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Multi-Discipline Review CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211723Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 211723 NME - Multi-disciplinary Review and Evaluation TAZVERIK (tazemetostat) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type New Molecular Entity/ Original New Drug Application Application Number(s) NDA 211723 Priority or Standard Priority Submit Date(s) May 23, 2019 Received Date(s) May 23, 2019 PDUFA Goal Date January 23, 2020 Division/Office Office of Oncologic Diseases / Division of Oncology 3 Established/Proper Name tazemetostat (Proposed) Trade Name TAZVERIK Code Name EPZ-6438, E7438 Pharmacologic Class methyltransferase inhibitor Applicant Epizyme, Inc. Doseage form Tablets, 200mg Applicant proposed Dosing 800 mg orally twice daily (BID) Regimen Applicant Proposed For the treatment of patients with metastatic or locally Indication(s)/Population(s) advanced epithelioid sarcoma who are not eligible for curative surgery Applicant Proposed Epithelioid sarcoma SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Accelerated approval Regulatory Action Recommended For the treatment of adults and pediatric patients aged 16 Indication(s)/Population(s) years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. Recommended SNOMED Epithelioid sarcoma CT Indication Disease Term for each Indication Recommended Dosing 800 mg orally twice daily Regimen 1 Version date: April 2, 2018 Reference ID: 4550626 NDA 211723 NME - Multi-disciplinary Review and Evaluation TAZVERIK (tazemetostat) Table of Contents Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 7 Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9 Glossary ......................................................................................................................................... 11 1 Executive Summary ............................................................................................................... 14 Product Introduction ...................................................................................................... 14 Conclusions on the Substantial Evidence of Effectiveness ............................................ 15 Benefit-Risk Assessment ................................................................................................ 19 Patient Experience Data ................................................................................................. 23 2 Therapeutic Context .............................................................................................................. 24 Analysis of Condition ...................................................................................................... 24 Analysis of Current Treatment Options ......................................................................... 24 3 Regulatory Background ......................................................................................................... 26 U.S. Regulatory Actions and Marketing History ............................................................. 26 Summary of Presubmission/Submission Regulatory Activity ........................................ 26 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 28 Office of Scientific Investigations (OSI) .......................................................................... 28 Product Quality .............................................................................................................. 28 Clinical Microbiology ...................................................................................................... 29 Devices and Companion Diagnostic Issues .................................................................... 29 5 Nonclinical Pharmacology/Toxicology................................................................................... 30 Executive Summary ........................................................................................................ 30 Referenced NDAs, BLAs, DMFs ....................................................................................... 34 Pharmacology ................................................................................................................. 34 ADME/PK ........................................................................................................................ 43 Toxicology ....................................................................................................................... 46 General Toxicology .................................................................................................. 46 Genetic Toxicology .................................................................................................. 56 Carcinogenicity ........................................................................................................ 57 Reproductive and Developmental Toxicology ........................................................ 57 Other Toxicology Studies ........................................................................................ 76 6 Clinical Pharmacology ............................................................................................................ 77 2 Version date: April 2, 2018 Reference ID: 4550626 NDA 211723 NME - Multi-disciplinary Review and Evaluation TAZVERIK (tazemetostat) Executive Summary ........................................................................................................ 77 Summary of Clinical Pharmacology Assessment ............................................................ 80 Pharmacology and Clinical Pharmacokinetics ........................................................ 80 General Dosing and Therapeutic Individualization ................................................. 80 Comprehensive Clinical Pharmacology Review ............................................................. 82 General Pharmacology and Pharmacokinetic Characteristics ................................ 82 Clinical Pharmacology Questions ............................................................................ 86 7 Sources of Clinical Data and Review Strategy ..................................................................... 100 Table of Clinical Studies ................................................................................................ 100 Review Strategy ............................................................................................................ 102 8 Statistical and Clinical and Evaluation ................................................................................. 103 Review of Relevant Individual Trials Used to Support Efficacy .................................... 103 Study EZH-202 ....................................................................................................... 103 Study Results ......................................................................................................... 107 8.1.3 Integrated Review of Effectiveness ...................................................................... 126 8.1.4 Integrated Assessment of Effectiveness ............................................................... 126 8.2 Review of Safety ........................................................................................................... 126 8.2.1 Safety Review Approach ....................................................................................... 126 8.2.2 Review of the Safety Database ............................................................................. 127 8.2.3 !ͳͷϤ̠̎͛ͩ ϖ΁ !ϢϢψζͩ͛Ϗϳδϩ ψζϏζͩ͛ψ η͛΁ͷϳ̠ !ϩϩͷϩϩώͷϏϳϩ .......................................... 128 8.2.4 Safety Results ........................................................................................................ 128 8.2.5 Analysis of Submission-Specific Safety Issues ....................................................... 137 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 137 8.2.7 Safety Analyses by Demographic Subgroups ........................................................ 137 8.2.8 Specific Safety Studies/Clinical Trials .................................................................... 139 8.2.9 Additional Safety Explorations .............................................................................. 139 8.2.10 Safety in the Postmarket Setting .......................................................................... 139 8.2.11 Integrated Assessment of Safety .......................................................................... 140 8.3 Statistical Issues ........................................................................................................... 140 8.4 Conclusions and Recommendations ............................................................................ 141 9 Advisory Committee Meeting and Other External Consultations ....................................... 144 10 Pediatrics
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