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761040Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761040Orig1s000 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 761040} {BESPONSA; Inotuzumab Ozogamicin} BLA 761040 Multi-disciplinary Review and Evaluation Application Type BLA Application Number(s) 761040 Priority or Standard Priority Submit Date(s) December 20, 2016 Received Date(s) December 20, 2016 PDUFA Goal Date August 20, 2017 Division/Office CDER/OHOP/DHP Review Completion Date August 15, 2017 Established Name Inotuzumab Ozogamicin (Proposed) Trade Name BESPONSA Pharmacologic Class Antibody-Drug Conjugate Code name PF-05208773 Applicant Pfizer Formulation(s) Injection Dosing Regimen Cycle 1: total dose is 1.8mg/m2 per 3 week cycle given as divided doses on day 1(0.8mg/m2), Day 8(0.5mg/m2) and Day 15(0.5mg/m2). For subsequent cycles, the dose is 1.5mg/m2 per 4 week cycle given as 3 divided doses on day 1(0.5mg/m2), day 8(0.5mg/m2) and Day 15(0.5mg/m2). Applicant Proposed Treatment of relapsed or refractory B-cell precursor acute Indication(s)/Population(s) lymphoblastic leukemia(ALL) Recommendation on Regular Approval Regulatory Action Recommended Treatment of adult patients with relapsed or refractory B-cell Indication(s)/Population(s) precursor acute lymphoblastic leukemia(ALL) (if applicable) 1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4140432 NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761040} {BESPONSA; Inotuzumab Ozogamicin} Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 12 Additional Reviewers of Application ............................................................................................. 12 Glossary ......................................................................................................................................... 14 1 Executive Summary ............................................................................................................... 18 1.1. Product Introduction ...................................................................................................... 18 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 18 1.3. Benefit-Risk Assessment ................................................................................................ 19 2 Therapeutic Context .............................................................................................................. 25 2.1. Analysis of Condition ...................................................................................................... 25 2.2. Analysis of Current Treatment Options ......................................................................... 25 3 Regulatory Background ......................................................................................................... 28 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 28 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 28 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 29 4.1. Office of Scientific Investigations (OSI) .......................................................................... 29 4.2. Product Quality .............................................................................................................. 29 4.3. Clinical Microbiology ...................................................................................................... 30 4.4. Devices and Companion Diagnostic Issues .................................................................... 30 5 Nonclinical Pharmacology/Toxicology................................................................................... 32 5.1. Executive Summary ........................................................................................................ 32 5.2. Referenced NDAs, BLAs, DMFs ....................................................................................... 35 5.3. Pharmacology ................................................................................................................. 35 5.4. ADME/PK ........................................................................................................................ 39 5.5. Toxicology ....................................................................................................................... 42 5.5.1. General Toxicology .................................................................................................. 42 5.5.2. Genetic Toxicology .................................................................................................. 47 5.5.3. Carcinogenicity ........................................................................................................ 48 5.5.4. Reproductive and Developmental Toxicology ........................................................ 48 2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4140432 NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761040} {BESPONSA; Inotuzumab Ozogamicin} 5.5.5. Other Toxicology Studies ........................................................................................ 52 6 Clinical Pharmacology ............................................................................................................ 57 6.1. Executive Summary ........................................................................................................ 57 6.1.1. Recommendations .................................................................................................. 57 6.1.2. Post-Marketing Requirements and Commitments ................................................. 58 6.2. Summary of Clinical Pharmacology Assessment ............................................................ 59 6.2.1. Pharmacology and Clinical Pharmacokinetics ........................................................ 59 6.2.2. General Dosing and Therapeutic Individualization ................................................. 59 6.3. Comprehensive Clinical Pharmacology Review ............................................................. 60 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................ 60 6.3.2. Clinical Pharmacology Questions ............................................................................ 63 7 Statistical and Clinical and Evaluation ................................................................................... 75 7.1. Sources of Clinical Data and Review Strategy ................................................................ 75 7.1.1. Table of Clinical Studies .......................................................................................... 75 7.1.2. Review Strategy ...................................................................................................... 80 7.2. Review of Relevant Individual Trials Used to Support Efficacy ...................................... 81 7.2.1. Study B1931022: An Open-Label, Randomized Phase 3 Study of Inotuzumab Ozogamicin Compared to a Defined Investigator’s Choice in Adult Patients with Relapsed or Refractory CD22 Positive Acute Lymphoblastic Leukemia (ALL) .................................. 81 7.2.2. Study Results ........................................................................................................... 94 7.2.3. Study 1931008 (Study 1008) ................................................................................. 127 7.2.4. Study 1931006(Study 1006) .................................................................................. 127 7.3. Integrated Review of Effectiveness .............................................................................. 127 7.3.1. Assessment of Efficacy Across Trials ..................................................................... 127 7.3.2. Integrated Assessment of Effectiveness ............................................................... 129 7.4. Review of Safety ........................................................................................................... 131 7.4.1. Safety Review Approach ....................................................................................... 131 7.4.2. Review of the Safety Database ............................................................................. 131 7.4.3. Adequacy of Applicant’s Clinical Safety Assessments .......................................... 135 7.4.4. Safety Results ........................................................................................................ 136 7.4.5. Analysis of Submission-Specific Safety Issues ....................................................... 165 7.4.6. Safety Analyses by Demographic Subgroups ........................................................ 181 3 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4140432 NDA/BLA Multi-disciplinary Review and Evaluation {BLA 761040} {BESPONSA; Inotuzumab Ozogamicin} 7.4.7. Specific Safety Studies/Clinical Trials .................................................................... 184 7.4.8. Additional
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