CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 214103Orig1s000 INTEGRATED REVIEW NDA 214103 Oxlumo (lumasiran) Integrated Review Table 1. Administrative Application Information Category Application Information Application type NDA Application number(s) 214103 Priority or standard Priority Submit date(s) 4/3/2020 Received date(s) 4/3/2020 PDUFA goal date 12/3/2020 Division/office Division of Cardiology and Nephrology (DCN) Review completion date 11/18/2020 Established/proper name Lumasiran (Proposed) proprietary name Oxlumo Pharmacologic class Small interfering RNA Code name AD-65585, ALN-65585, ALN-GO1 Applicant Alnylam Pharmaceuticals Dosage form(s)/formulation(s) Injectable 94.5 mg/0.5 mL single-dose vial Dosing regimen Subcutaneous injection based on body weight. Applicant proposed Treatment of primary hyperoxaluria type 1 (PH1) in pediatric and indication(s)/ population(s) adult patients. Proposed SNOMED indication 65520001 Primary hyperoxaluria, type 1 (disorder) Regulatory action Approval Approved dosage Body Weight <10 kg: 6 mg/kg monthly for 3 doses then 3 mg/kg monthly; 10 kg to <20 kg: 6 mg/kg monthly for 3 doses then 6 mg/kg every 3 months; 20 kg: 3 mg/kg monthly for 3 doses then 3 mg/kg every 3 months Approved indication For the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients Approved SNOMED term for 65520001 Primary hyperoxaluria, type 1 (disorder) indication i Integrated Review Template, version 2.0 (04/23/2020) Reference ID: 4704669 NDA 214103 Oxlumo (lumasiran) Table of Contents Table of Tables ............................................................................................................ vi Table of Figures ........................................................................................................... ix Glossary......................................................................................................................1 I. Executive Summary....................................................................................................3 1. Summary of Regulatory Action .............................................................................3 2. Benefit-Risk Assessment........................................................................................6 2.1. Benefit-Risk Framework .................................................................................6 2.2. Conclusions Regarding Benefit-Risk ..............................................................8 II. Interdisciplinary Assessment.....................................................................................9 3. Introduction ............................................................................................................9 3.1. Review Issue List...........................................................................................10 3.2. Approach to the Review ................................................................................10 4. Patient Experience Data .......................................................................................12 5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology............13 5.1. Nonclinical Assessment of Potential Effectiveness.......................................17 6. Assessment of Effectiveness ................................................................................18 6.1. Dose and Dose Responsiveness.....................................................................18 6.2. Clinical Trials Intended to Demonstrate Efficacy .........................................22 6.2.1. Results of Analyses, ILLUMINATE-A and -B ......................................22 6.2.2. Trial ALN-GO1-003 (ILLUMINATE-A)...............................................22 6.2.2.1. Design, ILLUMINATE-A................................................................22 6.2.2.2. Eligibility Criteria, ILLUMINATE-A..............................................25 6.2.2.3. Statistical Analysis Plan, ILLUMINATE-A ....................................25 6.2.2.4. Results of Analyses, ILLUMINATE-A ...........................................26 6.2.3. ALN-GO1-004 (ILLUMINATE-B)........................................................36 6.2.3.1. Design, ILLUMINATE-B ................................................................37 6.2.3.2. Eligibility Criteria, ILLUMINATE-B..............................................38 6.2.3.3. Statistical Analysis Plan, ILLUMINATE-B.....................................38 6.2.3.4. Results of Analyses, ILLUMINATE B ............................................39 6.3. Key Review Issues Relevant to Evaluation of Benefit..................................42 7. Risk and Risk Management..................................................................................42 ii Integrated Review Template, version 2.0 (04/23/2020) Reference ID: 4704669 NDA 214103 Oxlumo (lumasiran) 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data....................42 7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug- Specific Factors ..............................................................................................46 7.3. Potential Safety Concerns Identified Through Postmarket Experience ........47 7.4. FDA Approach to the Safety Review ............................................................47 7.5. Adequacy of Clinical Safety Database ..........................................................47 7.6. Safety Findings and Concerns Based on Review of Clinical Safety Database..........................................................................................................48 7.6.1. Safety Findings and Concerns, ILLUMINATE-A and -B......................48 7.6.2. Safety Findings and Concerns, ILLUMINATE-A..................................49 7.6.2.1. Overall Treatment-Emergent Adverse Event Summary, ILLUMINATE-A ....................................................................................49 7.6.2.2. Deaths, ILLUMINATE-A ................................................................49 7.6.2.3. Serious Adverse Events, ILLUMINATE-A.....................................49 7.6.2.4. Dropouts and/or Discontinuations Due to Adverse Events, ILLUMINATE-A ....................................................................................50 7.6.2.5. Treatment-Emergent Adverse Events, ILLUMINATE-A................50 7.6.2.6. Laboratory Findings, ILLUMINATE-A ..........................................53 7.6.3. Safety Findings and Concerns, ILLUMINATE-B..................................54 7.6.3.1. Overall Treatment-Emergent Adverse Event Summary, ILLUMINATE-B ....................................................................................54 7.6.3.2. Deaths, ILLUMINATE-B ................................................................54 7.6.3.3. Serious Adverse Events, ILLUMINATE-B .....................................55 7.6.3.4. Dropouts and/or Discontinuations Due to Adverse Events, ILLUMINATE-B ....................................................................................55 7.6.3.5. Treatment-Emergent Adverse Events, ILLUMINATE-B................55 7.6.3.6. Laboratory Findings, ILLUMINATE-B...........................................56 7.7. Key Review Issues Relevant to Evaluation of Risk ......................................57 8. Therapeutic Individualization ..............................................................................57 8.1. Intrinsic Factors .............................................................................................57 8.2. Drug Interactions ...........................................................................................60 8.3. Plans for Pediatric Drug Development ..........................................................60 8.4. Pregnancy and Lactation................................................................................60 9. Product Quality ....................................................................................................62 iii Integrated Review Template, version 2.0 (04/23/2020) Reference ID: 4704669 NDA 214103 Oxlumo (lumasiran) 9.1. Device or Combination Product Considerations ...........................................62 10. Human Subjects Protections/Clinical Site and Other Good Clinical Practice Inspections/Financial Disclosure........................................................................62 11. Advisory Committee Summary..........................................................................64 III. Appendices.............................................................................................................64 12. Summary of Regulatory History ........................................................................64 13. Pharmacology Toxicology: Additional Information and Assessment ...............65 13.1. Summary Review of Studies Submitted Under the IND.............................65 13.1.1. Primary Pharmacology..........................................................................65 13.1.2. Secondary Pharmacology......................................................................66 13.1.3. Toxicology ............................................................................................70 13.1.3.1. General Toxicology (Pivotal).........................................................70 13.1.3.2. Reproductive Toxicology ...............................................................77 13.1.3.3. Impurities/Degradants ....................................................................81 13.2.