CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

208082Orig1s000

MEDICAL REVIEW(S) CLINICAL REVIEW

2ND REVIEW CYCLE – COMPLETE RESPONSE

Application Type NDA 505(b)(2) Application Number 208082 Priority or Standard Class 2 Resubmission

Submit Date 2016 October 03 Received Date 2016 October 03 PDUFA Goal Date 2017 April 03 Division / Office DNP / ODE1 / OND

Reviewer Name(s) Kenneth Bergmann, MD Review Completion Date 2017 February 27

Established Name Deutetrabenazine (SD-809) (Proposed) Trade Name Austedo Therapeutic Class VMAT2 inhibitor Applicant Teva Pharmaceuticals, Inc.

Formulation Oral tablets: 6, 9, and12 mg Dosing Regimen Up to 24 mg BID Indication Treatment of chorea in Intended Population Huntington’s Disease

Reference ID: 4071773 Clinical Review Kenneth Bergmann, MD NDA 208082 Austedo (deutetrabenazine)

Table of Contents

1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ...... 6 1.1 Recommendation on Regulatory Action ...... 6 1.2 Risk Benefit Assessment ...... 6 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7 1.4 Recommendations for Postmarket Requirements and Commitments ...... 7 2 INTRODUCTION AND REGULATORY BACKGROUND ...... 7 2.1 Product Information ...... 7 2.5 Presubmission Regulatory Activity Related to Class 2 Resubmission ...... 7 3 ETHICS AND GOOD CLINICAL PRACTICES ...... 9 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ...... 9 4.4 Clinical Pharmacology ...... 9 5 SOURCES OF CLINICAL DATA...... 10 5.1 Tables of Studies/Clinical Trials ...... 10 5.2 Review Strategy ...... 10 6 REVIEW OF EFFICACY ...... 10 Efficacy Summary ...... 10 7 REVIEW OF SAFETY ...... 11 Safety Summary ...... 11 7.1 Methods ...... 12 7.1.1 Studies/Clinical Trials Used to Evaluate Safety ...... 12 7.1.2 Categorization of Adverse Events ...... 12 7.2 Adequacy of Safety Assessments ...... 13 7.2.1 Overall Exposure at Appropriate Doses/Durations ...... 14 7.3 Major Safety Results ...... 18 7.3.1 Deaths ...... 18 7.3.2 Serious Adverse Events ...... 19 7.3.3 Dropouts and/or Discontinuations ...... 20 7.3.4 Significant Adverse Events ...... 22 7.3.5 Submission Specific Primary Safety Concerns ...... 23 7.4 Supportive Safety Results ...... 26 7.4.1 Common Adverse Events ...... 26 7.4.2 Laboratory Findings ...... 28 7.4.3 Vital Signs ...... 28 7.4.4 Electrocardiograms (ECGs) ...... 29 7.6 Additional Safety Evaluations ...... 29 7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ...... 29

2 Reference ID: 4071773 Clinical Review Kenneth Bergmann, MD NDA 208082 Austedo (deutetrabenazine)

9 APPENDICES ...... 32 9.2 Labeling Recommendations ...... 32

APPEARS THIS WAY ON ORIGINAL

3 Reference ID: 4071773 Clinical Review Kenneth Bergmann, MD NDA 208082 Austedo (deutetrabenazine)

Table of Tables

Table 1 Clinical Studies (source: Complete Response Safety Update, page 16) ...... 10 Table 2 Duration of Exposure to SD-809 in combined Studies C-15 and C-16 in the first cycle review ...... 14 Table 3 Study C-16 Patients remaining in the study by visit week ...... 15 Table 4 Study C-16 Tally of important Treatment Emergent Adverse Events ...... 18 Table 5 Study C-16 Serious Adverse Events ...... 19 Table 6 Study C-16 Drop-outs and discontinuations (CR Safety Update, p 26) ...... 21 Table 7 Study C-16 Adverse events leading to discontinuation ...... 21 Table 8 Study C-16 Adverse events leading to dose reduction ...... 22 Table 9 Study C-15 Sponsor's summary of psychiatric adverse events (Response to information request, 1.11.4, Table 2, p 8) ...... 24 Table 10 Study C-16 Sponsor's summary of psychiatric adverse events (Response to information request, 1.11.4, Table 3, p 9) ...... 25 Table 11 Study C-16 Moderate and severe AEs by SOC ...... 26 Table 12 Study C-16 Nervous system disorders SOC AEs ...... 26 Table 13 Study C-16 Psychiatric SOC AEs ...... 27 Table 14 Study C-16 Most frequent relevant AEs