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Multi-Discipline Review CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213400Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi‐disciplinary Review and Evaluation 213400 Tazverik (tazemetostat) NDA/BLA Multi‐Disciplinary Review and Evaluation Application Type New Drug Application (NDA) Application Number(s) 213400 Priority or Standard Priority Submit Date(s) 18 December 2019 Received Date(s) 18 December 2019 PDUFA Goal Date 18 June 2019 Division/Office DHM2/OOD Review Completion Date 16 June 2020 Established/Proper Name Tazemetostat (Proposed) Trade Name Tazverik Pharmacologic Class Methyltransferase inhibitor Code name EPZ‐6438, E7438 Applicant Epizyme, Inc. Dosage form Tablets, 200mg Applicant proposed Dosing 800 mg orally twice daily Regimen Applicant Proposed Indicated for the treatment of patients with relapsed or Indication(s)/Population(s) refractory follicular lymphoma who have received at least two prior therapies Applicant Proposed Follicular Lymphoma SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Accelerated Approval Regulatory Action Recommended ▪ Adult patients with relapsed or refractory follicular Indication(s)/Population(s) lymphoma whose tumors are positive for an EZH2 mutation as (if applicable) detected by an FDA‐approved test and who have received at least 2 prior therapies ▪ Adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options Recommended SNOMED Follicular Lymphoma CT Indication Disease Term for each Indication (if applicable) Recommended Dosing 800 mg orally twice daily Regimen 1 Version date: April 2, 2018 Reference ID: 4626505 NDA/BLA Multi‐disciplinary Review and Evaluation 213400 Tazverik (tazemetostat) Table of Contents Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 7 Reviewers of Multi‐Disciplinary Review and Evaluation ................................................................ 8 Glossary ........................................................................................................................................... 9 1 Executive Summary ............................................................................................................... 11 Product Introduction ...................................................................................................... 11 Conclusions on the Substantial Evidence of Effectiveness ............................................ 11 Benefit‐Risk Assessment ................................................................................................ 14 Patient Experience Data ................................................................................................. 18 2 Therapeutic Context .............................................................................................................. 19 Analysis of Condition ...................................................................................................... 19 Analysis of Current Treatment Options ......................................................................... 21 3 Regulatory Background ......................................................................................................... 31 U.S. Regulatory Actions and Marketing History ............................................................. 31 Summary of Presubmission/Submission Regulatory Activity ........................................ 31 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 34 Office of Scientific Investigations (OSI) .......................................................................... 34 Product Quality .............................................................................................................. 35 Clinical Microbiology ...................................................................................................... 35 Devices and Companion Diagnostic Issues .................................................................... 35 5 Nonclinical Pharmacology/Toxicology................................................................................... 36 Executive Summary ........................................................................................................ 36 Referenced NDAs, BLAs, DMFs ....................................................................................... 41 Pharmacology ................................................................................................................. 41 ADME/PK ........................................................................................................................ 52 Toxicology ....................................................................................................................... 52 6 Clinical Pharmacology ............................................................................................................ 54 Executive Summary ........................................................................................................ 54 Summary of Clinical Pharmacology Assessment ............................................................ 54 Pharmacology and Clinical Pharmacokinetics ........................................................ 54 General Dosing and Therapeutic Individualization ................................................. 55 Comprehensive Clinical Pharmacology Review ............................................................. 55 2 Version date: April 2, 2018 Reference ID: 4626505 NDA/BLA Multi‐disciplinary Review and Evaluation 213400 Tazverik (tazemetostat) General Pharmacology and Pharmacokinetic Characteristics ................................ 55 Clinical Pharmacology Questions ............................................................................ 59 7 Sources of Clinical Data and Review Strategy ....................................................................... 64 Table of Clinical Studies .................................................................................................. 64 Review Strategy .............................................................................................................. 68 8 Statistical and Clinical and Evaluation ................................................................................... 69 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 69 Study E7438‐G000‐101 – An Open Label, Multicenter, Phase 1/2 Study of E7438 (EZH2 Histone Methyl Transferase (HMT) Inhibitor) as a Single Agent in Subjects with Advanced Solid Tumors or With B cell Lymphomas .................................................................................. 69 Integrated Assessment of Effectiveness ........................................................................ 99 Review of Safety ........................................................................................................... 101 Safety Review Approach ....................................................................................... 101 Review of the Safety Database .................................................................................... 101 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 104 Safety Results ........................................................................................................ 105 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 117 Safety Analyses by Demographic Subgroups ........................................................ 117 Specific Safety Studies/Clinical Trials .................................................................... 118 Additional Safety Explorations .............................................................................. 118 Safety in the Postmarket Setting .......................................................................... 119 Integrated Assessment of Safety ................................................................................. 119 Statistical Issues ........................................................................................................... 121 Conclusions and Recommendations ............................................................................ 121 9 Advisory Committee Meeting and Other External Consultations ....................................... 125 10 Pediatrics ............................................................................................................................. 126 11 Labeling Recommendations ................................................................................................ 127 11.1 Prescription Drug Labeling ....................................................................................... 127 11.2 Patient Labeling ........................................................................................................ 128 12 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 129 13 Postmarketing Requirements and Commitment ...............................................................
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