CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213026Orig1s000 CLINICAL REVIEW(S) Clinical Review David Hosford, Xiang Ling, Thomas Biel, Ashutosh Rao NDA 213,026: casimersen for DMD amenable to exon 45 skipping CLINICAL REVIEW Application Type NME, original NDA Application Number(s) NDA 213,026 (IND 118,086) Priority or Standard Priority Submit Date(s) 1/10/20 (submission 1 [clinical, nonclinical]) 6/25/20 (submission 2 [quality, complete NDA]) Received Date(s) 1/10/20; 6/25/20 PDUFA Goal Date 2/25/21 Division/Office DN1 / ON / OND / CDER Reviewer Name(s) David Hosford, ; Xiang Ling (Biometrics); Thomas Biel, Ashutosh Rao (Office of Biotechnology Products [OBP]) Review Completion Date 2/15/21 Established/Proper Name Casimersen (Proposed) Trade Name Amondys 45 Applicant Sarepta Therapeutics, Inc. (Cambridge, MA) Dosage Form(s) concentrated solution in a single use-vial for IV infusion Applicant Proposed Dosing 30mg/kg weekly Regimen(s) Applicant Proposed For the treatment of Duchenne muscular dystrophy (DMD) in Indication(s)/Population(s) patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping Recommendation on Accelerated Approval Regulatory Action Recommended For the treatment of Duchenne muscular dystrophy (DMD) in Indication(s)/Population(s) patients who have a confirmed mutation of the DMD gene that (if applicable) is amenable to exon 45 skipping 1 Reference ID: 4751845 Clinical Review David Hosford, Xiang Ling, Thomas Biel, Ashutosh Rao NDA 213,026: casimersen for DMD amenable to exon 45 skipping Table of Contents Glossary ........................................................................................................................................11 1. Executive Summary...............................................................................................................14 1.1. Product Introduction......................................................................................................14 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................15 1.3. Benefit-Risk Assessment ................................................................................................16 1.4. Patient Experience Data.................................................................................................25 2. Therapeutic Context..............................................................................................................25 2.1. Analysis of Condition......................................................................................................26 2.2. Analysis of Current Treatment Options .........................................................................27 3. Regulatory Background .........................................................................................................32 3.1. U.S. Regulatory Actions and Marketing History.............................................................32 3.2. Summary of Pre-submission/Submission Regulatory Activity .......................................32 3.2.1. PIND Meeting (minutes issued 6/11/13) ................................................................33 3.2.2. Fast Track Designation Granted..............................................................................33 3.2.3. Type A Meeting (minutes issued 11/18/14) ...........................................................33 3.2.4. Partial Clinical Hold Letter (letter issued 11/9/15) .................................................34 3.2.5. Type C Meeting (minutes issued 2/15/18) .............................................................34 3.2.6. Type C Meeting (minutes issued 8/23/18) .............................................................34 3.2.7. Orphan Drug Designation .......................................................................................35 3.2.8. Pre-NDA Meeting (minutes issued 6/27/19) ..........................................................35 3.2.9. Rolling Review Granted ..........................................................................................35 3.2.10. Proprietary Name Granted..............................................................................35 3.2.11. Priority Review Granted ..................................................................................36 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) ..........................................................................36 4.2. Office of Product Quality (OPQ).....................................................................................36 4.3. Clinical Microbiology......................................................................................................37 2 Reference ID: 4751845 Clinical Review David Hosford, Xiang Ling, Thomas Biel, Ashutosh Rao NDA 213,026: casimersen for DMD amenable to exon 45 skipping 4.4. Nonclinical Pharmacology/Toxicology ...........................................................................37 4.5. Clinical Pharmacology ....................................................................................................37 4.6. Devices and Companion Diagnostic Issues ....................................................................39 4.7. Consumer Study Reviews...............................................................................................39 5. Sources of Clinical Data and Review Strategy .......................................................................39 5.1. Table of Clinical Studies .................................................................................................39 5.1.1. Description of Three Completed Studies................................................................39 5.1.2. Description of Two Ongoing Studies.......................................................................43 5.1.3. Pediatric Enrollment Data for the Five Completed or Ongoing Studies .................46 5.2. Review Strategy .............................................................................................................47 5.2.1. Efficacy Review Strategy.........................................................................................47 5.2.2. Safety Review Strategy ...........................................................................................47 6. Review of Relevant Individual Trials Used to Support Efficacy .............................................48 6.1. Study 4045-301 ..............................................................................................................48 6.1.1. Study Design..........................................................................................................48 6.1.2. Study Results ..........................................................................................................67 6.2. Efficacy Results...............................................................................................................71 6.2.1. Primary Endpoint of Interim Analysis .....................................................................71 Effects of Casimersen and Placebo on the CFB to Week 48 in Dystrophin Expression as Quantitated by Western Blot Methodology.....................................................................71 Note on Subject IDs in the Muscle Biopsy Interim Analysis that Constitutes the Efficacy Assessments .....................................................................................................................71 6.2.2. Additional Efficacy Results......................................................................................96 6.2.3. Additional Analyses Conducted on the Individual Trial ........................................110 7. Integrated Review of Effectiveness.....................................................................................122 7.1. Assessment of Efficacy Across Trials............................................................................122 7.1.1. Primary Endpoints ................................................................................................122 7.1.2. Secondary and Other Endpoints...........................................................................122 7.1.3. Subpopulations.....................................................................................................122 7.1.4. Dose and Dose-Response .....................................................................................122 7.1.5. Onset, Duration, and Durability of Efficacy Effects...............................................122 3 Reference ID: 4751845 Clinical Review David Hosford, Xiang Ling, Thomas Biel, Ashutosh Rao NDA 213,026: casimersen for DMD amenable to exon 45 skipping 7.2. Additional Efficacy Considerations...............................................................................122 7.2.1. Considerations on Benefit in the Post-market Setting .........................................122 7.2.2. Other Relevant Benefits........................................................................................124 7.3. Integrated Assessment of Effectiveness ......................................................................124 8. Review of Safety..................................................................................................................132