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CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211155Orig1s000 211155Orig2s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 211155 Multi-disciplinary Review and Evaluation COPIKTRA (duvelisib) NDA/BLA Multi-disciplinary Review and Evaluation Application Type Original NDA Application Number(s) 211155 Priority or Standard Priority Submit Date(s) February 5, 2018 Received Date(s) February 5, 2018 PDUFA Goal Date October 5, 2018 Division/Office Division of Hematology Products / OHOP Review Completion Date September 18, 2018 Established Name Duvelisib (IPI-145) (Proposed) Trade Name COPIKTRA Pharmacologic Class Kinase inhibitor Code name Phosphatidylinositol 3-kinase inhibitor Applicant Verastem, Inc. Formulation(s) Capsules (25 mg, 15 mg) Dosing Regimen 25 mg orally twice daily (b) (4) Applicant Proposed Treatment of patients with: Indication(s)/Population(s) Chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), (b) (4) Follicular B-cell non-Hodgkin lymphoma (FL) who have received at least two prior therapies Recommendation on Approval Regulatory Action Recommended Treatment of adult patients with: Indication(s)/Population(s) Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies Relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies 1 Reference ID: 4324739 NDA 211155 Multi-disciplinary Review and Evaluation COPIKTRA (duvelisib) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation...............................................................10 Additional Reviewers of Application ............................................................................................10 Glossary ........................................................................................................................................11 1 Executive Summary...............................................................................................................13 1.1. Product Introduction......................................................................................................13 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................13 1.3. Benefit-Risk Assessment ................................................................................................15 1.4. Patient Experience Data.................................................................................................19 2 Therapeutic Context..............................................................................................................20 2.1. Analysis of Condition......................................................................................................20 2.2. Analysis of Current Treatment Options .........................................................................21 3 Regulatory Background .........................................................................................................25 3.1. U.S. Regulatory Actions and Marketing History.............................................................25 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................25 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................26 4.1. Office of Scientific Investigations (OSI) ..........................................................................26 4.2. Product Quality ..............................................................................................................26 4.3. Clinical Microbiology......................................................................................................27 4.4. Devices and Companion Diagnostic Issues ....................................................................27 5 Nonclinical Pharmacology/Toxicology ..................................................................................27 5.1. Executive Summary........................................................................................................27 5.1. Referenced NDAs, BLAs, DMFs ......................................................................................30 5.2. Pharmacology ................................................................................................................31 5.2.1. Primary Pharmacology............................................................................................31 5.2.2. Secondary Pharmacology .......................................................................................34 5.2.3. Safety Pharmacology ..............................................................................................35 5.3. ADME/PK........................................................................................................................36 5.4. Toxicology ......................................................................................................................40 2 Reference ID: 4324739 NDA 211155 Multi-disciplinary Review and Evaluation COPIKTRA (duvelisib) 5.4.1. General Toxicology .................................................................................................40 5.4.2. Genetic Toxicology..................................................................................................48 5.4.3. Carcinogenicity .......................................................................................................50 5.4.4. Reproductive and Developmental Toxicology ........................................................50 5.4.5. Other Toxicology Studies ........................................................................................58 6 Clinical Pharmacology ...........................................................................................................61 6.1. Executive Summary........................................................................................................61 6.2. Summary of Clinical Pharmacology Assessment............................................................62 6.2.1. Pharmacology and Clinical Pharmacokinetics.........................................................62 6.2.2. General Dosing and Therapeutic Individualization.................................................62 6.3. Comprehensive Clinical Pharmacology Review..............................................................64 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................64 6.3.2. Clinical Pharmacology Questions............................................................................65 7 Sources of Clinical Data and Review Strategy .......................................................................72 7.1. Table of Clinical Studies .................................................................................................72 7.2. Review Strategy .............................................................................................................72 8 Statistical and Clinical Evaluation..........................................................................................73 8.1. Chronic Lymphocytic Leukemia .....................................................................................73 8.1.1. Review of Relevant Individual Trials Used to Support Efficacy...............................73 8.1.2. Integrated Assessment of Effectiveness...............................................................109 8.2. Follicular Lymphoma....................................................................................................111 8.2.1. Review of Relevant Individual Trials Used to Support Efficacy.............................111 8.2.2. Integrated Assessment of Effectiveness...............................................................126 8.3. Review of Safety...........................................................................................................126 8.3.1. Safety Review Approach .......................................................................................126 8.3.2. Review of the Safety Database .............................................................................127 8.3.3. Adequacy of Applicant’s Clinical Safety Assessments...........................................130 8.3.4. Safety Results........................................................................................................130 8.3.5. Analysis of Submission-Specific Safety Issues.......................................................145 8.3.6. Clinical Outcome Assessment Analyses Informing Safety/Tolerability.................156 8.3.7. Safety Analyses by Demographic Subgroups........................................................156 3 Reference ID: 4324739 NDA 211155 Multi-disciplinary Review and Evaluation COPIKTRA (duvelisib) 8.3.8. Specific Safety Studies/Clinical Trials....................................................................158 8.3.9. Additional Safety Explorations..............................................................................159 8.3.10. Safety in the Postmarket Setting...................................................................160 8.3.11. Integrated Assessment of Safety...................................................................160 SUMMARY AND CONCLUSIONS – Statistical
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