CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 214120Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multidisciplinary Review and Evaluation Application Number NDA 214120 Application Type Type 3 Priority or Standard Priority Submit Date 3/3/2020 Received Date 3/3/2020 PDUFA Goal Date 9/3/2020 Office/Division OOD/DHM1 Review Completion Date 9/1/2020 Applicant Celgene Corporation Established Name Azacitidine (Proposed) Trade Name Onureg Pharmacologic Class Nucleoside metabolic inhibitor Formulations Tablet (200 mg, 300 mg) (b) (4) Applicant Proposed Indication/Population Recommendation on Regulatory Regular approval Action Recommended Indication/ For continued treatment of adult patients with acute Population myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy. SNOMED CT for the Recommended 91861009 Indication/Population Recommended Dosing Regimen 300 mg orally daily on Days 1 through 14 of each 28-day cycle Reference ID: 4664570 NDA Multidisciplinary Review and Evaluation NDA 214120 Onureg (azacitidine tablets) TABLE OF CONTENTS TABLE OF CONTENTS ................................................................................................................................... 2 TABLE OF TABLES ........................................................................................................................................ 5 TABLE OF FIGURES ...................................................................................................................................... 8 REVIEWERS OF THE MULTIDISCIPLINARY REVIEW AND EVALUATION ...................................................... 9 GLOSSARY .................................................................................................................................................. 10 1 EXECUTIVE SUMMARY ................................................................................................................. 12 1.1 Product Introduction ....................................................................................................... 12 1.2 Conclusions on the Substantial Evidence of Effectiveness ............................................. 12 1.3 Benefit-Risk Assessment ................................................................................................. 14 1.4 Patient Experience Data .................................................................................................. 16 2 THERAPEUTIC CONTEXT ............................................................................................................ 16 2.1 Analysis of Condition ........................................................................................................ 16 2.2 Analysis of Current Treatment Options ........................................................................... 18 3 REGULATORY BACKGROUND ................................................................................................... 18 3.1 U.S. Regulatory Actions and Marketing History ............................................................... 18 3.2 Summary of Presubmission/Submission Regulatory Activity ........................................... 18 4 SIGNIFICANT ISSUES FROM OTHER REVIEW DISCIPLINES PERTINENT TO CLINICAL CONCLUSIONS ON EFFICACY AND SAFETY ............................................................................. 19 4.1 Office of Scientific Investigations ..................................................................................... 19 4.2. Product Quality ............................................................................................................... 19 4.3 Devices and Companion Diagnostic Issues ...................................................................... 19 5 NONCLINICAL PHARMACOLOGY/TOXICOLOGY .................................................................. 20 5. 1 Executive Summary ......................................................................................................... 20 5.2 Referenced NDAs, BLAs, DMFs ........................................................................................ 21 5.3 Pharmacology ................................................................................................................... 22 5.3.1 Primary Pharmacology .......................................................................................... 22 5.3.2 Secondary Pharmacology ...................................................................................... 35 5.3.3 Safety Pharmacology ............................................................................................. 37 5.4 ADME/PK .......................................................................................................................... 39 5.5 Toxicology ........................................................................................................................ 41 5.5.1 General Toxicology ................................................................................................ 41 5.5.2 Genetic Toxicology ................................................................................................ 47 5.5.3 Carcinogenicity ...................................................................................................... 47 5.5.4 Reproductive and Developmental Toxicology ...................................................... 47 5.5.5 Other Toxicology Studies ....................................................................................... 49 2 Reference ID: 4664570 NDA Multidisciplinary Review and Evaluation NDA 214120 Onureg (azacitidine tablets) 6 CLINICAL PHARMACOLOGY ........................................................................................................ 56 6.1 Executive Summary ........................................................................................................... 56 6.2 Summary of Clinical Pharmacology Assessment .............................................................. 58 6.2.1 Pharmacology and Clinical Pharmacokinetics ...................................................... 58 6.2.2 General Dosing and Therapeutic Individualization............................................... 59 6.3 Comprehensive Clinical Pharmacology Review ................................................................ 61 6.3.1 General Pharmacology and Pharmacokinetic Characteristics ................................ 61 6.3.2 Clinical Pharmacology Questions .......................................................................... 64 7 SOURCES OF CLINICAL DATA AND REVIEW STRATEGY .................................................... 75 7.1 Table of Clinical Studies ..................................................................................................... 75 7.2 Review Strategy ............................................................................................................... 76 8 STATISTICAL AND CLINICAL EVALUATION .......................................................................... 77 8.1 Review of Relevant Individual Trials Used to Support Efficacy .......................................... 77 8.1.1. Study CC-486-AML-001 (QUAZAR) ....................................................................... 77 8.1.1. Additional Studies of Activity of Oral Azacitidine in AML .................................. 105 8.2 Integrated Review of Effectiveness ................................................................................ 107 8.2.1 Assessment of Efficacy Across Trials .................................................................. 107 8.2.2 Integrated Assessment of Effectiveness ............................................................. 112 8.3 Review of Safety ............................................................................................................. 113 8.3.1. Safety Review Approach .................................................................................... 113 8.3.2. Review of the Safety Database .......................................................................... 114 8.3.3. Adequacy of Applicant’s Clinical Safety Assessments ......................................... 116 8.3.4. Safety Results ..................................................................................................... 116 8.3.5 Analysis of Submission-Specific Safety Issues ..................................................... 127 8.3.6 Safety Analyses by Demographic Subgroups ...................................................... 127 8.3.7 Clinical Outcomes Assessments Informing Tolerability/Safety .......................... 128 8.3.8 Specific Safety Studies/Clinical Trials (including dose-related safety) ................ 128 8.3.9 Additional Safety Explorations ............................................................................ 130 8.3.10 Safety in the Postmarket Setting ...................................................................... 130 8.3.11 Integrated Assessment of Safety ....................................................................... 132 SUMMARY AND CONCLUSIONS ............................................................................................. 134 8.4 Statistical Issues .............................................................................................................