review · 2020. 12. 23. · nda 213969 zokinvy (lonafarnib) i integrated review template, version...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

213969Orig1s000

INTEGRATED REVIEW

NDA 213969Zokinvy (lonafarnib)

iIntegrated Review Template, version 2.0 (04/23/2020)

Integrated ReviewTable 1. Administrative Application InformationCategory Application InformationApplication type NDAApplication number(s) 213969Priority or standard PrioritySubmit date(s) 3/20/2020Received date(s) 3/20/2020PDUFA goal date 11/20/2020Division/office Division of Rare Diseases and Medical Genetics (DRDMG)Review completion date 11/20/2020Established/proper name Lonafarnib(Proposed) proprietary name

Zokinvy

Pharmacologic class Small moleculeCode name EBP994Applicant Eiger BioPharmaceuticals, Inc.Dosage form(s)/formulation(s)

Capsules, 50 mg and 75 mg.

Dosing regimen 115 mg/m2, dose up to 150 mg/m2 for HGPSApplicant proposed indication(s)/ population(s)

Treatment of Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL)

Proposed SNOMED indication

238870004 |Hutchinson-Gilford syndrome (disorder)

Regulatory action ApprovalApproved dosage (if applicable)

115 mg/m2, dose up to 150 mg/m2 for HGPS

Approved indication(s)/population(s) (if applicable)

Hutchinson-Gilford Progeria syndome and processing-deficient progeroid laminopathies

Approved SNOMED term for indication (if applicable)

238870004 |Hutchinson-Gilford syndrome (disorder)

Reference ID: 4705501


iiIntegrated Review Template, version 2.0 (04/23/2020)

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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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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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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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 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


(b) (6)


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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 d 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 # With ALT


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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



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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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Table of Figures

Figure 1. Predicted Lonafarnib AUC 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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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

-State Across Body Weight Tiers Under Different Dosing Regimens ..........................................162

-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



1Integrated Review Template, version 2.0 (04/23/2020)

GlossaryADME absorption, distribution, metabolism, excretion AE adverse eventAIDS acquired immunodeficiency syndromeALT alanine aminotransferaseANC absolute neutrophil countAPC absolute phagocyte count AR adverse reactionAST aspartate aminotransferaseAUC area under the concentration-time curveBID twice dailyBLA biologics license applicationBSA body surface areaBW body weightCDER Center for Drug Evaluation and ResearchCL clearanceCmax maximum plasma concentrationCMC chemistry, manufacturing, and controlsCMH Cochran-Mantel-HaenszelCSR clinical study reportCTCAE Common Terminology Criteria for Adverse EventsDDI drug-drug interactionDMSO dimethyl sulfoxideEC50 half-maximal effective concentrationECG electrocardiogramERG electroretinogramFDA Food and Drug AdministrationFTI farnesyltransferase inhibitorGFR glomerular filtration rateGLP good laboratory practicesGOF goodness-of-fitHGPS Hutchinson-Gilford progeria syndromeHIV human immunodeficiency virusHLM human liver microsomeIC50 half-maximal inhibitory concentrationICH International Council for HarmonisationIIV interindividual variabilityIND investigational new drugLOA letter of authorizationLVH left ventricular hypertrophyNDA new drug applicationNOAEL no observed adverse effect levelOCP Office of Clinical PharmacologyOR odds ratio




OVF objective function valuePDE permitted daily exposurePI prescribing informationPK pharmacokineticsPL progeroid laminopathiesPPK population pharmacokineticsPTT partial thromboplastin timePRF Progeria Research FoundationPT prothrombin timeRR risk ratioSAE serious adverse eventSAP statistical analysis planSGOT serum glutamic oxaloacetic transaminaseSGPT serum glutamic pyruvic transminaseTEAE treatment-emergent adverse eventTmax time to maximum concentrationTQT thorough QTULN upper limit of normalV volume of distributionVPC visual predictive checkWBC white blood cell




I. Executive Summary

1. Summary of Regulatory ActionEiger 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.




2. Benefit-Risk Assessment2.1. Benefit-Risk Framework

Table 2. Benefit-Risk FrameworkDimension Evidence and Uncertainties Conclusions and ReasonsAnalysis of Condition

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, autosomal dominant disorder caused by a single nucleotide 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.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.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 aclinical phenotype similar to HGPS. Characterization of PL is limited by its extreme rarity and heterogeneity in its presentation.

HGPS and PL are serious, life-shorteningdiseases.

Current Treatment Options

There are no current treatment options, other than supportive care.

HGPS and PL patients have significant morbidiy and early mortality with no approved treatmentsother 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.




Benefit The survival benefit in HGPS for lonafarnib, afarnesyltransferase inhibitor, was established by comparing mortality in 62 patients with HGPS pooled from two adequate and well controlled trials (ProLon1 and ProLon2) with that of a contemporaneously well-matched untreated cohort. The maximum follow-up time was 11 years (median: 3 years)for ProLon1 and ProLon2 and 13 years (median: 2.6 years) forthe matched untreated cohort.The lifespan 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 time of 11 years compared to untreated patients.The analysis plan was not submitted prior to analyzing the data, which raises the likelihood of a type I error and concluding the drug is effective when it is not. These concerns were minimizedby the objective mortality endpoint and steps taken by the trial investigators and applicant to mitigate potential sources of bias. 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.Confirmatory evidence of effectiveness for HGPS is derived from mechanistic studies showing that lonafarnib preventsfarnesylation 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

Lonafarnib demonstrated a clinically meaningful mortality benefit in patients with HGPS who currently have no approved treatment options.The clinical trial design and the survival endpoint were appropriate, given the rarity of HGPS and itshigh mortality. The large mortality benefit after 11 years of follow-up using a well-matched external control and mitigated sources of bias overcome the limitations of non-randomization.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. Availability of lonafarnib will provide the firstapproved treatment for HGPS and processing-deficient PL patients.




Dimension Evidence and Uncertainties Conclusions and Reasonsthe 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.




Risk and Risk Management

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 patients treated with lonafarnib in ProLon1 and ProLon2.It was challenging to determine drug causality versus natural history of the disease or other non-drug effect for many of the safety events in ProLon1 and ProLon2 due to the lack of a control group for safety. Safety concerns in nonclinical studies included nephrotoxicity in rats, retinal toxicity in monkeys, impaired fertility and testicular toxicity in rats, male reproductive tract toxicity in monkeys, and embryo-fetal toxicity in rats and rabbits – all at or near clinically relevant exposures.There are several clinically significant drug interactions (e.g., increased lonafarnib exposures with strong CYP3A inhibitors, reduced lonafarnib exposures with strong CYP3A inducers, 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.Other noteworthy on-treatment findings included liver enzyme elevations, electrolyte abnormalities (hyperkalemia, hypokalemia, hyponatremia, hypercalcemia, orhypermagnesemia), 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). Hypertension was reported in a third of HGPS patients and was associated with a higher risk of mortality. It is unclear whether

The safety database was adequate for a safety assessment of lonafarnib for the proposed indication, patient population, dosage regimen, and duration. The identified safety concerns do not outweigh the benefit of improved mortality and can be adequately mitigated with labeling alone.We are requiring a new thorough QT study, the carcinogenicity study, and the CYP2C9 drug-drug interaction study post-approval. 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, devastatingdisease 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.Safety risks have not been identified that require risk management beyond standard pharmacovigilance.




Dimension Evidence and Uncertainties Conclusions and Reasonsthis is a drug effect or related to the natural history of the disease.QT prolongation was only studied with concomitant ritonavir and the effect of lonafarnib alone could not be determined.

A carcinogenicity study has not been conducted pre-approval. The effect of CYP2C9 inhibitors on lonafarnib exposure havenot been adequately studied pre-approval.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-RiskHutchinson-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




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 tofurther 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.




II. Interdisciplinary Assessment

3. IntroductionLonafarnib 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 progeriasyndrome (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 instability.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% and20% 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.




There are no approved therapies for HGPS and PL. Current treatment includes supportive careand 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 ListThe 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

Mitigating disparities between treated and untreated HGPS patientsPost hoc nature of the analysis planCriteria and algorithm for matching treated patients to controlsDisparity in censoring rate in the treated and untreated cohortLimited stratified analysisData discrepancy identified by clinical inspectionReduced efficacy due to drug interactionsBioavailability of drug suspensionMeeting the substantial evidence standard for processing-deficient progeroid laminopathies

3.1.2. Key Review Issues Relevant to Evaluation of Risk

QTc safety assessmentAdverse reactions due to drug interactions Hypertension and mortalityDosing in hepatic impairmentDosing in renal impairmentNephrotoxicityRetinal toxicityImpaired fertility Embryo-fetal toxicity




3.2. Approach to the ReviewTable 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 35patients 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 patientswith 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.




Table 3. Clinical Trials Submitted in Support of Efficacy and/or Safety Determinations for Lonafarnib

Trial Identifier Trial Population Trial DesignRegimen (Number Treated), Duration

Primary and Key Secondary Endpoints

No. of Subjects Planned; Actual Randomized

Number of Centers and Countries

07-01-0007NCT#00425607 ProLon1

Pediatric patients with Hutchinson-Gilford progeria syndrome (HGPS) or other progeroid laminopathies

Control Type:No treatment concurrent (single-arm)

Randomization:No randomization (single-arm)

Blinding:Open-label

Biomarkers:No biomarkers

Innovative design features:None

Drug:Lonafarnib

Dose: 115 mg/m2BID, after 4 mo. of treatment, 150 mg/m2 BID

Number treated: 28

Duration (quantity and units):24 mo1

NDA Defined Endpoint:Time to all-causemortality

Initially Planned Primary: At least a 50% increase in the annual rate of weight gain over the rate documented at study entry

Initially PlannedSecondary:Changes in carotid artery ultrasonography; corrected Carotid-Femoral Pulse Wave Velocity (PWVcf), DXA BMD, pQCT parameters, height; BMI, body composition by DXA scan, ABI, and FMD.

Planned: 29

Actual: 28

Centers: 1

Countries: 16

1The duration of ProLon1 is reported as 24 to 30 months in the clinical study report. For this review, we will refer to ProLon1 as a 2-year trial.




Trial Identifier Trial Population Trial DesignRegimen (Number Treated), Duration

Primary and Key Secondary Endpoints

No. of Subjects Planned; Actual Randomized

Number of Centers and Countries

Group 2 of 09-06-0298NCT#00916747 ProLon2

Pediatric patients with Hutchinson-Gilford progeria syndrome or other progeroid laminopathies

Control Type:No treatment concurrent (single-arm)

Randomization:No randomization (single-arm)

Blinding:Open-label

Biomarkers:No biomarkers

Innovative design features:None

Drug:Lonafarnib

Dose: 150 mg/m2BID

Number treated: 35

Duration (quantity and units):36 mo

NDA Defined Endpoint:Time to all-causemortality

Initially Planned Primary:At least a 50% increase in the annual rate of weight gain over the rate documented at study entry

Initially PlannedSecondary:Changes in carotid artery ultrasonography; corrected Carotid-Femoral Pulse Wave Velocity (PWVcf), DXA BMD, pQCT parameters, height; BMI, body composition by DXA scan, ABI, and FMD.

Planned: 40

Actual: 35

Centers: 1

Countries: 20

Source: Review teamAbbreviations: 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




4. Patient Experience DataTable 4. Patient Experience Data Submitted or ConsideredData Submitted in the ApplicationCheck if Submitted Type of Data

Section Where Discussed, if Applicable

Clinical outcome assessment data submitted in the applicationPatient-reported outcome 6.2.1.4 Results of AnalysesObserver-reported outcome 7.6 Safety FindingsClinician-reported outcome Performance outcome

Other patient experience data submitted in the applicationPatient-focused drug development meeting summaryQualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel)Observational survey studiesNatural history studies 6 Assessment of

EffectivenessPatient preference studies Other: (please specify)If no patient experience data were submitted by Applicant, indicate here.

Data Considered in the Assessment (But Not Submitted by Applicant)Check if Considered Type of Data

Section Where Discussed, if Applicable

Perspectives shared at patient stakeholder meeting Patient-focused drug development meeting summary report Other stakeholder meeting summary report Observational survey studies Other: (please specify)




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 PharmacokineticsCharacteristic Drug Information

Pharmacologic ActivityEstablished pharmacologic class (EPC)

Lonafarnib is a farnesyltransferase inhibitor.

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 InformationBioanalysis 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.




Characteristic Drug InformationDrug exposure at steady state following the therapeutic dosing regimen

The pharmacokinetics of lonafarnib at steady state are summarized in the table below following multiple oral administration twice daily (BID) of lonafarnib with food in patients with HGPS.Pharmacokinetics of Lonafarnib at Steady State Following Multiple Oral Administration BID of Lonafarnib With Food in Patients With HGPS

Lonafarnib DoseMedian (Range)

Tmax (hr)Mean (SD)

Cmax (ng/mL)Mean (SD)

AUC0-8hr (ng*hr/mL)Mean (SD)

AUCtau (ng*hr/mL)115 mg/m2

N 23 23 23 15Results 2 (0, 6) 1777 (1083) 9869 (6327) 12365 (9135)

150 mg/m2N 18 18 18 8Results 4 (0, 12) 2695 (1090) 16020 (4978) 19539 (6434)

Abbreviations: BID, twice daily; HGPS, Hutchinson-Gilford progeria syndrome; SD, standard deviation

Range of effective dosage(s) or exposure

The recommended starting dose of lonafarnib is 115 mg/m2 BID. After 4 months, increase the dosage to 150 mg/m2 twice 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-state

Steady state was achieved by approximately 3 days after multiple dosing.

Bridge between to-be-marketed and clinical trial formulations

The to-be-marketed capsules (50-mg and 75-mg) were used in the clinical efficacy and safety studies. The clinical studies also used a suspension formulation by mixing the contents of the capsules with Ora Blend SF and Ora-Plus.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.




Characteristic Drug InformationAbsorption

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)Geometric least square mean and 90% CI

Both the high-fat/high calorie and low-fat/low-calorie meals decreased the absorption and delayed the Tmax of lonafarnib by approximately 2 hours and 1 hour, respectively, following single dose administration. Lonafarnib was administered with food in the pivotal studies in patients with HGPS and PL.

Effect of High-Fat/High-Calorie and Low-Fat/Low-Calorie Mealson the Pharmacokinetics of Single Dose Lonafarnib

Parameter NGeometric LSM

GMR 90% CILNF + High Fat (Test) LNF Fasted (Ref)Cmax (ng/mL) 14 117 248 0.47 0.42–0.53AUCt (ng*hr/mL) 14 1080 1500 0.72 0.65–0.80AUCinf (ng*hr/mL) 13 1150 1560 0.74 0.67–0.82Parameter N LNF + Low Fat (Test) LNF Fasted (Ref) GMR 90% CICmax (ng/mL) 14 194 248 0.78 0.66–0.93AUCt (ng*hr/mL) 14 1250 1500 0.84 0.72–0.97AUCinf (ng*hr/mL) 12 1240 1560 0.83 0.70–0.99

Abbreviations: CI, confidence interval; LNF, lonafarnib; LSM, least square mean; Ref, reference

DistributionVolume 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 betweenDrug as substrate of transporters

Lonafarnib is not a substrate of transporters OATP1B1, OATP1B3, or BCRP, but is likely a marginal substrate of P-gp.




Characteristic Drug InformationElimination

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



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 Effectiveness6.1. Dose and Dose Responsiveness

6.1.1. ProLon1 and ProLon2Dose 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 oftreatment 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 ( ) 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 ( ), who had diarrhea approximately 2 weeks prior to dose reduction.


(b) (6)

(b) (6)



The dose selection for the pivotal studies was based on the findings of the maximal tolerateddose 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.

In adult patients with cancer, the maximum tolerated dose was 200 mg (approximately115 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).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-limiting 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.




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.

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.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 variability 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 modelshowed that, following the proposed BSA-based dosing regimens, the lonafarnibexposures (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 theproposed 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 AUC at Steady-State Across Body Weight and BSA Groups

Source: PK simulation conducted by Review teamNote: The solid horizontal l ine in each box represents the simulated median value of AUCtau; each box represents the simulated 25thto 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 under the plasma concentration-time curve over dosing interval; BSA, body surface area




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

Source: PK simulation conducted by Review teamNote: The solid horizontal l ine in each box represents the simulated median value of Cmax; each box represents the simulated 25th to 75th percentiles under each dosing regimen for each body weight tier. In the simulation, the demographic characteristics of the 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

PK ParameterLonafarnib Dose

115 mg/m2 150 mg/m2Cmax (ng/mL)

N 23 18Results 1777 (1083) 2695 (1090)

AUCtau (ng·hr/mL)N 15 8Results 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 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.

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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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 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 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 for HGPS and PL Patients at 12 Months OldThe 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.

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.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 ProLon26.2.1.1. 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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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 by150 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 lonafarnibmonotherapy 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).




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-analysisThe excluded Progeroid Laminopathy patient in ProLon1 (patient ) 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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The main efficacy assessment was based on the survival data of treated patients

review · 2020. 12. 23. · nda 213969 zokinvy (lonafarnib) i integrated review template, version...

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