compared to baseline in HGPS and PL populations.

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR We note that the proposed indication for PL is different than that proposed for HPGS with an emphasis on treatment instead of reduction in mortality. We recommend that DRDMG consider if other (non-cardiac) data provided for HGPS and PL might support the proposed treatment indication in PL patients given the rarity of PL, mechanistic and phenotypic overlap between HGPS and PL, and limited data available.

Background Information/Regulatory History Hutchinson-Gilford-Progeria Syndrome (HGPS) and Progeroid Laminopathies (PL) collectively are known as progeria.

HGPS is a rare multi-systemic “premature ageing” disease caused by a genetic mutation in exon 11 of the lamin A/C (LMNA) gene. This genetic mutation results in accumulation of a farnesylated abnormal lamin A protein (progerin). Lamin A is a protein necessary for maintaining the integrity of nuclear membranes. The incidence of HGPS is about 1 in 4 million live births with prevalence of 1 in 20 million living individuals. HGPS patients develop an accelerated form of atherosclerosis commonly seen in adults in the sixth and seventh decades of life. The two most significant age-related cardiovascular changes in the HGPS population are arterial stiffness, resulting in increased pulse wave velocity (PWV), and endothelial dysfunction. The average age of death is 14.5 years of age with the most common cause due to severe atherosclerosis.

PLs are a collection of diseases with a continuum of disease severity. PLs are caused by mutations in ZMPSTE24 and LMNA genes leading to accumulation of progerin-like proteins. PLs are subcategorized into processing- proficient and processing deficient forms with the latter producing permanently farnesylated prelamin A. Therefore, processing deficient forms of PLs are more likely to produce overlapping clinical features with HGPS. However, unlike HGPS, all children with PL do not experience severe disease manifestations. PLs, rarer than HGPS, have been identified in fewer than 40 children worldwide, nine of which are in the United States.

In murine models, progerin has been shown to induce loss of vascular smooth muscle cells and replacement with extracellular matrix resulting in fibrosis in addition to progerin-related atherosclerosis and increased plaque vulnerability. According to Eigar, the above normal echodensity of carotid arteries (intima media, near/deep adventitia) is representative of fibrotic changes that occur in carotid arteries. Therefore, Eigar proposes that reduction in carotid artery echodensity is suggestive of a reduction in vascular wall inflammation and fibrosis. Moreover, Eigar states these vascular wall changes are correlated with reductions in PWVcf, an independent predictor of cardiovascular risk.12 Eigar hypothesizes that improved vascular function may potentially translate into improved longer-term cardiovascular outcomes in HGPS and PL patients.

Lonafarnib is a farnesyltransferase inhibitor with a proposed mechanism of action of preventing farnesylation and subsequent accumulation in the inner nuclear membrane of progerin and progerin-like proteins. This accumulation of progerin or progerin-like proteins is thought to be responsible for the clinical manifestations of HGPS and processing-deficient forms of PL. Lonafarnib is not approved for any adult or pediatric indications and there are no approved treatments or cures for HGPS or PL. Lonafarnib has been granted the following FDA designations: rare pediatric disease (2018) for treatment of HGPS and PL, breakthrough therapy (2018), and orphan drug (2019). Because lonafarnib has orphan drug designation, the Pediatric Research Equity Act does not apply.

The Agency met with Eiger at pre-Investigation New Drug Application (PIND) and pre-NDA meetings in 2018 and 2019, respectively. DRDMG, formerly part of DGEIP, twice consulted DCN on this development program in 2014 and 2018 (Dr. Karen Hicks was the DCN clinical reviewer). A summary of clinical data from most of the clinical studies submitted in this NDA package was previously reviewed by DCN. (b) (4)

1 Mattace-Raso FU, van der Cammen TJ, Hofman A, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation. 2006;113:657–63. 2 Willum-Hansen T, Staessen JA, Torp-Pedersen C, et al. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation. 2006;113:664–70. 2

Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

(b) (4)

In 2018, DGEIP consulted DCN for PIND 139923, lonafarnib for treatment of patients with HGPS. DGEIP requested DCN provide input on a sponsor plan to submit PWV and echobrightness of carotid artery adventitia results from two studies in HGPS, one with lonafarnib as monotherapy and the other with triple therapy (lonafarnib, pravastatin, and zoledronic acid). DCN was asked to specifically provide input on whether the Agency agrees that observed improvements in carotid echodensity and PWVcf would be provide mechanistic supportive data for the primary endpoint of survival in a single-arm dose-escalation study in HGPS patients. Dr. Hicks responded, “Yes, we agree that improvement in arterial wall density and stiffness could provide mechanistic supportive data for a primary endpoint of survival but…data provided in the Briefing Package are insufficient to do so because of missing data and conflicting results.”

Eiger submitted NDA 213969 for lonafarnib as a rolling submission starting in December 2019 to support approval for the following indications: reduce mortality in patients 12 months of age or older with HGPS; and treatment of PL in patients 12 months of age or older with a processing-deficient mutation in LMNA or ZMPSTE24. Eiger submitted the last portion of their original NDA in March 2020, which included the clinical modules. In this submission, Eiger provided results from a pivotal observational cohort survival study that included patient data from two investigator-sponsored Phase 2 studies in patients with HGPS and PL (Studies 07- 01-0007 and 09-06-0298). Efficacy results for submitted clinical studies are summarized in the next section of this review.

Eigar provided data in their NDA submission for four PL patients but did not include these patients in their efficacy analyses. However, in addition to HGPS, Eiger is seeking to label lonafarnib for treatment of PL based on a mechanistic rationale similar to HGPS and supportive evidence including CIMT, PWV, and qCT to measure bone mineral density. DRDMG specifically requests that DCN provide input on the limitations of the cardiovascular endpoints proposed to provide supportive evidence for an indication in PL.

Study 07-01-007 (ProLon1)

ProLon1 was a Phase 2, open-label, single arm, dose-escalation study with lonafarnib monotherapy in pediatric patients with HGPS or PL, 3 years of age and older. Lonafarnib was initiated at a dose of 115 mg/m2 and escalated to 150 mg/m2 every 12 hours (BID) oral after about 4 months if therapy was well tolerated. Of the 29 patients enrolled, 28 were treated – 26 patients had classic HGPS, one patient had a non-classic mutation, and one had PL. All patients successfully escalated to 150 mg/m2 BID oral and continued therapy for 24 to 30 months. The primary efficacy endpoint was achievement of at least 50% increase in the annual rate of weight gain over the rate documented at study entry. Secondary efficacy endpoints included changes in carotid artery ultrasonography, changes in corrected PWVcf, changes in ankle-brachial index (ABI), and changes in endothelium-dependent flow- mediated vasodilatation (FMD).

Descriptive statistics were provided for each secondary endpoint over time with no plan for multiplicity adjustments for primary or secondary efficacy endpoints given the small sample size. The Sponsor reported a statistically significant (p<0.0001) rate of weight gain in 11 out of 28 patients (39.3%) who achieved at least 50% 3

Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR increase in weight slope for weight gain or change from negative to a positive slope. The Sponsor reported improved “cardiovascular status” in children with HGPS and PL based on decrease in echodensity of CIMT and near/deep adventitia from baseline to end of therapy. The Sponsor reported that these carotid echodensity measures were not different from that of controls and lower than controls for deep adventitia by end of therapy. In addition, at end of therapy, the Sponsor reported improved PWVcf with lonafarnib treatment with median percent decrease from baseline of 15.3% (range -43.6% to 34.1%). The single PL patient had a median percent decrease from baseline in PWVcf of 13.6% with no p-value calculated. At end of therapy, Eigar reported ABI was similar to that at baseline and no change in FMD was observed from baseline. See Table 1 and Figure 1 below for PWVcf data in HGPS and PL patients. See Table 3 in Appendix for detailed carotid echodensity data.

Table 1. Corrected Carotid-Femoral Pulse Wave Velocity - Summary of Percent Change from Baseline to End of Therapy [Intention-To-Treat (ITT) Population]

Non-Classic Classic HGPS PL Total Parameter Statistics HGPS (N=26) (N=1) (N=28) (N=1) Baseline n221 1 24 Mean (SD) 12.7 (3.9) 14.0 (N/A) 8.8 (N/A) 12.6 (3.8) Median 12.9 14.0 8.8 12.9 Min, Max 7.2, 18.8 14.0, 14.0 8.8, 8.8 7.2, 18.8 Percent Change from Baseline n171 1 19 Mean (SD) -15.9 (21.6) -35.0 (N/A) -13.6 (N/A) -16.8 (20.8) Median -15.3 -35.0 -13.6 -15.3 Min, Max -43.6, 34.1 -35.0, -35.0 -13.6, -13.6 -43.6, 34.1

p-valuea 0.01 N/A N/A 0.03 a P-value for Wilcoxon signed-rank test. N/A = Not Applicable Source Table 14.2.2.2 in Study Report.

Figure 1. Corrected Carotid-Femoral Pulse Wave Velocity Improvement with Lonafarnib Therapy in HGPS Patients (ITT Population)

Note PWV for each patient baseline (circles) and end of therapy (squares); connecting lines show change in PWV for each child. Published normal range (4.8 -6.6 m/s) is plotted as a solid horizontal gray bar for comparison. Decrease from baseline shows improvement in PWV. End of Therapy is the last post baseline treatment visit for the patient. Source Figure 14.2.2.2.1 in Final Study Report.

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Reviewer Comments: Even considering that PL is an ultra-rare condition, conclusions on efficacy cannot be drawn from the PWVcf data from a single PL patient in this study. Because of limited data in PL patients, Eigar has proposed using HGPS data to support conclusions on efficacy in PL patients given phenotypic overlap between syndromes. Although the median change in PWVcf from baseline to end of therapy in HGPS patients was statistically significant, patient-level data shown in Figure 1 suggests that the summative results are driven by three patients with the highest baseline values for PWVcf. We note that not all patients had a decrease in PWVcf and, for those patients with a decrease, the median reduction was marginal. I question the clinical significance of a marginal change in PWVcf. Therefore, the HGPS PWVcf data does not help overcome data interpretability issues with PWVcf data in PL patients.

Study 09-06-0298 Triple therapy/Monotherapy Extension/ProLon2

This study was a Phase 2, open-label, single-arm study to evaluate triple therapy (lonafarnib, pravastatin, and zoledronic acid) in patients with HGPS or PL. The triple therapy patient cohort (Group 1) was treated for up to 60 months. The primary efficacy endpoint was achievement of at least a 50% increase in annual rate of weight gain over rate documented at study entry. Pertinent to this review were changes in the following secondary efficacy endpoints: carotid artery ultrasonography, changes in PWVcf, ABI, FMD, echocardio data, and magnetic resonance imaging/magnetic resonance angiogram data.

Descriptive statistics were provided for changes in each secondary endpoint over time. This review will focus on the carotid artery ultrasonography and PWVcf data to address DRDMG’s consult question.

Because Eigar did not observe additional benefit with triple drug therapy compared to available lonafarnib monotherapy data, treatment with pravastatin and zoledronic acid was discontinued and triple therapy patients were permitted to enter a lonafarnib monotherapy extension. In addition, the study was amended to allow enrollment of a new treatment-naïve patient cohort for treatment with lonafarnib monotherapy (Group 2/ProLon 2) for a 24-month duration of therapy with 12-month extension.

Subject Enrollment x Group 1 (Triple Therapy) Eigar enrolled 47 patients age 1 year and older in Group 1, 39 of which had classic HGPS, four had non- classic mutations, and four had PL. Twenty-six of these participants had previously received at least 2 years of continuous lonafarnib monotherapy in Study 07-01-007 and 21 were treatment-naïve. Lonafarnib dose was 150 mg/m2 BID oral. Pravastatin was administered orally once daily at either 5 mg or 10 mg if a patient weighed < or > 10 kg, respectively and zoledronic acid was administered intravenously over 30 minutes at a starting dose of 0.0125 mg/kg then increased to 0.05 mg/kg at 6, 12, and 18 months and at study end. The primary efficacy endpoint was assessed at 40 to 52 months.

x Group 1 Monotherapy Extension Eigar enrolled 36 Group 1 patients into the monotherapy extension, 18 patients continued from ProLon1 and 18 patients were initially treatment-naïve and had received triple therapy. In total, Group 1 patients were treated with lonafarnib 150 mg/m2 BID up to 96 months (up to 60 months as part of triple therapy and 36 months as monotherapy).

x Group 2/ProLon2 Monotherapy Extension Lonafarnib monotherapy expanded to include 40 treatment-naïve patients (Group 2). Of the 40 planned patients, 35 treatment-naïve patients were enrolled and received 150 mg/m2 BID.

Efficacy Analyses

In Group 1 (triple therapy), the primary efficacy endpoint was achieved in 12 of 40 patients (30.0%) (95% CI 16.6, 46.5) (p<0.0001). In Group 1 Monotherapy Extension, the primary endpoint was achieved in 6 of 23 patients 5

Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR (26.1%) (95% CI 10.2, 48.4) (p=0.0002). In Group 2/ProLon2, the primary endpoint was achieved in 8 of 22 patients (36.4%) (95% CI 17.2, 59.3) (p<0.0001). Per Eiger, lonafarnib monotherapy, but not triple therapy resulted in reduction in carotid artery echodensity in pediatric patients with HGPS and PL. By the end of the therapy, Eiger reported PWVcf improved amongst treatment-naïve Group 2/ProLon2 monotherapy patients. ABI and FMD did not significantly improve in any treatment group. Eigar stated the ABI is an unreliable measure of peripheral artery disease in patients with less compressible arteries. For Group 1 (triple therapy) and Group 1 Monotherapy Extension, Eigar stated that an insignificant change in FMD is not an unexpected finding in patients with HGPS. More details on cardiovascular efficacy endpoints summarized below.

Cardiovascular Efficacy Analyses

Group 1 (Triple Therapy) In HGPS patients, median echodensity (50th percentile) of the carotid artery adventitia luminal near wall [46.3 (range -77.0, 151.5), p<0.0001], adventitia deep near wall [79.5 (range -101.0, 216.0), p<0.001], and intima media [21.00 (-74.0, 197.0), p=0.0004] all increased from baseline to end of therapy. For PL patients (n=4), similar results were seen as in HGPS patients. At baseline, carotid arteries demonstrated similar echodensity compared to controls at the 50th percentile. By the end of therapy, carotid echodensities were higher in HGPS patients compared to controls. PWVcf did not change compared to baseline at end of therapy (p=0.98). See Figure 2 below for PWVcf results. At end of therapy, ABI was comparable to baseline. Echocardiographic data for left ventricular size, systolic function, and mass did not change with therapy, however available data were sparse according to Eigar.

Figure 2. Corrected Carotid-Femoral Pulse Wave Velocity Improvement with Lonafarnib Therapy in HGPS Patients (ITT Population)

In PL patients (n=4), echodensity was similar at baseline but higher at end of therapy compared to controls. At end of therapy, PWVcf did not change. Baseline values were not available for PL patients (n=4). In PL patients (n=4), baseline and end of therapy ABI measurements were provided, but all had normal measurements at all visits. For FMD, there was no change in from baseline in PL patients. See Table 4 in Appendix for detailed carotid echodensity data.

Group 1 Triple Therapy Monotherapy Extension 6

Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR In HGPS patients, echodensity (10th and 50th percentiles) of the carotid artery adventitia luminal near wall, adventitia deep near wall, and intima media all decreased from baseline to end of therapy with lonafarnib (p <0.0001 to 0.0003). There was no statistically significant change from baseline in median PWVcf (p=0.27). See Figure 3 below for PWVcf results. At end of therapy, ABI was comparable to baseline. For FMD, there was no change from baseline with therapy. Echocardiographic data for left ventricular size, systolic function, and mass did not change, however available data were sparse according to Eigar.

Figure 3. Corrected Carotid-Femoral Pulse Wave Velocity Improvement with Lonafarnib Therapy for Group 1: Triple Therapy Monotherapy Extension (ITT Population)

In the three PL patients, similar results were seen except for no decrease in the adventitia luminal near wall 10th percentile. There was a decrease in PWVcf for PL patients (n=3) but no p-value was calculated. The three PL patients had normal ABI measures at baseline and at end of therapy. See Table 2 below for PWVcf data in Group 1 Monotherapy Extension PL patients. See Table 5 in Appendix for detailed carotid echodensity data.

Table 2. Carotid-Femoral Pulse Wave Velocity (PWVcf) in Group 1 Monotherapy Extension PL Patients

Patient Study Baseline Date ID Populations Age / Visit [Study Day #] PWVcf (m/sec) for Analyses Gender

(b) (6) Safety 19/ Female Month 60 16SEP2014 [1805] 8.8 (Baseline) ITT Month 84-96 29AUG2017 [2883] 7.9 Safety 6/ Male Month 60 26JAN2015 [1841] 5.8 (Baseline) 7

Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

ITT Unscheduled 03AUG2016 [2396] 6.9 (b) (6) Safety 9/ Male Month 60 26JAN2015 [1841] 8.2 (Baseline) ITT Unscheduled 03AUG2016 [2396] 6.5

Source Listing 16.2.6.2.2 in Final Study Report.

Patient-Level Summary Data for PWVcf in PL Patients Across All Trials

x Patient (b) (6) , young adult Eigar reported that although there were fluctuations in PWVcf during participation across three clinical trials, the PWVcf measured after 36 months of lonafarnib monotherapy extension was not significantly increased after 10 years of increasing age while receiving lonafarnib. We note that 2701’s PWVcf fluctuated from 8.8 m/sec at baseline to a high of 10.4 m/sec at 40-56 months on triple therapy and, finally, 7.9 m/sec after 36 months of therapy in the lonafarnib monotherapy extension cohort. In this case, 2701’s final PWVcf is not significantly different from baseline.

Reviewer Comment: We might consider prevention of worsening PWVcf, which may be associated with increased cardiovascular risk for an event, a potential benefit. However, study data for none of the patients confirm if slowing the progression of PWVcf as opposed to reducing PWVcf is associated with improved survival or reduced cardiovascular risk.

x Patient (b) (6) , school-age child Regarding data from this patient, Eigar concluded, “there are insufficient data to determine the effect of lonafarnib on the disease course in this patient…therefore, the potential benefit of blocking protein farnesylation is unclear and clinical benefit is unexpected.” Eigar stated that this patient likely does not express a farnesylated prelamin A variant.

x Patient (b) (6) , school-age child Triple therapy was initiated in 2010 at 1.1 years of age with continued lonafarnib therapy through, at least, December 2019. This patient had no baseline PWVcf, but the initial PWVcf at 12 months of triple therapy was within the normal range then elevated by 18 months into the extension trial at which time this patient would have been on lonafarnib treatment for 78 months. Eigar concluded, “the effect of treatment on PWV is difficult to interpret given the lack of baseline measurement and the patients’ young age.” Of note, prior to switching to lonafarnib monotherapy extension, he was treated with a combination of lonafarnib and everolimus for 2 years.

x Patient (b) (6) , school-age child PWVcf was not measured at baseline but elevated at initial measurement, 12 months on triple therapy. By 18 months of therapy in the lonafarnib monotherapy extension (had received 78 months of lonafarnib therapy), the PWV was in the normal range.

Reviewer Comments: In Study 09-06-0298, Eigar provided PWVcf from three PL patients. Again, these data are not interpretable due to lack of baseline data for comparison. As previously stated, Eigar intends to support efficacy data in PL patients with data from HGPS patients. In Group 1 Monotherapy Extension HGPS patients, there was no statistically significant change from baseline in median PWVcf. Therefore, these HGPS PWVcf data would not adequately support that there is a clinically meaningful effect of lonafarnib on PWVcf.

For carotid echodensity, Eigar concluded that a decrease in echodensity in the carotid artery intima media and adventitia indicates a reduction in carotid artery wall thickness suggesting a reduction in vascular wall inflammation and fibrosis. According to the study protocol and raw data provided, carotid wall thickness was measured among other carotid ultrasound parameters including echodensity. However, Eigar drew a conclusion

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR about carotid artery wall thickness while only presenting data for carotid echodensity as measured in pixels. Even among HGPS patients, the carotid echodensity data are not interpretable. It is unclear what the echodensity measure is comprised of e.g., visible plaques in the artery wall or linear measurement of wall thickness.

In my review of published literature on prediction of cardiovascular events based on carotid artery wall thickness, I could not find data describing a threshold for density in pixels associated with increased risk for a cardiovascular event. Typically, published literature described linear measurements of carotid artery thickness i.e. millimeters in relation to prediction of cardiovascular risk events. For echodensity, I primarily found literature sources describing assessment of plaques within the carotid artery wall and plaque vulnerability. In earlier IND communications with Eigar, they specifically mentioned assessing for carotid artery plaque. However, there is no mention of assessment for plaque in the materials reviewed. Therefore, it would be informative if Eigar provided analyzed CIMT data with linear measurements in HGPS and PL populations. In addition, Eigar could consider performing analyses to demonstrate what proportion of the treatment effect on the survival benefit seen in HGPS patients can be attributed to changes in PWVcf or carotid ultrasound parameters.

At the time of the 2014 consult for this product, reference was made by DGEIP to the CRESTOR (rosuvastatin) program, which used CIMT to support an indication for slowing the progression of atherosclerosis. In our consult response to the 2014 consult, we specified that DCN has not previously accepted carotid ultrasonography as a valid surrogate for improvement in cardiovascular outcomes. This continues to DCN’s practice.

Group 2/Prolon2 Echodensity (10th and 50th percentiles) of the carotid artery adventitia luminal near wall, adventitia deep near wall, and intima media all decreased from baseline to end of therapy with lonafarnib (p <0.0001 to 0.04). Carotid arteries had greater wall echodensity at baseline at all three sites compared to controls. By end of therapy, echodensity of the adventitial luminal wall (near/deep near) and intima media were not different from that of controls.

At the end of therapy, PWVcf improved with lonafarnib monotherapy treatment with median decrease by 7.68 m/sec (range 5.1, 11.5) representing a median decrease in baseline of 5.60% (range -57.7%, 24.7%) (p=0.02). Although Eigar collected PWVcf data from all patients, they limited data analyses to patients 7 years of age and older because published normative data they referenced is only available for patients 7 years of age and older. See Figure 4 below for PWVcf results. ABI was comparable at end of therapy compared to baseline. For FMD, there was a statistically significant decrease at end of therapy compared to baseline with median decrease of 6.8 (range -13.5, -0.8; p=0.01). Echocardiographic data with left ventricular size, systolic function, and mass did not change, however available data were sparse according to Eigar. No PL patients were enrolled in Group 2. See Table 6 in Appendix for detailed carotid echodensity data.

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Figure 4. Corrected Carotid-Femoral Pulse Wave Velocity Improvement with Lonafarnib Therapy for Group 2/ProLon2: Monotherapy (ITT Population)

Safety Overview Eigar reported the most common treatment-emergent adverse events (AEs) were gastrointestinal, elevated liver enzymes, fatigue, and decreased appetite but no patient withdrew due to AEs. In addition, there was no obvious drug effect on QTc interval although, long QT intervals have been previously reported in untreated HGPS pediatric patients. One patient died as a result of stroke, which Eigar considers a common cause of death in HGPS.

Observational Cohort Survival Study Because it was not feasible for Eigar to perform an adequately powered prospective, randomized, blinded, and controlled trial due to the rarity of HGPS and PL and diverse geographical distribution, Eigar conducted an observational cohort survival study. The primary endpoint was all-cause mortality using data from Studies 07-01- 007 and 09-06-0298 (n=62), summarized above, matched to historical control patient data (n=81) stratified by age at start of lonafarnib treatment, gender, and continent. Eigar identified a cohort of 196 untreated patients identified from the Progeria Research Foundation (PRF) International Progeria Registry with no prior exposure to lonafarnib. Published scientific and news articles in addition to publicly available databases were used to identify study patients and their associated data. Of the 196 patients identified from the PRF registry, 173 were identified as potential matches and used for ITT sensitivity analyses, 81 were identified as contemporaneous matched controls for main analyses. According to Eigar, the natural history cohort of untreated patients and treated patients from Phase 2 studies were representative of the entire worldwide distribution of HGPS identified to date. PL patients were excluded from assessment and not included in data analyses.

Eigar considered all survival analyses as post-hoc because survival was not a pre-specified endpoint in ProLon1 and ProLon2 efficacy analyses nor did Eigar think either study would have been powered to conduct a survival 10

Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR analysis.

The primary efficacy endpoint was time to eligible all-cause mortality with key secondary endpoints of incidence of eligible all-cause mortality and incidence of eligible all-cause mortality adjusted for patient-time. Deaths considered eligible were those that occurred before starting triple therapy or initiation of everolimus therapy (Study 000017505, not discussed in this review). Deaths considered ineligible were either excluded or censored from analyses. Safety outcomes were not analyzed. The main analysis population was a ProLon1 and ProLon 2 contemporaneous ITT population, which included all HGPS patients treated with lonafarnib from ProLon1 and ProLon 2 combined.

For the primary endpoint, comparison between treated and matched untreated controls was made using a log-rank test stratified by sex and continent. In addition, Eigar utilized five alternative matching methods designed to be biased against lonafarnib to study the robustness of the survival analyses with respect to selection of the matching untreated patients. Kaplan-Meier survival curves were produced with survival defined as not experiencing eligible all-cause mortality through a maximum follow-up time up to 3 years post age at time of treatment start.

Eigar observed improved survival time (censored at 3 years) associated with lonafarnib therapy compared to untreated controls (means 2.8 versus 2.3 years; p=0.0002). The random untreated match method had a hazard ratio (HR) 0.17 with 95% CI of 0.06 to 0.48. Per Eigar, the least favorable matching method lost statistical significance as they expected with HR 0.35 (95% CI 0.11 to 1.18). Secondary endpoint and sensitivity analyses are not discussed in this review. Eigar concluded lonafarnib provided a consistent survival benefit compared to no therapy, regardless of matching method. In addition, Eigar concluded that treatment with lonafarnib monotherapy results in a clinically meaningful and statistically significant increase in survival up to 2.8 years and lower mortality rate in patients with HGPS. See Figures 5 and 6 below for Kaplan-Meier Survival Curves and Forest Plot of Hazard Ratios.

Figure 5. Kaplan-Meier Survival Curve of Treated versus Random Untreated Match (Censored at 3 Years) – Main Analysis Population (N=143)

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR Figure 6. Forest Plot of Hazard Ratios and 95% Confidence Intervals (Censored at 3 Years) – Main Analysis Population (N=143)

Reviewer Comments: While I would agree the survival data are promising in HGPS patients, the mechanism for how lonafarnib improves survival is unclear. It seems that Eigar is implying that improved survival is related to reduction in cardiovascular risk, which is the leading contributor to death in HGPS patients. However, Eigar has not provided data to demonstrate there is an association between a treatment effect seen on any cardiovascular endpoint assessed and a survival benefit.

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Appendix

Table 3. Carotid Echodensity Changes (Density in Pixels) from Baseline in Study 07-01-007 (ITT Population)

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=1) (N=28) (N=26) (N=1)

Adventitia Luminal 10 Near Wall Change from Baseline n 20 1 1 22

Mean (SD) -34.3 (61.7) 30.5 (N/A) 5.0 (N/A) -29.57 (60.781) Median -21.5 30.5 5.0 -15.8 Min, Max -152.5, 80.5 30.5, 30.5 5.0, 5.0 -152.5, 80.5 p-valuea 0.04 N/A N/A 0.07 Adventitia Luminal 50 Change from Baseline n 20 1 1 22 Near Wall Mean (SD) -33.0 (57.7) 42.0 (N/A) 0.0 (N/A) -28.1 (57.5) Median -30.5 42.0 0.0 -17.0 Min, Max -142.0, 70.0 42.0, 42.0 0.0, 0.0 -142.0, 70.0 p-valuea 0.02 N/A N/A 0.04

Adventitia Deep 10 Change from Baseline n 20 1 1 22 Near Wall

Mean (SD) -39.3 (73.2) 2.5 (N/A) -24.5 (N/A) -36.7 (70.2) Median -35.3 2.0 -24.5 -29.0 Min, Max -173.0, 85.0 2.5, 2.5 -24.5, -24.5 -173.0, 85.0 p-valuea 0.04 N/A N/A 0.03

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=1) (N=28) (N=26) (N=1)

Adventitia Deep 50 Change from Baseline n 20 1 1 22 Near Wall

Mean (SD) -42.3 (79.6) -20.0 (N/A) -27.0 (N/A) -40.6 (75.9) Median -48.0 -20.0 -27.0 -42.5 Min, Max -180.0, 108.0 -20.0, -20.0 -27.0, -27.0 -180.0, 108.0

p-valuea 0.05 N/A N/A 0.03

Intima Media 10 Change from Baseline n 20 1 1 22 Mean (SD) -23.3 (34.4) 20.0 (N/A) -5.0 (N/A) -20.5 (34.1) Median -24.3 20.0 -5.0 -15.3 Min, Max -109.0, 34.0 20.0, 20.0 -5.0, -5.0 -109.0, 34.0 p-valuea 0.01 N/A N/A 0.01 Intima Media 50 Change from Baseline n 20 1 1 22 Mean (SD) -30.1 (38.3) 15.5 (N/A) -18.0 (N/A) -27.4 (37.8) Median -30.0 15.5 -18.0 -23.5 Min, Max -98.0, 38.0 15.5, 15.5 -18.0, -18.0 -98.0, 38.0

p-valuea 0.002 N/A N/A 0.002 aP-value for Wilcoxon signed-rank test. Source Table 14.2.2.1 in Final Study Report

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR Table 4. Carotid Echodensity Changes (Density in Pixels) from Baseline in Study 09-06-0298 Triple therapy (ITT Population)

Group 1: Triple Therapy

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=4) (N=47) (N=38) (N=5)

Adventitia Luminal 50 Change from Baseline n 35 3 4 42 Near Wall

Mean (SD) 52.5 (53.1) 42.0 (41.0) 56.5 (65.4) 52.2 (52.4) Median 41.5 40.0 74.0 46.3 Min, Max -77.0, 151.5 2.0, 84.0 -37.0, 115.0 -77.0, 151.5 p-value2 <0.0001 N/A N/A <0.0001

Adventitia Deep 50 Change from Baseline n 35 3 4 42 Near Wall

Mean (SD) 70.2 (75.2) 68.3 (58.3) 94.5 (65.1) 72.4 (72.2) Median 71.0 101.0 103.0 79.5 Min, Max -101.0, 216.0 1.0, 103.0 12.0, 160.0 -101.0, 216.0 p-value2 <0.0001 N/A N/A <0.0001

Intima Media 50 Change from Baseline n 34 3 4 41 Mean (SD) 29.3 (50.7) 39.8 (99.3) 56.8 (51.0) 32.7 (53.7) Median 14.3 84.5 62.0 21.0 Min, Max -60.0, 197.0 -74.0, 109.0 -10.0, 113.0 -74.0, 197.0

p-value2 0.002 N/A N/A 0.0004

Source Table 14.2.2.1.1 [2] P-value for Wilcoxon signed-rank test. 15

Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Table 5. Carotid Echodensity Changes (Density in Pixels) from Baseline in Study 09-06-0298 Monotherapy Extension (ITT Population)

Group 1: Monotherapy Extension

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=3) (N=36) (N=30) (N=3)

Adventitia Luminal 10 Change from Baseline n 23 1 3 27 Near Wall

Mean (SD) -47.1 (61.3) -76.5 (N/A) 17.0 (30.9) -41.1 (61.0)

Median -30.0 -76.5 11.0 -20.5

Min, Max -218.0, 22.5 -76.5, -76.5 -10.5, 50.5 -218.0, 50.5

p-value2 <0.0001 N/A N/A 0.0003

Adventitia Luminal 50 Change from Baseline n 23 1 3 27 Near Wall Mean (SD) -32.5 (51.4) -21.0 (N/A) 0.0 (13.1) -28.5 (48.6) Median -11.0 -21.0 -2.0 -11.0 Min, Max -193.0, 16.0 -21.0, -21.0 -12.0, 14.0 -193.0, 16.0 p-value2 <0.0001 N/A N/A <0.0001

Adventitia Deep 10 Change from Baseline n 23 1 3 27 Near Wall

Mean (SD) -51.5 (67.4) -67.5 (N/A) -16.3 (24.4) -48.2 (63.5)

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Group 1: Monotherapy Extension

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=3) (N=36) (N=30) (N=3)

Median -48.0 -67.5 -7.0 -44.0

Min, Max -170.0, 82.0 -67.5, -67.5 -44.0, 2.0 -170.0, 82.0

p-value2 0.001 N/A N/A 0.0003

Adventitia Deep 50 Change from Baseline n 23 1 3 27 Near Wall

Mean (SD) -52.4 (64.8) -57.0 (N/A) -19.7 (12.2) -49.0 (60.6) Median -52.0 -57.0 -17.0 -33.0 Min, Max -167.0, 68.0 -57.0, -57.0 -33.0, -9.0 -167.0, 68.0 p-value2 0.001 N/A N/A 0.0002 Intima Media 10 Change from Baseline n 23 1 3 27 Mean (SD) -23.2 (39.4) 45.0 (N/A) -33.5 (45.3) -21.8 (40.7) Median -16.5 45.0 -36.0 -16.5 Min, Max -94.0, 52.5 45.0, 45.0 -77.5, 13.0 -94.0, 52.5

p-value2 0.02 N/A N/A 0.02 Intima Media 50 Change from Baseline n 23 1 3 27 Mean (SD) -26.5 (41.7) 34.0 (N/A) -36.8 (47.0) -25.4 (42.3) 17

Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Group 1: Monotherapy Extension

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=3) (N=36) (N=30) (N=3)

Median -20.0 34.0 -36.5 -20.0 Min, Max -99.0, 60.0 34.0, 34.0 -84.0, 10.0 -99.0, 60.0

p-value2 0.01 N/A N/A 0.01 Source Table 14.2.2.1.1 [2] P-value for Wilcoxon signed-rank test.

Table 6. Carotid Echodensity Changes (Density in Pixels) from Baseline in Study 09-06-0298 ProLon2 (ITT Population)

Group 2: ProLon 2

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=1) (N=0) (N=35) (N=34) Adventitia Luminal 10 Change from Baseline n 21 1 0 22 Near Wall

Mean (SD) -45.3 (39.3) 57.0 (N/A) -45.85 (38.4)

Median -44.0 -57.0 -48.5

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Group 2: ProLon 2

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=1) (N=0) (N=35) (N=34)

Min, Max -111.5, 27.2 -57.00,-57.00 -111.5, 27.2

p-value2 <0.0001 N/A N/A <0.0001

Adventitia Luminal 50 Change from Baseline n 21 1 0 22 Near Wall Mean (SD) -30.1 (41.4) -69.0 (N/A) -31.9 (41.2) Median -28.0 -69.0 -31.5 Min, Max -101.0, 57.0 -69.0, -69.0 -101.0, 57.0 p-value2 0.03 N/A N/A 0.001

Adventitia Deep 10 Change from Baseline n 21 1 0 22 Near Wall 0 Mean (SD) -61.8 (43.9) -88.5 (N/A) -63.0 (43.2)

Median -47.0 -88.5 -53.5

Min, Max -156.5, 8.0 -88.5, -88.5 -156.5, 8.0

p-value2 <0.0001 N/A N/A <0.0001

Adventitia Deep 50 Change from Baseline n 21 1 0 22 Near Wall

Mean (SD) -68.2 (47.9) -72.0 (N/A) -68.3 (46.7) Median -59.0 -72.0 -59.5

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Reference ID: 4629295 NDA 213969 DCN Consult Response Shetarra Walker, MD, MSCR

Group 2: ProLon 2

Classic Non-Classic PL Total Site Percentile Parameter Statistics HGPS HGPS (N=1) (N=0) (N=35) (N=34) Min, Max -181.0, -7.5 -72.0, -72.0 -181.0, -7.5 p-value2 <0.0001 N/A N/A <0.0001

Intima Media 10 Change from Baseline n 21 1 0 22 Mean (SD) -20.3 (39.1) 4.0 (N/A) -19.2 (38.5) Median -17.0 4.0 -11.8 Min, Max -94.0, 52.5 4.0, 4.0 -98.0, 56.0

p-value2 0.03 N/A N/A 0.04 Intima Media 50 Change from Baseline n 21 1 0 22 Mean (SD) -28.5 (38.2) 1.0 (N/A) -27.2 (37.8) Median -26.0 1.0 -22.0 Min, Max -107.0, 42.0 1.0, 1.0 -107.0, 42.0

p-value2 0.003 N/A N/A 0.002

Source Table 14.2.2.1.1 [2] P-value for Wilcoxon signed-rank test.

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Reference ID: 4629295 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/ ------

SHETARRA E WALKER 06/22/2020 04:42:09 PM

FORTUNATO F SENATORE 06/22/2020 07:30:22 PM

NORMAN L STOCKBRIDGE 06/23/2020 06:20:57 AM

Reference ID: 4629295