CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209830Orig1s000 CLINICAL REVIEW(S) Clinical Review David H. Millis, MD NDA 209830 Aripiprazole lauroxil / Aristada Initio CLINICAL REVIEW Application Type NDA Application Number(s) 209830 Priority or Standard Standard Submit Date(s) August 31, 2017 Received Date(s) August 31, 2017 PDUFA Goal Date June 30, 2018 Division/Office Division of Psychiatry Products Reviewer Name(s) David H. Millis, MD Review Completion Date June 28, 2018 Established/Proper Name aripiprazole lauroxil (Proposed) Trade Name Aristada Initio Applicant Alkermes Dosage Form(s) intramuscular Applicant Proposed Dosing 675 mg single intramuscular injection Regimen(s) Applicant Proposed initiation of treatment of schizophrenia with Aristada Indication(s)/Population(s) Recommendation on Approve Regulatory Action Recommended initiation of treatment of schizophrenia with Aristada Indication(s)/Population(s) (if applicable) 1 Reference ID: 4284747 Clinical Review David H. Millis, MD NDA 209830 Aripiprazole lauroxil / Aristada Initio Table of Contents Glossary ........................................................................................................................................... 7 1. Executive Summary ................................................................................................................. 9 Product Introduction ........................................................................................................ 9 Conclusions on the Substantial Evidence of Effectiveness ............................................ 10 Benefit-Risk Assessment ................................................................................................ 10 Patient Experience Data ................................................................................................. 15 2. Therapeutic Context .............................................................................................................. 16 Analysis of Condition ...................................................................................................... 16 Analysis of Current Treatment Options ......................................................................... 16 3. Regulatory Background ......................................................................................................... 17 U.S. Regulatory Actions and Marketing History ............................................................. 17 Summary of Presubmission/Submission Regulatory Activity ........................................ 17 Foreign Regulatory Actions and Marketing History ....................................................... 18 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 18 Office of Scientific Investigations (OSI) .......................................................................... 18 Product Quality .............................................................................................................. 18 Clinical Microbiology ...................................................................................................... 19 Nonclinical Pharmacology/Toxicology ........................................................................... 19 Clinical Pharmacology .................................................................................................... 20 Devices and Companion Diagnostic Issues .................................................................... 21 Consumer Study Reviews ............................................................................................... 21 5. Sources of Clinical Data and Review Strategy ....................................................................... 21 Clinical Studies ................................................................................................................ 22 Review Strategy .............................................................................................................. 22 6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 22 Study ALK9072-B101 (short name: B101) ...................................................................... 22 Study Design............................................................................................................ 22 2 Reference ID: 4284747 Clinical Review David H. Millis, MD NDA 209830 Aripiprazole lauroxil / Aristada Initio Study Results ........................................................................................................... 27 Study ALK9072-B102 (short name: B102) ...................................................................... 29 Study Design............................................................................................................ 29 Study Results ........................................................................................................... 35 Study ALK9072-B103 (short name: B103) ...................................................................... 39 Study Design............................................................................................................ 39 Study Results ........................................................................................................... 42 7. Integrated Review of Effectiveness ....................................................................................... 44 Assessment of Efficacy Across Trials .............................................................................. 44 8. Review of Safety .................................................................................................................... 44 Safety Review Approach ................................................................................................ 44 Review of the Safety Database ...................................................................................... 45 Overall Exposure ..................................................................................................... 45 Relevant characteristics of the safety population:................................................. 46 Adequacy of the safety database: .......................................................................... 48 Adequacy of Applicant’s Clinical Safety Assessments .................................................... 48 Issues Regarding Data Integrity and Submission Quality ....................................... 48 Categorization of Adverse Events ........................................................................... 49 Routine Clinical Tests .............................................................................................. 49 Safety Results ................................................................................................................. 49 Deaths ..................................................................................................................... 49 Serious Adverse Events ........................................................................................... 50 Dropouts and/or Discontinuations Due to Adverse Effects ................................... 51 Significant Adverse Events ...................................................................................... 52 Treatment Emergent Adverse Events and Adverse Reactions ............................... 52 Laboratory Findings ................................................................................................ 56 Vital Signs ................................................................................................................ 61 Electrocardiograms (ECGs) ...................................................................................... 62 QT ............................................................................................................................ 62 Immunogenicity ............................................................................................... 64 3 Reference ID: 4284747 Clinical Review David H. Millis, MD NDA 209830 Aripiprazole lauroxil / Aristada Initio Analysis of Submission-Specific Safety Issues ................................................................ 64 Injection Site Reactions ........................................................................................... 64 Abnormal Movement Scales ................................................................................... 65 Columbia-Suicide Severity Rating Scale .................................................................. 65 Safety Analyses by Demographic Subgroups ................................................................. 66 Specific Safety Studies/Clinical Trials ............................................................................. 66 Additional Safety Explorations ....................................................................................... 66 Human Carcinogenicity or Tumor Development .................................................... 66 Human Reproduction and Pregnancy ..................................................................... 66 Pediatrics and Assessment of Effects on Growth ................................................... 66 Overdose, Drug Abuse Potential, Withdrawal, and Rebound ................................ 66 Safety in the Postmarket Setting.................................................................................... 66 Safety