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209241Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209241Orig1s000 MEDICAL REVIEW(S) Clinical Review Michael C. Davis, MD, PhD and Brian J. Miller, MD, MBA, MPH NDA 209241 Ingrezza (valbenazine) CLINICAL REVIEW Application Type New Molecular Entity Application Number(s) 209241 Priority or Standard Priority Submit Date(s) August 11, 2016 Received Date(s) August 11, 2016 PDUFA Goal Date April 11, 2017 Division/Office Division of Psychiatry Products/Office of New Drugs Reviewer Name(s) Michael C. Davis, MD, PhD and Brian J. Miller, MD, MBA, MPH Review Completion Date April 4, 2017 Established Name Valbenazine (Proposed) Trade Name Ingrezza Applicant Neurocrine Biosciences Formulation(s) Capsule (40 mg) Dosing Regimen 1-2 capsules by mouth once daily (recommended dose = 80 mg) Proposed Indication(s) Tardive Dyskinesia Intended Population(s) Adults with tardive dyskinesia Recommendation on Approve Regulatory Action Recommended Indication(s) (if applicable) CDER Clinical Review Template 2015 Edition 1 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4079314 Clinical Review Michael C. Davis, MD, PhD and Brian J. Miller, MD, MBA, MPH NDA 209241 Ingrezza (valbenazine) 1 Table of Contents 1 Table of Contents..................................................................................................................... 2 Glossary ......................................................................................................................................... 12 1 Executive Summary ............................................................................................................... 14 1.1. Product Introduction ...................................................................................................... 14 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 15 1.3. Benefit-Risk Assessment ................................................................................................ 15 2 Therapeutic Context .............................................................................................................. 24 2.1. Analysis of Condition ...................................................................................................... 24 2.2. Analysis of Current Treatment Options ......................................................................... 25 3 Regulatory Background ......................................................................................................... 27 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 27 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 28 3.3. Foreign Regulatory Actions and Marketing History ....................................................... 32 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 32 4.1. Office of Scientific Investigations (OSI) .......................................................................... 32 4.2. Product Quality .............................................................................................................. 33 4.3. Clinical Microbiology ...................................................................................................... 33 4.4. Nonclinical Pharmacology/Toxicology ........................................................................... 33 4.5. Clinical Pharmacology .................................................................................................... 35 4.5.1. Mechanism of Action .............................................................................................. 35 4.5.2. Pharmacodynamics ................................................................................................. 35 4.5.3. Pharmacokinetics .................................................................................................... 38 4.6. Devices and Companion Diagnostic Issues .................................................................... 42 4.7. Consumer Study Reviews ............................................................................................... 42 5 Sources of Clinical Data and Review Strategy ....................................................................... 42 CDER Clinical Review Template 2015 Edition 2 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4079314 Clinical Review Michael C. Davis, MD, PhD and Brian J. Miller, MD, MBA, MPH NDA 209241 Ingrezza (valbenazine) 5.1. Table of Clinical Studies .................................................................................................. 42 5.2. Review Strategy .............................................................................................................. 45 6 Review of Relevant Individual Trials Used to Support Efficacy ............................................. 46 6.1. Study 1304: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel, Fixed- Dose Study to Assess the Efficacy, Safety, and Tolerability of Valbenazine for the Treatment of Tardive Dyskinesia ................................................................................................................ 46 6.1.1. Study Design............................................................................................................ 46 6.1.2. Study Results ........................................................................................................... 63 6.2. Study 1202: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose Titration Study to Assess the Safety, Tolerability, and Efficacy of Valbenazine for the Treatment of Tardive Dyskinesia .................................................................................................................... 87 6.2.1. Study Design............................................................................................................ 87 6.2.2. Study Results ......................................................................................................... 101 6.3. Study 1201: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Valbenazine for the Treatment of Tardive Dykinesia in Subjects with Schizophrenia or Schizoaffective Disorder ............................................................................. 119 6.3.1. Study Design.......................................................................................................... 119 6.3.2. Study Results ......................................................................................................... 127 6.4. Study 1402: A Phase 3, Open-Label, Safety and Tolerability Study of Valbenazine for the Treatment of Tardive Dyskinesia ...................................................................................... 136 6.4.1. Study Design.......................................................................................................... 136 6.4.2. Study Results ......................................................................................................... 141 7 Integrated Review of Effectiveness ..................................................................................... 148 7.1. Assessment of Efficacy Across Trials ............................................................................ 148 7.1.1. Primary Endpoints ................................................................................................. 148 7.1.2. Secondary and Other Endpoints ........................................................................... 154 7.1.3. Subpopulations ..................................................................................................... 155 7.1.4. Dose and Dose-Response...................................................................................... 158 7.1.5. Onset, Duration, and Durability of Efficacy Effects .............................................. 159 7.2. Additional Efficacy Considerations ............................................................................... 161 7.2.1. Considerations on Benefit in the Postmarket Setting .......................................... 161 7.2.2. Other Relevant Benefits ........................................................................................ 162 CDER Clinical Review Template 2015 Edition 3 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4079314 Clinical Review Michael C. Davis, MD, PhD and Brian J. Miller, MD, MBA, MPH NDA 209241 Ingrezza (valbenazine) 7.3. Integrated Assessment of Effectiveness ...................................................................... 162 8 Review of Safety .................................................................................................................. 164 8.1. Safety Review Approach .............................................................................................. 164 8.2. Review of the Safety Database .................................................................................... 167 8.2.1. Overall Exposure ................................................................................................... 174 8.2.2. Relevant characteristics of the safety population: ............................................... 175 8.2.3. Adequacy of the safety database: .......................................................................
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