CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211765Orig1s000 CLINICAL REVIEW(S) Clinical Review Laura Jawidzik, MD NDA 211765 Ubrogepant/UBRELVY CLINICAL REVIEW Application Type NDA Application Number(s) 211765 Priority or Standard Standard Submit Date(s) 12/26/2018 Received Date(s) 12/26/2018 PDUFA Goal Date 12/26/2019 Division/Office Division of Neurology Products/Office of New Drugs Reviewer Name(s) Laura Jawidzik, MD Review Completion Date 12/19/2019 Established/Proper Name Ubrogepant (Proposed) Trade Name Ubrelvy Applicant Allergan Sales, LLC Dosage Form(s) Tablet Applicant Proposed Dosing 50 mg or 100 mg orally; a second dose may be administered at Regimen(s) least 2 hours after the initial dose; maximum 200 mg daily Applicant Proposed Acute treatment of migraine with or without aura Indication(s)/Population(s) Recommendation on Approval of 25 mg, 50 mg, and 100 mg Regulatory Action Recommended Treatment of acute migraine with or without aura in adults Indication(s)/Population(s) (if applicable) 1 Reference ID: 4533406 Clinical Review Laura Jawidzik, MD NDA 211765 Ubrogepant/UBRELVY Table of Contents Glossary ........................................................................................................................................10 1. Executive Summary ...............................................................................................................13 1.1. Product Introduction......................................................................................................13 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................13 1.3. Benefit-Risk Assessment ................................................................................................13 1.4. Patient Experience Data.................................................................................................19 2. Therapeutic Context..............................................................................................................20 2.1. Analysis of Condition......................................................................................................20 2.2. Analysis of Current Treatment Options .........................................................................20 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 .......................................................23 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................23 4.1. Office of Scientific Investigations (OSI) ..........................................................................23 4.2. Product Quality ..............................................................................................................23 4.3. Nonclinical Pharmacology/Toxicology ...........................................................................23 4.4. Clinical Pharmacology ....................................................................................................24 4.5. Devices and Companion Diagnostic Issues ....................................................................24 4.6. Consumer Study Reviews...............................................................................................24 5. Sources of Clinical Data and Review Strategy .......................................................................24 5.1. Table of Clinical Studies .................................................................................................24 5.2. Review Strategy .............................................................................................................26 6. Review of Relevant Individual Trials Used to Support Efficacy .............................................26 6.1. UBR-MD-01: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Single Attack Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of Migraine ...................................................................................................26 2 Reference ID: 4533406 Clinical Review Laura Jawidzik, MD NDA 211765 Ubrogepant/UBRELVY 6.1.1. Study Design ...........................................................................................................26 6.1.2. Study Results ..........................................................................................................34 6.2 UBR-MD-02: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Single Attack Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of Migraine ...................................................................................................46 6.2.1. Study Design ...........................................................................................................46 6.2.2. Study Results ..........................................................................................................46 7. Integrated Review of Effectiveness.......................................................................................57 7.1. Assessment of Efficacy Across Trials ..............................................................................57 7.1.1. Primary Endpoints ..................................................................................................57 7.1.2. Secondary and Other Endpoints .............................................................................58 7.1.3. Subpopulations .......................................................................................................59 7.1.4. Dose and Dose-Response .......................................................................................62 7.1.5. Onset and Durability of Efficacy Effects..................................................................62 7.2. Additional Efficacy Considerations.................................................................................65 7.2.1. Considerations on Benefit in the Postmarket Setting.............................................65 7.3. Integrated Assessment of Effectiveness ........................................................................65 8. Review of Safety....................................................................................................................66 8.1. Safety Review Approach ................................................................................................66 8.2. Review of the Safety Database ......................................................................................68 8.2.1. Overall Exposure.....................................................................................................68 8.2.2. Relevant characteristics of the safety population: .................................................71 8.2.3. Adequacy of the safety database: ..........................................................................72 8.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................72 8.3.1. Issues Regarding Data Integrity and Submission Quality........................................72 8.3.2. Categorization of Adverse Events...........................................................................72 8.3.3. Routine Clinical Tests..............................................................................................73 8.4. Safety Results.................................................................................................................74 8.4.1. Deaths.....................................................................................................................74 8.4.2. Serious Adverse Events...........................................................................................74 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects....................................80 3 Reference ID: 4533406 Clinical Review Laura Jawidzik, MD NDA 211765 Ubrogepant/UBRELVY 8.4.4. Significant Adverse Events......................................................................................82 8.4.5. Treatment Emergent Adverse Events and Adverse Reactions ...............................83 8.4.6. Laboratory Findings ................................................................................................88 8.4.7. Vital Signs................................................................................................................92 8.4.8. Electrocardiograms (ECGs) .....................................................................................98 8.4.9. QT .........................................................................................................................100 8.4.10. Immunogenicity.............................................................................................100 8.5. Analysis of Submission-Specific Safety Issues ..............................................................101 8.5.1. Cardiovascular, Cerebrovascular, and Peripheral Vascular Disease .....................101 8.5.2. Hepatotoxic Effects...............................................................................................105