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209606Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209606Orig1s000 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(s) NDA 209606 Application Type Original 505(b)(1) Priority or Standard Priority Submit Date(s) December 30, 2016 Received Date(s) December 30, 2016 PDUFA Goal Date August 30, 2017 Division/Office DHP/OHOP Review Completion Date July 28, 2017 Applicant Celgene Corporation Established Name Enasidenib (Proposed) Trade Name IDHIFA® Pharmacologic Class Isocitrate dehydrogenase 2 inhibitor Formulation(s) Tablets, 50mg and 100mg Dosing Regimen 100 mg once daily Applicant Proposed IDHIFA is indicated for the treatment of patients with relapsed or Indication(s)/Population(s) refractory acute myeloid leukemia with an IDH2 mutation Recommendation on Regular approval Regulatory Action Recommended IDHIFA is an isocitrate dehydrogenase-2 inhibitor indicated for the Indication(s)/Population(s) treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test. Reference ID: 4131433 Multidisciplinary Review and Evaluation NDA 209606 IDHIFA® (enasidenib) Table of Contents Table of Contents ........................................................................................................................... 2 Table of Tables ............................................................................................................................... 6 Table of Figures .............................................................................................................................. 9 Reviewers of Multidisciplinary Review and Evaluation ................................................................ 10 Additional Reviewers of Application ............................................................................................. 10 Glossary ......................................................................................................................................... 11 1 Executive Summary ............................................................................................................... 14 1.1. Product Introduction ...................................................................................................... 14 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 14 1.3. Benefit-Risk Assessment ................................................................................................ 16 2 Therapeutic Context .............................................................................................................. 18 2.1. Analysis of Condition ...................................................................................................... 18 2.2. Analysis of Current Treatment Options ......................................................................... 18 3 Regulatory Background ......................................................................................................... 20 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 20 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 20 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 21 4.1. Office of Scientific Investigations ................................................................................... 21 4.2. Product Quality .............................................................................................................. 21 4.3. Devices and Companion Diagnostic Issues .................................................................... 22 5 Nonclinical Pharmacology/Toxicology................................................................................... 23 5.1. Executive Summary ........................................................................................................ 23 5.2. Referenced NDAs, BLAs, DMFs ....................................................................................... 27 5.3. Pharmacology ................................................................................................................. 27 5.4. ADME/PK ........................................................................................................................ 40 5.5. Toxicology ....................................................................................................................... 44 2 Reference ID: 4131433 Multidisciplinary Review and Evaluation NDA 209606 IDHIFA® (enasidenib) 5.5.1. General Toxicology .................................................................................................. 44 5.5.2. Genetic Toxicology .................................................................................................. 50 5.5.3. Carcinogenicity ........................................................................................................ 51 5.5.4. Reproductive and Developmental Toxicology ........................................................ 51 6 Clinical Pharmacology ............................................................................................................ 58 6.1. Executive Summary ........................................................................................................ 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 ............................................................................ 61 7 Statistical and Clinical Evaluation .......................................................................................... 69 7.1. Sources of Clinical Data and Review Strategy ................................................................ 69 7.1.1. Table of Clinical Studies .......................................................................................... 69 7.1.2. Review Strategy ...................................................................................................... 69 7.2. Review of Relevant Individual Trials Used to Support Efficacy ...................................... 71 7.2.1. AG221-C-001 ........................................................................................................... 71 7.2.2. Study Results ........................................................................................................... 81 7.2.3. Study Results Addendum ........................................................................................ 99 7.3. Integrated Review of Effectiveness .............................................................................. 105 7.3.1. Assessment of Efficacy Across Trials ..................................................................... 105 7.3.2. Integrated Assessment of Effectiveness ................................................................ 108 7.4. Review of Safety ........................................................................................................... 108 7.4.1. Safety Review Approach ....................................................................................... 108 7.4.2. Review of the Safety Database ............................................................................. 109 7.4.3. Adequacy of Applicant’s Clinical Safety Assessments .......................................... 111 7.4.4. Safety Results ........................................................................................................ 112 7.4.5. Analysis of Submission-Specific Safety Issues ....................................................... 134 7.4.6. Safety Analyses by Demographic Subgroups ........................................................ 134 7.4.7. Specific Safety Studies/Clinical Trials .................................................................... 134 3 Reference ID: 4131433 Multidisciplinary Review and Evaluation NDA 209606 IDHIFA® (enasidenib) 7.4.8. Additional Safety Explorations .............................................................................. 135 7.4.9. Safety in the Postmarket Setting .......................................................................... 135 7.4.10. Integrated Assessment of Safety ................................................................... 136 SUMMARY AND CONCLUSIONS .................................................................................................. 137 7.5. Statistical Issues ........................................................................................................... 137 7.6. Conclusions and Recommendations ............................................................................ 138 8 Advisory Committee Meeting and Other External Consultations ......................................
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