CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213793Orig1s000 CLINICAL REVIEW(S) Clinical Review Ovidiu Galescu NDA213793 IMCIVREE (setmelanotide) injection CLINICAL REVIEW Application Type NDA Application Number(s) 213793 Priority or Standard Priority Submit Date(s) 2020-03-27 Received Date(s) 2020-03-27 PDUFA Goal Date 2020-11-24 Division/Office DDLO/OCHEN Reviewer Name(s) Ovidiu Galescu Review Completion Date 2020-11-23 Established Name Setmelanotide (RM-493) (Proposed) Trade Name IMCIVREE (setmelanotide) injection Applicant Rhythm Pharmaceuticals, Inc. Formulation(s) 10mg/mL solution Dosing Regimen 1mg to 3mg once daily subcutaneous injection Applicant Proposed Indicated for the treatment of obesity (b) (4) Indication(s)/Population(s) associated with pro-opiomelanocortin (POMC), including PCSK1, deficiency obesity or leptin receptor (LEPR) deficiency obesity Recommendation on approval Regulatory Action Recommended adults and children 6 years of age and older with obesity due to Indication(s)/Population(s) POMC, PCSK1 deficiency or LEPR deficiency (if applicable) CDER Clinical Review Template 2015 Edition 1 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4706637 Clinical Review Ovidiu Galescu NDA213793 IMCIVREE (setmelanotide) injection Table of Contents Glossary ........................................................................................................................................15 1 Executive Summary...............................................................................................................17 1.1. Product Introduction......................................................................................................17 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................18 1.3. Benefit-Risk Assessment ................................................................................................18 2 Therapeutic Context..............................................................................................................27 2.1. Analysis of Condition......................................................................................................27 2.2. Analysis of Current Treatment Options .........................................................................30 3 Regulatory Background .........................................................................................................32 3.1. U.S. Regulatory Actions and Marketing History.............................................................32 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................32 3.3. Foreign Regulatory Actions and Marketing History .......................................................36 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................36 4.1. Office of Scientific Investigations (OSI) ..........................................................................37 4.2. Product Quality ..............................................................................................................37 4.3. Clinical Microbiology......................................................................................................39 4.4. Nonclinical Pharmacology/Toxicology ...........................................................................40 4.5. Clinical Pharmacology ....................................................................................................40 4.5.1. Mechanism of Action..............................................................................................40 4.5.2. Pharmacodynamics.................................................................................................41 4.5.3. Pharmacokinetics....................................................................................................41 4.6. Devices and Companion Diagnostic Issues ....................................................................41 4.7. Consumer Study Reviews...............................................................................................42 5 Sources of Clinical Data and Review Strategy .......................................................................42 5.1. Table of Clinical Studies .................................................................................................42 5.2. Review Strategy .............................................................................................................46 6 Review of Relevant Individual Trials Used to Support Efficacy .............................................46 CDER Clinical Review Template 2015 Edition 2 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4706637 Clinical Review Ovidiu Galescu NDA213793 IMCIVREE (setmelanotide) injection 6.1. RM-493-012 ...................................................................................................................48 6.1.1. Study Design ...........................................................................................................48 6.1.2. Study Results ..........................................................................................................61 6.2. [Insert Study Name] .......................................................................................................77 6.2.1. Study Design ...........................................................................................................77 6.2.2. Study Results ..........................................................................................................77 6.3.............................................................................................................................................78 6.4.............................................................................................................................................78 7 Integrated Review of Effectiveness.......................................................................................78 7.1. Assessment of Efficacy Across Trials..............................................................................79 7.1.1. Primary Endpoints ..................................................................................................79 7.1.2. Secondary and Other Endpoints.............................................................................80 7.1.3. Subpopulations.......................................................................................................80 7.1.4. Dose and Dose-Response .......................................................................................81 7.1.5. Onset, Duration, and Durability of Efficacy Effects.................................................82 7.2. Additional Efficacy Considerations.................................................................................82 7.2.1. Considerations on Benefit in the Postmarket Setting.............................................82 7.2.2. Other Relevant Benefits..........................................................................................83 7.3. Integrated Assessment of Effectiveness ........................................................................83 8 Review of Safety....................................................................................................................86 8.1. Safety Review Approach ................................................................................................87 8.2. Review of the Safety Database ......................................................................................88 8.2.1. Overall Exposure.....................................................................................................89 8.2.2. Relevant characteristics of the safety population: .................................................90 8.2.3. Adequacy of the safety database: ..........................................................................91 8.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................91 8.3.1. Issues Regarding Data Integrity and Submission Quality........................................91 8.3.2. Categorization of Adverse Events...........................................................................92 8.3.3. Routine Clinical Tests..............................................................................................94 8.4. Safety Results.................................................................................................................95 8.4.1. Deaths.....................................................................................................................97 CDER Clinical Review Template 2015 Edition 3 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 4706637 Clinical Review Ovidiu Galescu NDA213793 IMCIVREE (setmelanotide) injection 8.4.2. Serious Adverse Events...........................................................................................98 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects....................................98 8.4.4. Significant Adverse Events......................................................................................98 8.4.5. Treatment Emergent Adverse Events and Adverse Reactions ...............................99 8.4.6. Laboratory Findings ..............................................................................................100