BLA 125370/s-064 and BLA 761043/s-007 Multi-disciplinary Review and Evalaution Benlysta® (belimumab) for Intravenous Infusion in Children 5 to 17 Years of Age with SLE NDA/BLA Multi-Disciplinary Review and Evaluation Application Type Postmarketing Required Pediatric Study Application Number(s) sBLA 125370/s-064 and BLA 761043/s-007 Priority or Standard Priority Submit Date(s) October 26, 2018 Received Date(s) October 26, 2018 PDUFA Goal Date April 26, 2019 Division/Office Division of Pulmonary, Allergy and Rheumatology Products (DPARP)/ODE2 Review Completion Date See Electronic Stamp Date Established/Proper Name Belimumab (Proposed) Trade Name BENLYSTA Pharmacologic Class Monoclonal Anti-BLyS Antibody Code name N/A Applicant Human Genome Sciences Dosage form 10 mg/kg via Intravenous Infusion Applicant proposed Dosing 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week Regimen intervals thereafter Applicant Proposed Treatment of patients aged 5 years and older with active, Indication(s)/Population(s) autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy Recommendation on Approval Regulatory Action Recommended Treatment of patients aged 5 years and older with active, Indication(s)/Population(s) autoantibody-positive, systemic lupus erythematosus (SLE) who (if applicable) are receiving standard therapy Recommended Dosing 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week Regimen intervals thereafter 1 Version date: October 12, 2018 Reference ID: 4424800 BLA 125370/s-064 and BLA 761043/s-007 Multi-disciplinary Review and Evalaution Benlysta® (belimumab) for Intravenous Infusion in Children 5 to 17 Years of Age with SLE Table of Contents Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 9 Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 11 Glossary ......................................................................................................................................... 14 1 Executive Summary ............................................................................................................... 16 Product Introduction ...................................................................................................... 16 Conclusions on the Substantial Evidence of Effectiveness ............................................ 16 Benefit-Risk Assessment ................................................................................................ 18 Patient Experience Data ................................................................................................. 24 2 Therapeutic Context .............................................................................................................. 25 Analysis of Condition ...................................................................................................... 25 Analysis of Current Treatment Options ......................................................................... 27 3 Regulatory Background ......................................................................................................... 29 U.S. Regulatory Actions and Marketing History ............................................................. 29 Summary of Presubmission/Submission Regulatory Activity ........................................ 29 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 31 Office of Scientific Investigations (OSI) .......................................................................... 31 Product Quality .............................................................................................................. 31 Clinical Microbiology...................................................................................................... 31 Devices and Companion Diagnostic Issues .................................................................... 31 5 Nonclinical Pharmacology/Toxicology................................................................................... 32 Executive Summary ........................................................................................................ 32 6 Clinical Pharmacology ............................................................................................................ 35 Summary of Clinical Pharmacology Assessment ............................................................ 35 Pharmacology and Clinical Pharmacokinetics ........................................................ 35 General Dosing and Therapeutic Individualization ................................................. 37 Comprehensive Clinical Pharmacology Review ............................................................. 37 General Pharmacology and Pharmacokinetic Characteristics ................................ 37 Clinical Pharmacology Questions ............................................................................ 37 7 Sources of Clinical Data and Review Strategy ....................................................................... 60 Table of Clinical Studies .................................................................................................. 60 Review Strategy .............................................................................................................. 63 2 Version date: October 12, 2018 Reference ID: 4424800 BLA 125370/s-064 and BLA 761043/s-007 Multi-disciplinary Review and Evalaution Benlysta® (belimumab) for Intravenous Infusion in Children 5 to 17 Years of Age with SLE 8 Statistical and Clinical and Evaluation ................................................................................... 64 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 64 Study Results ........................................................................................................... 78 8.1.1.1. Primary Efficacy Analysis ................................................................................. 88 8.1.1.2. Efficacy Results – Secondary or exploratory COA (PRO) endpoints ................ 95 8.1.1.3. Analysis of Biomarkers .................................................................................... 98 8.1.1.4. Additional Analyses Conducted on the Individual Trial ................................... 99 8.1.1.4.1. Bayesian Analysis of Efficacy Endpoints......................................................... 99 8.1.1.4.2. Findings in subgroup populations ................................................................ 106 8.1.1.5. Statistical Issues ............................................................................................. 108 8.1.1.5.1. Potential Impacts of Missing Data ............................................................... 108 8.1.1.5.2. Power and Sample size ................................................................................ 108 Integrated Assessment of Effectiveness ............................................................... 108 8.1.2.1. Conclusions and Recommendations ............................................................. 109 Review of Safety ........................................................................................................... 109 Safety Review Approach ....................................................................................... 109 Review of the Safety Database ............................................................................. 110 Safety Results ........................................................................................................ 111 Analysis of Submission-Specific Safety Issues ....................................................... 133 8.2.4.1. Infections ....................................................................................................... 133 8.2.4.2. Hypersensitivity Spectrum Reactions Including Anaphylaxis ........................ 134 8.2.4.3. Depression, Suicide and Self-Injury ............................................................... 136 8.2.4.3 Hepatotoxicity ..................................................................................................... 139 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 141 Safety Analyses by Demographic Subgroups ........................................................ 141 Specific Safety Studies/Clinical Trials .................................................................... 142 Additional Safety Explorations .............................................................................. 142 Integrated Assessment of Safety .......................................................................... 146 Statistical Issues ........................................................................................................... 148 Conclusions and Recommendations ............................................................................ 148 9 Advisory Committee Meeting and Other External Consultations....................................... 151 10 Pediatrics ............................................................................................................................