CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213422Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 213422 Multidisciplinary Review and Evaluation WYNZORA (calcipotriene/betamethasone dipropionate) Cream, 0.005%/0.064% NDA/BLA Multidisciplinary Review and Evaluation Application Type NDA Application Number(s) 213422 Priority or Standard Standard Submit Date(s) September 20, 2019 Received Date(s) September 20, 2019 PDUFA Goal Date July 20, 2020 Division/Office Division of Dermatology and Dentistry Review Completion Date July 17, 2020 Established/Proper Name calcipotriene and betamethasone dipropionate (Proposed) Trade Name WYNZORA Pharmacologic Class Vitamin D analog/Corticosteroid Code Name MC2-01 Applicant MC2 Therapeutics Ltd (part of MC2 Therapeutics) Dosage Form Cream Applicant proposed Dosing Apply to affected areas once daily for up to 8 weeks. Regimen Therapy should be discontinued when control is achieved. Applicant Proposed For the topical treatment of plaque psoriasis in patients Indication(s)/Population(s) 18 years of age and older Applicant Proposed For the topical treatment of plaque psoriasis SNOMED CT Indication Disease Term for Each Proposed Indication Recommendation on Approval Regulatory Action Recommended Indicated for the topical treatment of plaque psoriasis in Indication(s)/Population(s) patients 18 years of age and older. (if applicable) Recommended SNOMED CT Indication Disease Term for each Indication (if applicable) Recommended Dosing Apply to affected areas once daily for up to 8 weeks. Rub in Regimen gently to ensure that the plaques are saturated with the cream. Discontinue therapy when control is achieved. i Reference ID: 46416444693884 NDA 213422 Multidisciplinary Review and Evaluation WYNZORA (calcipotriene/betamethasone dipropionate) Cream, 0.005%/0.064% Table of Contents Table of Tables....................................................................................................................5 Table of Figures...................................................................................................................8 Reviewers of Multidisciplinary Review and Evaluation ......................................................9 Signatures .........................................................................................................................10 Glossary ............................................................................................................................12 1 Executive Summary.....................................................................................................14 1.1. Product Introduction.............................................................................................14 1.2. Conclusions on the Substantial Evidence of Effectiveness ...................................14 1.3. Benefit-Risk Assessment .......................................................................................16 1.4. Patient Experience Data........................................................................................21 2 Therapeutic Context ...................................................................................................22 2.1. Analysis of Condition ............................................................................................22 2.2. Analysis of Current Treatment Options ................................................................23 3 Regulatory Background...............................................................................................33 3.1. U.S. Regulatory Actions and Marketing History....................................................33 3.2. Summary of Presubmission/Submission Regulatory Activity ...............................33 4 Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety.............................................................................36 4.1. Office of Scientific Investigations..........................................................................36 4.2. Product Quality .....................................................................................................37 4.2.1. Drug Substances ............................................................................................37 4.2.2. Drug Product..................................................................................................39 4.3. Clinical Microbiology.............................................................................................39 4.4. Devices and Companion Diagnostic Issues ...........................................................39 5 Nonclinical Pharmacology/Toxicology ........................................................................39 5.1. Executive Summary...............................................................................................39 5.2. Referenced New Drug Applications, Biologics License Applications, Drug Master Files...........................................................................................................40 5.3. Pharmacology .......................................................................................................40 5.4. Absorption, Distribution, Metabolism, Excretion/PK............................................40 5.5. Toxicology .............................................................................................................40 5.5.1. General Toxicology ........................................................................................40 5.5.2. Genetic Toxicology.........................................................................................44 5.5.3. Carcinogenicity ..............................................................................................44 5.5.4. Reproductive and Developmental Toxicology ...............................................45 ii Reference ID: 46416444693884 NDA 213422 Multidisciplinary Review and Evaluation WYNZORA (calcipotriene/betamethasone dipropionate) Cream, 0.005%/0.064% 5.5.5. Other Toxicology Studies ...............................................................................47 6 Clinical Pharmacology .................................................................................................48 6.1. Executive Summary...............................................................................................48 6.1.1. Recommendations.........................................................................................50 6.1.2. Postmarketing Requirement(s) and Commitments(s) ...................................50 6.2. Summary of Clinical Pharmacology Assessment...................................................50 6.2.1. Pharmacology and Clinical Pharmacokinetics................................................50 6.2.2. General Dosing and Therapeutic Individualization ........................................51 6.3. Comprehensive Clinical Pharmacology Review ....................................................52 6.3.1. General Pharmacology and Pharmacokinetic Characteristics .......................52 6.3.2. Clinical Pharmacology Questions...................................................................64 7 Sources of Clinical Data and Review Strategy.............................................................66 7.1. Table of Clinical Studies ........................................................................................66 7.2. Review Strategy ....................................................................................................69 8 Statistical and Clinical and Evaluation.........................................................................69 8.1. Review of Relevant Individual Trials Used to Support Efficacy .............................69 8.1.1. Study Design and Endpoints ..........................................................................69 8.1.2. Statistical Methodologies ..............................................................................73 8.1.3. Subject Disposition, Demographics, and Baseline Disease Characteristics ...............................................................................................76 8.1.4. Results of the Primary Efficacy Endpoint.......................................................78 8.1.5. Results of Secondary Efficacy Endpoints .......................................................79 8.1.6. Efficacy Over Time .........................................................................................82 8.1.7. Findings in Special/Subgroup Populations.....................................................82 8.1.8. Investigational Site.........................................................................................84 8.2. Review of Safety ...................................................................................................84 8.2.1. Safety Review Approach ................................................................................84 8.2.2. Review of the Safety Database ......................................................................85 8.2.3. Adequacy of Applicant’s Clinical Safety Assessments....................................86 8.2.4. Safety Results.................................................................................................88 8.2.5. Analysis of Submission-Specific Safety Issues................................................95 8.2.6. Clinical Outcome Assessment Analyses Informing Safety/Tolerability..........97