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Multi-Discipline Review CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211810Orig1s000 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 Application Type New Drug Application (NDA)/New Molecular Entity (NME) Application Number(s) 211810 Priority or Standard Priority Submit Date(s) December 01, 2018 Received Date(s) December 03, 2018 PDUFA Goal Date August 03, 2019 Division/Office DOP2/OHOP Review Completion Date July 31, 2019 Established Name Pexidartinib (Proposed) Trade Name TURALIO Pharmacologic Class Kinase inhibitor Code name PLX3397; PLX3397 hydrochloride Applicant Daiichi Sankyo Inc. Formulation(s) 200 mg Capsules Dosing Regimen 400 mg (2 capsules) orally twice daily on an empty stomach Applicant Proposed For the treatment of adult patients with symptomatic tenosynovial Indication(s)/Population(s) giant cell tumor (TGCT) also referred to as giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery Recommendation on Approval Regulatory Action Recommended For the treatment of adult patients with symptomatic tenosynovial Indication(s)/Population(s) giant cell tumor (TGCT) which is associated with severe morbidity or (if applicable) functional limitations, and which is not amenable to improvement with surgery Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4470487 NDA/BLA Multi-disciplinary Review and Evaluation NDA 211810 TURALIO (pexidartinib) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ................................................... xii Additional Reviewers of Application .................................................................................. xii Glossary ............................................................................................................................... 1 1. Executive Summary ......................................................................................................... 3 1.1. Product Introduction ................................................................................................ 3 1.2. Conclusions on the Substantial Evidence of Effectiveness ...................................... 4 1.3. Benefit-Risk Assessment .......................................................................................... 5 1.4. Patient Experience Data ......................................................................................... 12 2. Therapeutic Context ..................................................................................................... 13 2.1. Analysis of Condition .............................................................................................. 13 2.2. Analysis of Current Treatment Options ................................................................. 13 3. Regulatory Background ................................................................................................. 15 3.1. U.S. Regulatory Actions and Marketing History ..................................................... 15 3.2. Summary of Presubmission/Submission Regulatory Activity ................................ 15 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................. 23 4.1. Office of Scientific Investigations (OSI) .................................................................. 23 4.2. Product Quality and Clinical Microbiology ............................................................. 23 4.3. Devices and Companion Diagnostic Issues ............................................................ 24 5. Nonclinical Pharmacology/Toxicology .......................................................................... 25 5.1. Executive Summary ................................................................................................ 25 5.2. Referenced NDAs, BLAs, DMFs ............................................................................... 28 5.3. Pharmacology ......................................................................................................... 28 5.4. ADME/PK ................................................................................................................ 33 5.5. Toxicology ............................................................................................................... 34 5.5.1. General Toxicology .......................................................................................... 34 5.5.2. Genetic Toxicology ........................................................................................... 45 5.5.3. Carcinogenicity ................................................................................................ 46 5.5.4. Reproductive and Developmental Toxicology ................................................. 46 5.5.5. Other Toxicology Studies ................................................................................. 54 6. Clinical Pharmacology ................................................................................................... 55 6.1. Executive Summary ................................................................................................ 55 6.2. Summary of Clinical Pharmacology Assessment .................................................... 57 6.2.1. Pharmacology and Clinical Pharmacokinetics ................................................. 57 6.2.2. General Dosing and Therapeutic Individualization ......................................... 59 ii Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4470487 NDA/BLA Multi-disciplinary Review and Evaluation NDA 211810 TURALIO (pexidartinib) 6.3. Comprehensive Clinical Pharmacology Review ..................................................... 63 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ......................... 63 6.3.2. Clinical Pharmacology Questions .................................................................... 68 7. Sources of Clinical Data and Review Strategy ............................................................... 90 7.1. Review Strategy ...................................................................................................... 97 7.1.1. Review Strategy ............................................................................................... 97 8. Statistical and Clinical and Evaluation .......................................................................... 98 8.1. Review of Relevant Individual Trials Used to Support Efficacy .............................. 98 8.1.1. PLX108-10 (ENLIVEN) ....................................................................................... 98 8.1.2. Study Results .................................................................................................. 111 8.2. PLX108-01 ............................................................................................................. 129 8.2.1. Study Design .................................................................................................. 129 8.2.2. Study Results .................................................................................................. 134 8.2.3. Integrated Assessment of Effectiveness ........................................................ 138 8.3. Review of Safety ................................................................................................... 140 8.3.1. Safety Review Approach ................................................................................ 140 8.3.2. Review of the Safety Database ...................................................................... 141 8.3.3. Safety Results ................................................................................................. 145 8.3.4. Analysis of Submission-Specific Safety Issues ............................................... 165 8.3.5. Safety Analyses by Demographic Subgroups................................................. 186 8.3.6. Specific Safety Studies/Clinical Trials............................................................. 187 8.3.7. Additional Safety Explorations ...................................................................... 187 8.3.8. Safety in the Postmarket Setting ................................................................... 188 8.3.9. Integrated Assessment of Safety ................................................................... 188 SUMMARY AND CONCLUSIONS ...................................................................................... 191 8.4. Statistical Issues .................................................................................................... 191 8.5. Conclusions and Recommendations .................................................................... 192 9. Advisory Committee Meeting and Other External Consultations .............................. 195 10. Pediatrics ................................................................................................................... 198 11. Labeling Recommendations ...................................................................................... 199 11.1. Prescription Drug Labeling ................................................................................. 199 11.2.
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