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Pimavanserin) NUPLAZID™ (pimavanserin) SPONSOR BACKGROUND INFORMATION FOR A MEETING OF THE PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE ON 29 MARCH 2016 ACADIA Pharmaceuticals Inc. San Diego, CA, USA Advisory Committee Briefing Materials: Available for Public Release NUPLAZID™ Advisory Committee Briefing Document Table of Contents List of Tables............................................................................................................................. 4 List of Figures ........................................................................................................................... 7 Abbreviations and Acronyms.................................................................................................. 9 1 Executive Summary ................................................................................................... 13 2 Pimavanserin for the Treatment of Parkinson’s Disease Psychosis ...................... 20 3 Parkinson’s Disease Psychosis: Significant Unmet Medical Need ....................... 21 3.1 Parkinson’s Disease and Associated Psychosis ............................................................. 21 3.2 Parkinson’s Disease Psychosis Prevalence, Evaluation, and Symptomatology ......... 21 3.3 Impact of Parkinson’s Disease Psychosis on Patient Morbidity ................................. 23 3.4 Impact of Parkinson’s Disease Psychosis on Caregivers ............................................. 24 3.5 Impact of Parkinson’s Disease Psychosis on Nursing Home Placement .................... 24 3.6 Management of Parkinson’s Disease Psychosis ............................................................ 25 4 Pimavanserin Product Description and Regulatory History ................................. 28 4.1 Product Description ........................................................................................................ 28 4.2 Pimavanserin Regulatory History ................................................................................. 28 5 Pimavanserin Pharmacology and Nonclinical Development ................................. 30 5.1 Targeted Pharmacologic Approach to Treatment of Psychotic Symptoms in Parkinson’s Disease ........................................................................................................ 30 5.2 Pimavanserin’s In Vivo Pharmacodynamic Profile ..................................................... 31 5.3 Safety Pharmacology ...................................................................................................... 32 5.4 Nonclinical Toxicology Summary .................................................................................. 32 5.5 Pimavanserin ADME Properties ................................................................................... 34 6 Pimavanserin Clinical Pharmacology ...................................................................... 35 6.1 Pharmacokinetic Properties ........................................................................................... 35 6.2 Drug-Drug Interactions .................................................................................................. 36 7 Overview of Clinical Development Program ........................................................... 38 8 Efficacy Studies and Results ..................................................................................... 41 8.1 Controlled Phase 2 and Phase 2b/3 Studies .................................................................. 41 8.1.1 Phase 2 Study 006 ........................................................................................................ 41 8.1.2 Phase 2b/3 Study 012 ................................................................................................... 42 8.1.3 Phase 2b/3 Study 014 ................................................................................................... 48 8.2 Key Learnings from Phase 2b/3 Studies Taken into Further Development .............. 50 8.3 Pivotal Study 020 ............................................................................................................. 51 8.3.1 Pivotal Study 020 Design, Endpoints, and Statistical Analyses .................................. 51 8.3.1.1 Study 020 Design and Patient Population............................................................................51 8.3.1.1.1 Study 020 Primary Endpoint SAPS-PD ..........................................................................52 8.3.1.1.2 Secondary Endpoints ......................................................................................................54 ACADIA Pharmaceuticals Inc. Page 2 of 173 NUPLAZID™ Advisory Committee Briefing Document 8.3.1.1.3 Exploratory Efficacy Measures .......................................................................................55 8.3.1.1.4 Statistical Analyses .........................................................................................................56 8.3.2 Efficacy Results for Study 020: Pivotal Phase 3 Trial ................................................ 57 8.3.2.1 Disposition, Demographics and Baseline Characteristics ...................................................57 8.3.2.2 Primary Efficacy Analysis ...................................................................................................59 8.3.2.3 Efficacy Sensitivity Analyses ..............................................................................................61 8.3.2.4 Secondary Efficacy Endpoints .............................................................................................64 8.3.2.4.1 Key Secondary Analysis (UPDRS Parts II+III) ..............................................................64 8.3.2.4.2 Secondary Efficacy Endpoints – CGI-S and CGI-I ........................................................65 8.3.2.5 Exploratory Measures for Caregiver Burden and Sleep ......................................................66 8.3.2.5.1 Caregiver Burden as Measured by the 22-Item Zarit Caregiver Burden Scale ...............66 8.3.2.5.2 SCOPA-Sleep Endpoints ................................................................................................67 8.3.2.6 Responder Analyses ............................................................................................................68 8.3.2.7 Clinical Importance and Consistency of Efficacy Results from Study 020 .........................71 8.3.2.7.1 Clinical Context of the Effect Size Observed .................................................................71 8.3.2.7.2 Consistency of Results across Multiple Efficacy Measures and Different Reporters/Raters.................................................................................................................................71 8.3.2.7.3 Sensitivity and Confirmatory Efficacy Analyses ............................................................74 8.3.2.8 Study 020 Efficacy Summary ..............................................................................................74 8.4 Efficacy Data from the Long-Term Open-Label Studies ............................................ 75 8.5 Pimavanserin Efficacy Conclusions .............................................................................. 77 9 Safety Data.................................................................................................................. 78 9.1 Overall Clinical Safety Exposure ................................................................................... 78 9.2 Pimavanserin Exposure in the Safety Analysis Population ......................................... 78 9.2.1 Safety Analysis Populations ......................................................................................... 79 9.3 Review of Adverse Events from the Non-PDP studies ................................................. 80 9.4 PD Psychosis Placebo-Controlled, 6-Week Studies (PDP6 Population) ..................... 81 9.4.1 Demographics and Other Characteristics (PDP6 Population) ...................................... 81 9.4.2 Adverse Events (PDP6 Population) ............................................................................. 82 9.4.2.1 Most Frequent Treatment-Emergent Adverse Events ..........................................................82 9.4.2.2 Adverse Events Leading to Discontinuation .......................................................................84 9.4.2.3 Serious Adverse Events .......................................................................................................86 9.4.2.4 Deaths ..................................................................................................................................87 9.4.3 Clinical Laboratory Evaluations (PDP6 Population) ................................................... 89 9.4.4 Vital Signs and Physical Findings (PDP6 Population) ................................................ 91 9.5 PD Psychosis Open-Label, Long-Term Studies (PDPLT Population) ....................... 92 9.5.1 Demographics and Other Characteristics (PDPLT Population) ................................... 92 9.5.2 Duration of Subject Participation (PDPLT Population) ............................................... 94 9.5.3 Adverse Events (PDPLT Population) .......................................................................... 94 9.5.3.1 Most Frequent Treatment-Emergent Adverse Events ..........................................................94 9.5.3.2 Adverse Events Leading to Discontinuation .......................................................................95 9.5.3.3 Serious Adverse Events .......................................................................................................96
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