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203568Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 203568Orig1s000 MEDICAL REVIEW(S) CLINICAL REVIEW Application Type NDA-Type 1 NME 505 (b)(1) Application Number(s) 203568 Priority or Standard Standard Submit Date(s) 29 March 2012 Received Date(s) 29 March 2012 PDUFA Goal Date 29 January 2013 Division / Office DMEP/ ODE II/ OND Reviewer Name(s) Eileen M. Craig, MD Review Completion Date 06 November 2012 Established Name Mipomersen sodium (Proposed) Trade Name Kynamro Therapeutic Class Lipid lowering; antisense inhibitor Applicant Genzyme Corp. Formulation(s) Injection Dosing Regimen 200 mg SQ weekly Indication(s) to reduce LDL-C, apo B, TC, non-HDL-C and lipoprotein (a) Intended Population(s) Homozygous familial hypercholesterolemia Template Version: March 6, 2009 Reference ID: 3221077 Clinical Review Eileen M. Craig, MD NDA 203568 Kynamro (mipomersen sodium) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ....................................... 10 1.1 Recommendation on Regulatory Action ........................................................... 10 1.2 Risk Benefit Assessment.................................................................................. 10 1.2.1 Efficacy ......................................................................................................... 10 1.2.2. Safety........................................................................................................... 14 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 20 1.4 Recommendations for Postmarket Requirements and Commitments .............. 21 2 INTRODUCTION AND REGULATORY BACKGROUND ...................................... 23 2.1 Product Information .......................................................................................... 27 2.2 Tables of Currently Available Treatments for Proposed Indications ................. 28 2.3 Availability of Proposed Active Ingredient in the United States ........................ 28 2.4 Important Safety Issues With Consideration to Related Drugs......................... 28 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 29 2.6 Other Relevant Background Information .......................................................... 33 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 35 3.1 Submission Quality and Integrity ...................................................................... 35 3.2 Compliance with Good Clinical Practices ......................................................... 35 3.3 Financial Disclosures........................................................................................ 35 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 36 4.1 Chemistry Manufacturing and Controls ............................................................ 36 4.2 Clinical Microbiology......................................................................................... 36 4.3 Preclinical Pharmacology/Toxicology ............................................................... 36 4.4 Clinical Pharmacology...................................................................................... 41 4.4.1 Mechanism of Action.................................................................................. 41 4.4.2 Pharmacodynamics.................................................................................... 42 4.4.3 Pharmacokinetics....................................................................................... 44 5 SOURCES OF CLINICAL DATA............................................................................ 46 5.1 Tables of Studies/Clinical Trials ....................................................................... 46 5.2 Review Strategy ............................................................................................... 47 5.3 Discussion of Individual Studies/Clinical Trials................................................. 48 5.3.1 Phase 1......................................................................................................... 48 5.3.2 Phase 2......................................................................................................... 48 5.3.3 Phase 3......................................................................................................... 49 6 REVIEW OF EFFICACY......................................................................................... 53 Efficacy Summary...................................................................................................... 53 See Section 1.2.1 Efficacy......................................................................................... 53 2 Reference ID: 3221077 Clinical Review Eileen M. Craig, MD NDA 203568 Kynamro (mipomersen sodium) 6.1 Indication .......................................................................................................... 53 6.1.1 Methods ..................................................................................................... 53 6.1.2 Demographics............................................................................................ 61 6.1.3 Subject Disposition..................................................................................... 67 6.1.4 Analysis of Primary Endpoint(s) ................................................................. 70 6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 80 6.1.6 Tertiary Endpoints...................................................................................... 84 6.1.7 Subpopulations .......................................................................................... 88 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 89 6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 89 6.1.10 Additional Efficacy Issues/Analyses........................................................... 91 7 REVIEW OF SAFETY............................................................................................. 91 Safety Summary ........................................................................................................ 91 7.1 Methods............................................................................................................ 91 7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 91 7.1.2 Categorization of Adverse Events.............................................................. 92 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence.................................................................................................... 93 7.2 Adequacy of Safety Assessments .................................................................... 93 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations..................................................................................... 93 7.2.2 Explorations for Dose Response................................................................ 95 7.2.3 Special Animal and/or In Vitro Testing ....................................................... 95 7.2.4 Routine Clinical Testing ............................................................................. 96 7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 96 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 96 7.3 Major Safety Results ........................................................................................ 96 7.3.1 Deaths........................................................................................................ 97 7.3.2 Nonfatal Serious Adverse Events .............................................................. 97 7.3.3 Dropouts and/or Discontinuations ............................................................ 102 7.3.4 Significant Adverse Events ...................................................................... 107 7.3.5 Submission Specific Primary Safety Concerns ........................................ 107 CONTRAINDICATIONS.............................................................................................. 143 WARNINGS AND PRECAUTIONS............................................................................. 146 7.4 Supportive Safety Results .............................................................................. 179 7.4.1 Common Adverse Events ........................................................................ 180 7.4.2 Laboratory Findings ................................................................................. 185 7.4.3 Vital Signs ................................................................................................ 187 7.4.4 Electrocardiograms (ECGs) ..................................................................... 188 7.4.5 Special Safety Studies/Clinical Trials....................................................... 190 7.4.6 Immunogenicity........................................................................................ 190 3 Reference ID: 3221077 Clinical Review Eileen M. Craig, MD NDA 203568 Kynamro (mipomersen sodium) 7.5 Other Safety Explorations............................................................................... 194 7.5.1 Dose Dependency for Adverse Events ...................................................
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