CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761149Orig1s000 CLINICAL REVIEW(S) Clinical Review Lawrence Rodichok MD BLA 761149 Enspryng/satralizumab-mwge CLINICAL REVIEW Application Type BLA Application Number(s) 761149 Priority or Standard Standard Submit Date(s) 8/15/19 Received Date(s) 8/15/19 PDUFA Goal Date 8/15/2020 Division/Office DN2/Office of Neuroscience Reviewer Name(s) Lawrence Rodichok MD Review Completion Date 5/28/20 (b) (4) Established/Proper Name Satralizumab-mwge (Proposed) Trade Name Enspryng Applicant Roche/Genentech Dosage Form(s) Injection:120mg/mL in a single-dose prefilled syringe Applicant Proposed Dosing 120 mg subcutaneous at Weeks 0, 2 and 4, and every 4 weeks (Q4W) thereafter Regimen(s) (b) (4) Applicant Proposed Adult with Indication(s)/Population(s) NMOSD. Recommendation on Approval Regulatory Action Recommended The treatment of neuromyelitis optica spectrum disorder Indication(s)/Population(s) (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) (if applicable) antibody positive CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4654184 Clinical Review Lawrence Rodichok MD BLA 761149 Enspryng/satralizumab-mwge Table of Contents Glossary ......................................................................................................................................... 11 1. Executive Summary ............................................................................................................... 14 Product Introduction ...................................................................................................... 14 Conclusions on the Substantial Evidence of Effectiveness ............................................ 14 Benefit-Risk Assessment ................................................................................................ 14 Patient Experience Data ................................................................................................. 17 2. Therapeutic Context .............................................................................................................. 19 Analysis of Condition ...................................................................................................... 19 Analysis of Current Treatment Options ......................................................................... 20 3. Regulatory Background ......................................................................................................... 22 U.S. Regulatory Actions and Marketing History ............................................................. 22 Summary of Presubmission/Submission Regulatory Activity ........................................ 22 Foreign Regulatory Actions and Marketing History ....................................................... 23 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 23 Office of Scientific Investigations (OSI) .......................................................................... 23 Product Quality .............................................................................................................. 23 Clinical Microbiology ...................................................................................................... 23 Nonclinical Pharmacology/Toxicology ........................................................................... 23 Clinical Pharmacology .................................................................................................... 24 Devices and Companion Diagnostic Issues .................................................................... 24 Consumer Study Reviews ............................................................................................... 24 5. Sources of Clinical Data and Review Strategy ....................................................................... 24 Table of Clinical Studies .................................................................................................. 25 Review Strategy .............................................................................................................. 25 6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 25 Study 309JG; bn40900. A Multicenter, Randomized, Double-Blind, Placebo-controlled Study To Evaluate The Efficacy And Safety of Satralizumab-mwge (SA237) As Monotherapy In CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4654184 Clinical Review Lawrence Rodichok MD BLA 761149 Enspryng/satralizumab-mwge Patients With Neuromyelitis Optica (NMO) and Neuromyelitis Optic Spectrum Disorder (NMOSD) ................................................................................................................................... 26 Study Design............................................................................................................ 26 Study Results ........................................................................................................... 35 6.2 Study 307JG; bn40898; A Multicenter, Randomized, Addition To Baseline Treatment, Double-Blind, Placebo-controlled, Phase 3 Study To Evaluate The Efficacy And Safety of Satralizumab-mwge (SA237) In Patients With Neuromyelitis Optica (NMO) And NMO Spectrum Disorder (NMOSD) .................................................................................................... 58 6.2.1 Study Design............................................................................................................ 58 6.2.2 Study Results ........................................................................................................... 62 7 Integrated Review of Effectiveness ....................................................................................... 86 7.2 Assessment of Efficacy Across Trials .............................................................................. 86 7.2.1 Primary Endpoints ................................................................................................... 86 7.2.2 Secondary and Other Endpoints ............................................................................. 86 7.2.3 Subpopulations ....................................................................................................... 86 7.2.4 Dose and Dose-Response........................................................................................ 86 7.2.5 Onset, Duration, and Durability of Efficacy Effects ................................................ 86 7.3 Additional Efficacy Considerations ................................................................................. 87 7.3.1 Considerations on Benefit in the Postmarket Setting ............................................ 87 7.3.2 Other Relevant Benefits .......................................................................................... 87 7.4 Integrated Assessment of Effectiveness ........................................................................ 87 8 Review of Safety .................................................................................................................... 87 8.2 Safety Review Approach ................................................................................................ 87 8.3 Review of the Safety Database ...................................................................................... 87 8.3.1 Overall Exposure ..................................................................................................... 87 8.3.2 Relevant characteristics of the safety population: ................................................. 88 8.3.3 Adequacy of the safety database: .......................................................................... 88 8.4 Adequacy of Applicant’s Clinical Safety Assessments .................................................... 88 8.4.1 Issues Regarding Data Integrity and Submission Quality ....................................... 89 8.4.2 Categorization of Adverse Events ........................................................................... 89 8.4.3 Routine Clinical Tests .............................................................................................. 89 CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4654184 Clinical Review Lawrence Rodichok MD BLA 761149 Enspryng/satralizumab-mwge 8.5 Safety Results ................................................................................................................. 89 8.5.1 Deaths ..................................................................................................................... 89 8.5.2 Serious Adverse Events ........................................................................................... 89 8.5.3 Dropouts and/or Discontinuations Due to Adverse Effects ................................... 94 8.5.4 Significant Adverse Events ...................................................................................... 95 8.5.5 Treatment Emergent Adverse Events and Adverse Reactions ............................... 95 8.5.6 Laboratory Findings .............................................................................................. 104 8.5.7 Vital Signs .............................................................................................................. 121 8.5.8 Electrocardiograms