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Enfortumab Vedotin-Ievx) NDA/BLA Multi-Disciplinary Review and Evaluation

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Enfortumab Vedotin-Ievx) NDA/BLA Multi-Disciplinary Review and Evaluation CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761137Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-disciplinary Review and Evaluation – BLA 761137 PADCEV™ (enfortumab vedotin-ievx) NDA/BLA Multi-disciplinary Review and Evaluation Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant, which do not necessarily reflect the positions of the FDA. Application Type BLA Application Number 761137 Priority or Standard Priority Submit Date July 15, 2019 Received Date July 15, 2019 PDUFA Goal Date March 15, 2020 Division/Office DO1/OOD/OND/CDER Review Completion Date December 17, 2019 Established Name enfortumab vedotin-ejfv (Proposed) Trade Name PADCEVTM Pharmacologic Class Nectin-4-directed antibody and microtubule inhibitor conjugate Code name Applicant Astellas Pharma US, Inc. Formulation injection, powder, lyophilized for solution Dosing Regimen 1.25 mg/kg (up to a maximum dose of 125 mg) given as an IV infusion over 30 minutes on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity (b) (4) Applicant Proposed Indication(s)/Population(s) Recommendation on Accelerated Approval Regulatory Action Recommended For the treatment of adult patients with locally advanced or Indication(s)/Population(s) metastatic urothelial cancer who have previously received a (if applicable) programmed death receptor-1 (PD-1) or programmed death- ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting 1 Version date: June 11, 2019 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4536389 NDA/BLA Multi-disciplinary Review and Evaluation – BLA 761137 PADCEV™ (enfortumab vedotin-ievx) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 10 Additional Reviewers of Application ............................................................................................. 10 Glossary ......................................................................................................................................... 11 1 Executive Summary ............................................................................................................... 14 Product Introduction ...................................................................................................... 14 Conclusions on the Substantial Evidence of Effectiveness ............................................ 14 Benefit-Risk Assessment (BRA) ...................................................................................... 16 Patient Experience Data ................................................................................................. 18 2 Therapeutic Context .............................................................................................................. 20 Analysis of Condition ...................................................................................................... 20 Analysis of Current Treatment Options ......................................................................... 22 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 ................................................................................................................. 29 Office of Scientific Investigations (OSI) .......................................................................... 29 Product Quality .............................................................................................................. 29 Clinical Microbiology ...................................................................................................... 29 Devices and Companion Diagnostic Issues .................................................................... 29 5 Nonclinical Pharmacology/Toxicology................................................................................... 31 Executive Summary ........................................................................................................ 31 Referenced NDAs, BLAs, DMFs ....................................................................................... 37 Pharmacology ................................................................................................................. 37 ADME/PK ........................................................................................................................ 52 Toxicology ....................................................................................................................... 60 General Toxicology .................................................................................................. 60 Genetic Toxicology .................................................................................................. 81 2 Version date: June 11, 2019 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4536389 NDA/BLA Multi-disciplinary Review and Evaluation – BLA 761137 PADCEV™ (enfortumab vedotin-ievx) Carcinogenicity ........................................................................................................ 83 Reproductive and Developmental Toxicology ........................................................ 84 Other Toxicology Studies ........................................................................................ 92 6 Clinical Pharmacology .......................................................................................................... 100 Executive Summary ...................................................................................................... 100 Summary of Clinical Pharmacology Assessment .......................................................... 101 Pharmacology and Clinical Pharmacokinetics ...................................................... 101 General Dosing and Therapeutic Individualization ............................................... 102 6.2.2.1. General Dosing .............................................................................................. 102 6.2.2.2. Therapeutic Individualization ........................................................................ 104 6.2.2.3. Outstanding Issues ........................................................................................ 107 Comprehensive Clinical Pharmacology Review ........................................................... 107 General Pharmacology and Pharmacokinetic Characteristics .............................. 107 Clinical Pharmacology Questions .......................................................................... 113 7 Sources of Clinical Data ....................................................................................................... 123 Table of Clinical Studies ................................................................................................ 123 8 Statistical and Clinical Evaluation ........................................................................................ 127 Review of Relevant Individual Trials Used to Support Efficacy .................................... 127 Study EV-201 ......................................................................................................... 127 Study Results ......................................................................................................... 143 Integrated Review of Effectiveness ...................................................................... 169 Assessment of Efficacy Across Trials ..................................................................... 169 Integrated Assessment of Effectiveness ............................................................... 173 Review of Safety ........................................................................................................... 175 Safety Review Approach ....................................................................................... 175 Review of the Safety Database ............................................................................. 176 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 184 Safety Results ........................................................................................................ 188 Analysis of Submission-Specific Safety Issues ....................................................... 213 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 234 3 Version date: June 11, 2019 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4536389 NDA/BLA Multi-disciplinary Review and Evaluation
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