CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213217Orig1s000 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 NDA 213217 BRUKINSA (zanubrutinib) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type 505 (b)(1) Application Number(s) NDA 213217 Priority or Standard Priority Submit Date(s) June 27, 2019 Received Date(s) June 27, 2019 PDUFA Goal Date February 27, 2020 Division/Office Division of Hematology Products/Office of Hematology and Oncology Products Review Completion Date November 14, 2019 Established/Proper Name Zanubrutinib (Proposed) Trade Name BRUKINSA Pharmacologic Class Kinase inhibitor Code name BGB-3111 Applicant BeiGene USA Doseage form Capsules Applicant proposed Dosing 160mg orally twice daily, approximately every 12 hours Regimen Applicant Proposed Treatment of adult patients with mantle cell lymphoma who Indication(s)/Population(s) have received at least one prior therapy Applicant Proposed Mantle cel llymphoma SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Accelerated Approval Regulatory Action Recommended Treatment of adult patients with mantle cell lymphoma (MCL) Indication(s)/Population(s) who have received at least one prior therapy (if applicable) Recommended SNOMED Mantle cell lymphoma CT Indication Disease Term for each Indication (if applicable) Recommended Dosing 160mg orally twice daily or 320mg once daily Regimen 1 Reference ID: 4519846 NDA/BLA Multi-disciplinary Review and Evaluation NDA 213217 BRUKINSA (zanubrutinib) Table of Contents Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 8 Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 10 Glossary ......................................................................................................................................... 11 1 Executive Summary ............................................................................................................... 14 Product Introduction ...................................................................................................... 14 Conclusions on the Substantial Evidence of Effectiveness ............................................ 14 Benefit-Risk Assessment ................................................................................................ 15 Patient Experience Data ................................................................................................. 20 2 Therapeutic Context .............................................................................................................. 21 Analysis of Condition ...................................................................................................... 21 Analysis of Current Treatment Options ......................................................................... 22 3 Regulatory Background ......................................................................................................... 23 U.S. Regulatory Actions and Marketing History ............................................................. 23 Summary of Presubmission/Submission Regulatory Activity ........................................ 23 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 24 Office of Scientific Investigations (OSI) .......................................................................... 24 Product Quality .............................................................................................................. 24 Clinical Microbiology ...................................................................................................... 24 Devices and Companion Diagnostic Issues .................................................................... 24 5 Nonclinical Pharmacology/Toxicology................................................................................... 25 Executive Summary ........................................................................................................ 25 Referenced NDAs, BLAs, DMFs ....................................................................................... 27 Pharmacology ................................................................................................................. 27 ADME/PK ........................................................................................................................ 30 Toxicology ....................................................................................................................... 33 General Toxicology .................................................................................................. 33 Genetic Toxicology .................................................................................................. 37 Carcinogenicity ........................................................................................................ 39 Reproductive and Developmental Toxicology ........................................................ 39 Other Toxicology Studies ........................................................................................ 44 6 Clinical Pharmacology ............................................................................................................ 45 Executive Summary ........................................................................................................ 45 2 Reference ID: 4519846 NDA/BLA Multi-disciplinary Review and Evaluation NDA 213217 BRUKINSA (zanubrutinib) Summary of Clinical Pharmacology Assessment ............................................................ 46 Pharmacology and Clinical Pharmacokinetics ........................................................ 46 General Dosing and Therapeutic Individualization ................................................. 47 Comprehensive Clinical Pharmacology Review ............................................................. 48 General Pharmacology and Pharmacokinetic Characteristics ................................ 48 Clinical Pharmacology Questions ............................................................................ 52 7 Sources of Clinical Data and Review Strategy ....................................................................... 64 Table of Clinical Studies .................................................................................................. 64 Review Strategy .............................................................................................................. 66 8 Statistical and Clinical and Evaluation ................................................................................... 68 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 68 8.1.1 Study BGB-3111-206 ............................................................................................... 68 Study Results ..................................................................................................................... 73 Study BGB-3111-AU-003 ......................................................................................... 85 Study Results ..................................................................................................................... 90 8.1.3 Integrated Assessment of Effectiveness ................................................................. 97 Review of Safety ............................................................................................................. 98 Safety Review Approach ......................................................................................... 98 Review of the Safety Database ............................................................................... 99 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 102 Safety Results ........................................................................................................ 103 8.2.5 Analysis of Submission-Specific Safety Issues ....................................................... 119 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 122 8.2.7 Safety Analyses by Demographic Subgroups ........................................................ 122 8.2.8 Specific Safety Studies/Clinical Trials .................................................................... 124 8.2.9 Additional Safety Explorations .............................................................................. 124 8.2.10 Safety in the Postmarket Setting ................................................................... 125 8.2.11 Integrated Assessment of Safety ................................................................... 125 8.3 Statistical Issues ........................................................................................................... 127 8.4 Conclusions and Recommendations ............................................................................ 127 9 Advisory Committee Meeting and Other External Consultations ......................................