CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761068Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review MultiͲDisciplinary Review BLA 761068 (burosumab Ͳ twza) MULTIͲDISCIPLINARY REVIEW Application Type BLA Application Number(s) 761068 Priority or Standard Priority Submit Date(s) 8/17/2017 Received Date(s) 8/17/2017 PDUFA Goal Date 4/17/2018 Division/Office Division of Bone, Reproductive and Urologic Products/ Office of Drug Evaluation III Review Completion Date 4/5/2018 Established/Proper Name Burosumab (Proposed) Trade Name Crysvita Applicant Ultragenyx Pharmaceutical Inc. Dosage Form(s) 10, 20 and 30 mg/mL solution for injection in singleͲdose vial Applicant Proposed Dosing Pediatric: 0.8 mg/kg SC Q2 weeks (starting dose; titration to Regimen(s) max 2.0 mg/kg Q2weeks based on serum phosphorus; minimum dose 10 mg, maximum dose 90 mg) Adult: 1 mg/kg SC Q4 weeks, maximum dose 90 mg Applicant Proposed Treatment of XͲlinked hypophosphatemia (XLH) in adult and Indication(s)/Population(s) pediatric patients 1 year of age and older Recommendation on Approval for both adult and pediatric patients Regulatory Action Recommended Treatment of XͲlinked hypophosphatemia (XLH) in adult and Indication(s)/Population(s) pediatric patients 1 year of age and older (if applicable) 1 Reference ID: 4247337 MultiͲDisciplinary Review BLA 761068 (burosumab Ͳ twza) Table of Contents Reviewers of MultiͲDisciplinary Review and Evaluation .............................................................. 12 Additional Reviewers of Application............................................................................................. 14 Glossary......................................................................................................................................... 15 1. Executive Summary ............................................................................................................... 17 1.1. Product Introduction...................................................................................................... 17 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 17 1.3. BenefitͲRisk Assessment ................................................................................................ 17 1.4. Patient Experience Data................................................................................................. 28 2. Therapeutic Context.............................................................................................................. 28 2.1. Analysis of Condition...................................................................................................... 29 2.2. Analysis of Current Treatment Options ......................................................................... 30 3. Regulatory Background ......................................................................................................... 33 3.1. U.S. Regulatory Actions and Marketing History............................................................. 33 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 34 3.3. Foreign Regulatory Actions and Marketing History....................................................... 37 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 37 4.1. Office of Scientific Investigations (OSI) .......................................................................... 37 4.2. Product Quality .............................................................................................................. 38 4.3. Devices and Companion Diagnostic Issues .................................................................... 41 4.4. Consumer Study Reviews............................................................................................... 41 5. Nonclinical Pharmacology/Toxicology................................................................................... 41 5.1. Executive Summary........................................................................................................ 41 5.2. Referenced NDAs, BLAs, DMFs....................................................................................... 44 5.3. Pharmacology................................................................................................................. 45 5.4. ADME/PK........................................................................................................................ 51 5.5. Toxicology....................................................................................................................... 54 5.5.1. General Toxicology.................................................................................................. 54 2 Reference ID: 4247337 MultiͲDisciplinary Review BLA 761068 (burosumab Ͳ twza) 5.5.2. Genetic Toxicology.................................................................................................. 69 5.5.3. Carcinogenicity........................................................................................................ 69 5.5.4. Reproductive and Developmental Toxicology........................................................ 70 5.5.5. Other Toxicology Studies ........................................................................................ 76 5.5.6 Toxicology Studies: Exposure Multiples .................................................................. 76 5.6. Nonclinical Safety Issues ................................................................................................ 78 5.7. Nonclinical Labeling........................................................................................................ 83 6. Clinical Pharmacology............................................................................................................ 87 6.1. Executive Summary........................................................................................................ 87 6.2. Summary of Clinical Pharmacology Assessment............................................................ 89 6.2.1. Pharmacology and Clinical Pharmacokinetics ........................................................ 89 6.2.2. General Dosing and Therapeutic Individualization................................................. 90 6.3. Comprehensive Clinical Pharmacology Review ............................................................. 91 6.3.1. General Pharmacology and Pharmacokinetic Characteristics................................ 91 6.3.2. Clinical Pharmacology Review Questions .............................................................. 96 6.4. Clinical Pharmacology Appendices............................................................................... 105 6.4.1. Summary of Bioanalytical Method Validation and Performance......................... 105 6.4.2. Biopharmaceutics ................................................................................................. 113 6.4.3. Individual Clinical Pharmacology Study Summary................................................ 116 6.4.4. Immunogenicity .................................................................................................... 128 6.4.5. Population PK Analysis.......................................................................................... 130 6.4.6. ExposureͲresponse analyses................................................................................. 140 7. Sources of Clinical Data and Review Strategy ..................................................................... 148 7.1.1. Table of Clinical Studies ........................................................................................ 149 7.1.2. Review Strategy .................................................................................................... 151 8. Statistical and Clinical Evaluation ........................................................................................ 152 8.1. Review of Relevant Individual Trials Used to Support Efficacy.................................... 152 8.1.1. Study UX023ͲCL201............................................................................................... 152 8.1.2. Study UX023ͲCL002............................................................................................... 187 8.1.3. Study UX023ͲCL205............................................................................................... 192 8.1.4. Study UX023ͲCL303............................................................................................... 201 3 Reference ID: 4247337 MultiͲDisciplinary Review BLA 761068 (burosumab Ͳ twza) 8.1.5. Study UX023ͲCL304............................................................................................... 231 8.2. Integrated Review of Effectiveness.............................................................................. 239 8.2.1. Assessment of Efficacy across Trials ..................................................................... 239 8.2.2. Integrated Assessment of Effectiveness............................................................... 246 8.3. Review of Safety........................................................................................................... 254 8.3.1. Safety Review Approach ......................................................................................