CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207318Orig1s000 MEDICAL REVIEW(S) Clinical Review Paul J. Andreason, MD NDA 207-318 Nuplazid® (pimavanserin) CLINICAL REVIEW Application Type NDA Application Number(s) 207318 Priority or Standard Priority Submit Date(s) 1 September 2015 Received Date(s) 1 September 2015 PDUFA Goal Date Division/Office Division of Psychiatry Products Reviewer Name(s) Paul J. Andreason MD Review Completion Date 3 February 2016 Established Name Pimavanserin (Proposed) Trade Name Nuplazid® Applicant ACADIA Pharmaceuticals Inc Formulation(s) 17mg coated tablet Dosing Regimen 34mg PO daily Proposed Indication(s) Psychosis associated with Parkinson’s disease Intended Population(s) Adults with Parkinson’s Disease Recommendation on Do not approve, Complete response 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: 3882135 Clinical Review Paul J. Andreason, MD NDA 207-318 Nuplazid® (pimavanserin) Table of Contents Glossary ........................................................................................................................................... 9 1 Executive Summary ............................................................................................................... 11 1.1. Product Introduction ...................................................................................................... 11 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 11 1.3. Benefit-Risk Assessment ................................................................................................ 12 2 Therapeutic Context .............................................................................................................. 20 2.1. Analysis of Condition ...................................................................................................... 20 2.2. Analysis of Current Treatment Options ......................................................................... 21 3 Regulatory Background ......................................................................................................... 22 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 22 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 22 3.3. Foreign Regulatory Actions and Marketing History ....................................................... 24 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 24 4.1. Office of Scientific Investigations (OSI) .......................................................................... 24 4.2. Product Quality .............................................................................................................. 25 4.3. Clinical Microbiology ...................................................................................................... 25 4.4. Nonclinical Pharmacology/Toxicology ........................................................................... 25 4.5. Clinical Pharmacology .................................................................................................... 26 4.5.1. Mechanism of Action .............................................................................................. 26 4.5.2. Pharmacodynamics ................................................................................................. 26 4.5.3. Pharmacokinetics .................................................................................................... 26 4.6. Devices and Companion Diagnostic Issues .................................................................... 26 4.7. Consumer Study Reviews ............................................................................................... 27 5 Sources of Clinical Data and Review Strategy ....................................................................... 27 5.1. Table of Clinical Studies .................................................................................................. 27 5.2. Review Strategy .............................................................................................................. 31 CDER Clinical Review Template 2015 Edition 2 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 3882135 Clinical Review Paul J. Andreason, MD NDA 207-318 Nuplazid® (pimavanserin) 5.3. ACP-103-020 A Multi-Center, Placebo-Controlled, Double-Blind Trial to Examine the Safety and Efficacy of Pimavanserin in the Treatment of Psychosis in Parkinson’s Disease ... 32 5.3.1. Study Design............................................................................................................ 32 5.3.2. Study Results ........................................................................................................... 41 5.4. ACP 103-012 A Multi-Center, Placebo-Controlled, Double-Blind Trial to Examine the Safety and Efficacy of ACP-103 in the Treatment of Psychosis in Parkinson’s Disease............ 54 5.4.1. Study Design............................................................................................................ 54 5.4.2. Study Results ........................................................................................................... 57 5.5. ACP 103-014 A Multi-Center, Placebo-Controlled, Double-Blind Trial to Examine the Safety and Efficacy of ACP-103 in the Treatment of Psychosis in Parkinson’s Disease............ 59 5.5.1. Study Design............................................................................................................ 59 5.5.2. Study Results ........................................................................................................... 62 5.6. ACP 103-006 Phase 2, Multi-Center, Placebo-Controlled, Double-Blind Trial of ACP-103 in the Treatment of Psychosis in Parkinson’s Disease .............................................................. 64 5.6.1. Study Design............................................................................................................ 64 5.6.2. Study Results ........................................................................................................... 67 6 Integrated Review of Effectiveness ....................................................................................... 70 6.1. Assessment of Efficacy Across Trials .............................................................................. 70 6.1.1. Primary Endpoints ................................................................................................... 70 6.1.2. Secondary and Other Endpoints ............................................................................. 72 6.1.3. Subpopulations ....................................................................................................... 72 6.1.4. Dose and Dose-Response........................................................................................ 72 6.1.5. Onset, Duration, and Durability of Efficacy Effects ................................................ 73 6.2. Additional Efficacy Considerations ................................................................................. 73 6.2.1. Considerations on Benefit in the Postmarket Setting ............................................ 74 6.2.2. Other Relevant Benefits .......................................................................................... 77 6.3. Integrated Assessment of Effectiveness ........................................................................ 77 7 Review of Safety .................................................................................................................... 78 7.1. Safety Review Approach ................................................................................................ 78 7.2. Review of the Safety Database ...................................................................................... 79 7.2.1. Overall Exposure ..................................................................................................... 79 CDER Clinical Review Template 2015 Edition 3 Version date: April 9, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 3882135 Clinical Review Paul J. Andreason, MD NDA 207-318 Nuplazid® (pimavanserin) 7.2.2. Relevant characteristics of the safety population: ................................................. 80 7.2.3. Adequacy of the safety database: .......................................................................... 83 7.3. Adequacy of Applicant’s Clinical Safety Assessments .................................................... 84 7.3.1. Issues Regarding Data Integrity and Submission Quality ....................................... 84 7.3.2. Categorization of Adverse Events ........................................................................... 84 7.3.3. Routine Clinical Tests .............................................................................................. 85 7.4. Safety Results ................................................................................................................. 88 7.4.1. Deaths ..................................................................................................................... 88 7.4.2. Serious Adverse Events