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CLINICAL REVIEW(S) Clinical Review Kevin Krudys, Phd BLA 761178 Aduhelm (Aducanumab)

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CLINICAL REVIEW(S) Clinical Review Kevin Krudys, Phd BLA 761178 Aduhelm (Aducanumab) CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761178Orig1s000 CLINICAL REVIEW(S) Clinical Review Kevin Krudys, PhD BLA 761178 Aduhelm (aducanumab) FDA CLINICAL REVIEW Application Type BLA Application Number(s) 761178 Priority or Standard Priority Submit Date(s) 02/20/2020, 05/15/2020, 07/07/2020 Received Date(s) 07/07/2020 PDUFA Goal Date 06/07/2021 Division/Office Division of Neurology 1/Office of Neuroscience Reviewer Name(s) Kevin Krudys, PhD Review Completion Date 06/06/2021 Established/Proper Name aducanumab-avwa (Proposed) Trade Name Aduhelm Applicant Biogen Inc. Dosage Form(s) Solution for injection Applicant Proposed Dosing 10 mg/kg as an intravenous infusion every four weeks Regimen(s) Applicant Proposed To delay clinical decline in patients with Alzheimer’s disease Indication(s)/Population(s) Recommendation on Approval Regulatory Action Recommended Treatment of Alzheimer’s disease Indication(s)/Population(s) 1 Reference ID: 4807199 Clinical Review Kevin Krudys, PhD BLA 761178 Aduhelm (aducanumab) Table of Contents Glossary ........................................................................................................................................ 9 1. Executive Summary .............................................................................................................. 11 Product Introduction .................................................................................................... 11 Conclusions on Substantial Evidence of Effectiveness .................................................. 11 Benefit-Risk Assessment ............................................................................................... 14 Patient Experience Data ............................................................................................... 23 2. Therapeutic Context ............................................................................................................ 23 Analysis of Condition .................................................................................................... 23 Analysis of Current Treatment Options ........................................................................ 25 3. Regulatory Background ........................................................................................................ 25 U.S. Regulatory Actions and Marketing History ............................................................ 25 Summary of Presubmission/Submission Regulatory Activity ........................................ 25 Foreign Regulatory Actions and Marketing History ...................................................... 27 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................................................... 27 Office of Scientific Investigations (OSI) ......................................................................... 27 Product Quality ............................................................................................................. 28 Clinical Microbiology .................................................................................................... 28 Nonclinical Pharmacology/Toxicology .......................................................................... 28 Clinical Pharmacology ................................................................................................... 28 Devices and Companion Diagnostic Issues ................................................................... 28 Consumer Study Reviews.............................................................................................. 29 5. Sources of Clinical Data and Review Strategy ...................................................................... 29 Table of Clinical Studies ................................................................................................ 29 Review Strategy ............................................................................................................ 32 6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 33 2 Reference ID: 4807199 Clinical Review Kevin Krudys, PhD BLA 761178 Aduhelm (aducanumab) Study 302 (221AD302): A Phase 3 Multicenter, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer’s Disease ............................................................................................... 33 Study Design .......................................................................................................... 33 Study Results ......................................................................................................... 50 Study 301 (221AD301): A Phase 3 Multicenter, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer’s Disease ............................................................................................... 66 Study Design .......................................................................................................... 66 Study Results ......................................................................................................... 67 Study 103 (221AD103): A Randomized, Double-Blinded, Placebo-Controlled Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB037 in Subjects with Prodromal or Mild Alzheimer’s Disease ........................................... 79 Study Design .......................................................................................................... 79 Study Results ......................................................................................................... 89 7. Integrated Review of Effectiveness ...................................................................................... 99 Assessment of Efficacy Across Trials ............................................................................. 99 Primary Endpoints ................................................................................................. 99 Secondary and Other Endpoints .......................................................................... 101 Subpopulations .................................................................................................... 104 Dose and Dose-Response .................................................................................... 105 Onset, Duration, and Durability of Efficacy Effects .............................................. 105 Early Termination and Interpretation of Study 301 and Study 302 ..................... 109 Analysis of Discordant Results in Study 301 and Study 302 ................................. 112 Additional Efficacy Considerations ............................................................................. 129 Considerations on Benefit in the Postmarket Setting .......................................... 129 Integrated Assessment of Effectiveness ..................................................................... 130 8. Review of Safety ................................................................................................................ 132 9. Advisory Committee Meeting and Other External Consultations ...................................... 132 10. Labeling Recommendations ............................................................................................... 136 Prescription Drug Labeling ...................................................................................... 136 3 Reference ID: 4807199 Clinical Review Kevin Krudys, PhD BLA 761178 Aduhelm (aducanumab) Nonprescription Drug Labeling ............................................................................... 136 11. Risk Evaluation and Mitigation Strategies (REMS) ............................................................. 137 12. Postmarketing Requirements and Commitments .............................................................. 137 13. Appendices ........................................................................................................................ 137 References .............................................................................................................. 137 Financial Disclosure ................................................................................................. 139 4 Reference ID: 4807199 Clinical Review Kevin Krudys, PhD BLA 761178 Aduhelm (aducanumab) Table of Tables Table 1: Clinical Studies Contributing Efficacy Data and Relevant to the Review of this BLA ...... 30 Table 2: Dosing Scheme for Aducanumab by Treatment Group and ApoE ε4 Carrier Status ...... 36 Table 3: Dose Modification/Discontinuation Rules for ARIA-E by Protocol Version (Study 302) . 37 Table 4: Dose Modification/Discontinuation Rules for ARIA-H Microhemorrhage and Superficial Siderosis by Protocol Version (Study 302) ................................................................................... 38 Table 5: Study 302 Schedule of Key Assessments ....................................................................... 39 Table 6: Study 302 Patient Disposition ........................................................................................ 50 Table 7: Study 302 Baseline Demographics (ITT Population) ...................................................... 52 Table 8: Study 302 Disease Characteristics (ITT Population) ......................................................
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