CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207695Orig1s000 MEDICAL REVIEW(S) Clinical Review Melinda L McCord NDA 207695 EUCRISA (crisaborole) ointment, 2% CLINICAL REVIEW Application Type NDA Application Number(s) 207695 Priority or Standard Standard Submit Date(s) 01/07/2016 Received Date(s) 01/07/2016 PDUFA Goal Date 01/06/2017 Division/Office DDDP Reviewer Name(s) Melinda McCord, MD Review Completion Date 09/07/2016 Established Name Crisaborole ointment, 2% (Proposed) Trade Name EUCRISA Applicant Anacor Pharmaceuticals Inc. Formulation(s) Ointment Dosing Regimen Apply twice daily Applicant Proposed Treatment of mild to moderate atopic dermatitis in patients 2 Indication(s)/Population(s) years and older Recommendation on Approval Regulatory Action Recommended Treatment of mild to moderate atopic dermatitis in patients 2 Indication(s)/Population(s) years of age and older. (if applicable) CDER Clinical Review Template 2015 Edition 1 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 3983007 Clinical Review Melinda L McCord NDA 207695 EUCRISA (crisaborole) ointment, 2% 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 2 Therapeutic Context..............................................................................................................20 2.1. Analysis of Condition......................................................................................................20 2.2. Analysis of Current Treatment Options .........................................................................21 3 Regulatory Background .........................................................................................................26 3.1. U.S. Regulatory Actions and Marketing History.............................................................26 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................26 3.3. Foreign Regulatory Actions and Marketing History .......................................................28 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................28 4.1. Office of Scientific Investigations (OSI) ..........................................................................29 4.2. Product Quality ..............................................................................................................30 4.3. Clinical Microbiology......................................................................................................34 4.4. Nonclinical Pharmacology/Toxicology ...........................................................................34 4.5. Clinical Pharmacology ....................................................................................................37 4.5.1. Mechanism of Action..............................................................................................40 4.5.2. Pharmacodynamics.................................................................................................41 4.5.3. Pharmacokinetics....................................................................................................42 4.6. Devices and Companion Diagnostic Issues ....................................................................45 4.7. Consumer Study Reviews...............................................................................................45 5 Sources of Clinical Data and Review Strategy .......................................................................45 5.1. Table of Clinical Studies .................................................................................................45 5.2. Review Strategy .............................................................................................................51 6 Review of Relevant Individual Trials Used to Support Efficacy .............................................51 CDER Clinical Review Template 2015 Edition 2 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 3983007 Clinical Review Melinda L McCord NDA 207695 EUCRISA (crisaborole) ointment, 2% 6.1. Trial AN2728-AD-301 ..................................................................................................51 “A Multicenter, Randomized, Double-Blind, Vehicle-Controlled Study of the Safety and Efficacy of AN2728 Topical Ointment, 2% in Children, Adolescents, and Adults (Ages 2 Years and Older) With Atopic Dermatitis” .........................................................................................51 6.1.1. Study Design ...........................................................................................................51 6.1.2. Study Results ..........................................................................................................65 6.2. Trial AN2728-AD-302 .....................................................................................................78 “A Multicenter, Randomized, Double-Blind, Vehicle-Controlled Study of the Safety and Efficacy of AN2728 Topical Ointment, 2% in Children, Adolescents, and Adults (Ages 2 Years and Older) With Atopic Dermatitis.” ........................................................................................78 6.2.1. Study Design ...........................................................................................................78 6.2.2. Study Results ..........................................................................................................81 7 Integrated Review of Effectiveness.......................................................................................87 7.1. Assessment of Efficacy Across Trials..............................................................................87 7.1.1. Primary Endpoints ..................................................................................................87 7.1.2. Secondary and Other Endpoints.............................................................................88 7.1.3. Subpopulations.......................................................................................................90 7.1.4. Dose and Dose-Response .......................................................................................91 7.1.5. Onset, Duration, and Durability of Efficacy Effects.................................................94 7.1.6. Considerations on Benefit in the Postmarket Setting.............................................94 7.1.7. Other Relevant Benefits..........................................................................................95 7.2. Integrated Assessment of Effectiveness ........................................................................95 8 Review of Safety....................................................................................................................97 8.1. Safety Review Approach ................................................................................................97 8.2. Review of the Safety Database ......................................................................................98 8.2.1. Overall Exposure.....................................................................................................98 8.2.2. Relevant characteristics of the safety population: ...............................................100 8.2.3. Adequacy of the safety database .........................................................................101 8.3. Adequacy of Applicant’s Clinical Safety Assessments..................................................101 8.3.1. Issues Regarding Data Integrity and Submission Quality......................................101 8.3.2. Categorization of Adverse Events.........................................................................101 CDER Clinical Review Template 2015 Edition 3 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 3983007 Clinical Review Melinda L McCord NDA 207695 EUCRISA (crisaborole) ointment, 2% 8.3.3. Routine Clinical Tests............................................................................................103 8.4. Safety Results...............................................................................................................108 8.4.1. Deaths...................................................................................................................108 8.4.2. Serious Adverse Events.........................................................................................108 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects..................................118 8.4.4. Significant Adverse Events....................................................................................123 8.4.5. Treatment Emergent Adverse Events and Adverse Reactions .............................125 8.4.6. Laboratory Findings ..............................................................................................127