CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 214018Orig1s000 INTEGRATED REVIEW NDA 214018 Nulibry (fosdenopterin) Integrated Review Table 1. Administrative Application Information Category Application Information Application type NDA Application number(s) 214018 Priority or standard Priority Submit date(s) 6/29/2020 Received date(s) 6/29/2020 PDUFA goal date 2/28/2021 Division/office Division of Rare Diseases and Medical Genetics (DRDMG) Review completion date 2/26/2021 Established/proper name fosdenopterin (Proposed) proprietary name Nulibry Pharmacologic class Cyclic pyranopterin monophosphate Code name ALXN1101, ORGN001 Applicant Origin Biosciences, Inc. Dosage form(s)/formulation(s) Lyophilized Powder for Injection Dosing regimen 0.9 mg/kg intravenously daily Applicant proposed Treatment of MoCD Type A, including in neonates indication(s)/ population(s) Proposed SNOMED indication 29692004 |Combined molybdoflavoprotein enzyme deficiency (disorder) Regulatory action Approval Approved dosage (if For patients 1 year of age and older, 0.9 mg/kg administered as an applicable) intravenous infusion daily; for patients less than 12 months of age the dosage should be titrated up to 0.9 mg/kg over a period of 3 months Approved indication(s)/ Nulibry (fosdenopterin) for injection is indicated to reduce the risk population(s) (if applicable) of mortality in patients with molybdenum cofactor deficiency (MoCD) Type A Approved SNOMED term for 29692004 Combined molybdoflavoprotein enzyme deficiency indication (if applicable) (disorder) i Integrated Review Template, version 2.0 (04/23/2020) Reference ID: 4753847 NDA 214018 Nulibry (fosdenopterin) 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 ..............................................................................................5 2.1. Benefit-Risk Framework .......................................................................................5 2.2. Conclusions Regarding Benefit-Risk ....................................................................7 II. Interdisciplinary Assessment .........................................................................................10 3. Introduction ................................................................................................................10 3.1. Review Issue List .................................................................................................11 3.1.1. Key Review Issues Relevant to Evaluation of Benefit .................................11 3.1.1.1. Potential for Selection Bias Leading to a Spurious Mortality Benefit .................................................................................................11 3.1.1.2. Regulatory Framework for Establishing Substantial Evidence of Effectiveness .......................................................................................11 3.1.1.3. Post Hoc Nature of the Statistical Analysis Plan ....................................11 3.1.1.4. Use of Both rcPMP and cPMP in the Treatment Group ........................12 3.1.2. Key Review Issues Relevant to Evaluation of Risk ......................................12 3.1.2.1. Labeled Option for Administration by a Caregiver ................................12 3.1.2.2. Potential Risk of Phototoxicity ...............................................................12 3.2. Approach to the Review ......................................................................................12 4. Patient Experience Data .............................................................................................16 5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology ..................17 5.1. Nonclinical Assessment of Potential Effectiveness .............................................20 5.1.1. Fosdenopterin HBr ........................................................................................20 6. Assessment of Effectiveness ......................................................................................20 6.1. Dose and Dose Responsiveness ...........................................................................20 6.1.1. The Proposed Dosage Regimen ....................................................................20 6.1.2. Dose-Selection Rationale for Pivotal Studies ...............................................20 6.1.3. Dose Adjustment and Titration in Pediatric Patients <12 Months ................21 6.1.4. Pharmacodynamics .......................................................................................21 6.1.5. Exposure-Response .......................................................................................23 6.2. Clinical Trials Intended to Demonstrate Efficacy ...............................................24 6.2.1. Studies MCD-201, MCD-202, MCD-501, and MCD-502 ...........................24 6.2.1.1. Design .....................................................................................................24 6.2.1.2. Key Eligibility Criteria ...........................................................................25 ii Integrated Review Template, version 2.0 (04/23/2020) Reference ID: 4753847 NDA 214018 Nulibry (fosdenopterin) 6.2.1.3. Statistical Analysis Plan .........................................................................26 6.2.1.4. Results of Analyses ................................................................................29 6.3. Key Review Issues Relevant to Evaluation of Benefit ........................................39 6.3.1. Potential for Selection Bias ...........................................................................39 6.3.2. Potential for Detection Bias or a Spurious Mortality Benefit .......................41 6.3.3. Regulatory Framework for Establishing Substantial Evidence of Effectivesness ...........................................................................................42 6.3.4. Post Hoc Nature of the Analysis Plan ...........................................................43 6.3.5. Use of Both rcPMP and cPMP in Treated Patients .......................................44 7. Risk and Risk Management ........................................................................................45 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data ..........................45 7.1.1. Overall Safety Concern .................................................................................45 7.1.2. Safety Pharmacology and ADME .................................................................45 7.1.3. General Toxicology .......................................................................................46 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 ..............46 7.4. FDA Approach to the Safety Review ..................................................................47 7.5. Adequacy of the 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 .......................................................................48 7.6.1.1. Overall Treatment-Emergent Adverse Event Summary, Studies MCD-501, MCD-201, and MCD-202 ................................................48 7.6.1.2. Deaths, Studies MCD-501, MCD-201, and MCD-202 ..........................48 7.6.1.3. Serious Adverse Events, Studies MCD-501, MCD-201, and MCD-202 ............................................................................................49 7.6.1.4. Dropouts and/or Discontinuations Due to Adverse Events, Studies MCD-501, MCD-201, and MCD-202 ...................................50 7.6.1.5. Treatment-Emergent Adverse Events, Studies MCD-501, MCD• 201, and MCD-202 .............................................................................50 7.6.1.6. Laboratory Findings and Vital Signs, Studies MCD-501, MCD• 201, and MCD-202 .............................................................................52 7.7. Key Review Issues Relevant to Evaluation of Risk ............................................53 7.7.1. Labeled Option for Administration by a Caregiver ......................................53 7.7.2. Potential Risk of Phototoxicity .....................................................................54 8. Therapeutic Individualization ....................................................................................55 8.1. Intrinsic Factors ...................................................................................................55 8.1.1. Renal Impairment or Hepatic Impairment ....................................................55