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CLINICAL REVIEW(S) Clinical Review Natalie Branagan, MD NDA 022075 Nourianz/Istradefylline

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CLINICAL REVIEW(S) Clinical Review Natalie Branagan, MD NDA 022075 Nourianz/Istradefylline CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 022075Orig1s000 CLINICAL REVIEW(S) Clinical Review Natalie Branagan, MD NDA 022075 Nourianz/istradefylline CLINICAL REVIEW Application Type NDA Application Number(s) 022075 Priority or Standard Class 2 Resubmission Submit Date(s) February 27, 2019 Received Date(s) February 27, 2019 PDUFA Goal Date August 27, 2019 Division/Office DNP Reviewer Name(s) Natalie Branagan, MD Review Completion Date August 26, 2019 Established/Proper Name Istradefylline (Proposed) Trade Name Nourianz Applicant Kyowa Kirin Inc Dosage Form(s) Tablets Applicant Proposed Dosing Administer 20 mg orally once daily. The dose may be increased Regimen(s) to 40 mg once daily based on (b) (4) Applicant Proposed Adjunctive treatment to levodopa/carbidopa in adult patients Indication(s)/Population(s) with Parkinson’s disease experiencing “OFF” episodes. Recommendation on There do not appear to be safety concerns that would preclude Regulatory Action approval. If efficacy is demonstrated and the benefits of istradefylline outweight the risks, then I recommend that approval include appropriate labeling language addressing any adverse reactions of concerns. Recommended Adults Indication(s)/Population(s) (if applicable) CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 44827364484018 Clinical Review Natalie Branagan, MD NDA 022075 Nourianz/istradefylline Table of Contents Glossary ..........................................................................................................................................9 1. Executive Summary ...............................................................................................................11 1.1. Product Introduction......................................................................................................11 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................11 1.3. Benefit-Risk Assessment ................................................................................................11 1.4. Patient Experience Data.................................................................................................15 2. Therapeutic Context..............................................................................................................15 2.1. Analysis of Condition......................................................................................................15 2.2. Analysis of Current Treatment Options .........................................................................15 3. Regulatory Background .........................................................................................................15 3.1. U.S. Regulatory Actions and Marketing History.............................................................15 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................15 3.3. Foreign Regulatory Actions and Marketing History .......................................................15 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................15 4.1. Office of Scientific Investigations (OSI) ..........................................................................16 4.2. Product Quality ..............................................................................................................16 4.3. Clinical Microbiology......................................................................................................16 4.4. Nonclinical Pharmacology/Toxicology ...........................................................................16 4.5. Clinical Pharmacology ....................................................................................................16 4.6. Devices and Companion Diagnostic Issues ....................................................................16 4.7. Consumer Study Reviews...............................................................................................16 5. Sources of Clinical Data and Review Strategy .......................................................................16 5.1. Table of Clinical Studies .................................................................................................16 5.2. Review Strategy .............................................................................................................16 6. Review of Relevant Individual Trials Used to Support Efficacy .............................................17 7. Integrated Review of Effectiveness.......................................................................................17 CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 44827364484018 Clinical Review Natalie Branagan, MD NDA 022075 Nourianz/istradefylline 8. Review of Safety....................................................................................................................17 8.1. Safety Review Approach ................................................................................................17 8.2. Review of the Safety Database ......................................................................................19 8.2.1. Overall Exposure.....................................................................................................19 8.2.2. Relevant characteristics of the safety population: .................................................20 8.2.3. Adequacy of the safety database: ..........................................................................23 8.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................23 8.3.1. Issues Regarding Data Integrity and Submission Quality........................................24 8.3.2. Categorization of Adverse Events...........................................................................24 8.3.3. Routine Clinical Tests..............................................................................................25 8.4. Safety Results.................................................................................................................26 8.4.1. Deaths.....................................................................................................................26 8.4.2. Serious Adverse Events...........................................................................................29 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects....................................35 8.4.4. Significant Adverse Events......................................................................................37 8.4.5. Treatment Emergent Adverse Events and Adverse Reactions ...............................39 8.4.1. Laboratory Findings ................................................................................................49 8.4.2. Vital Signs................................................................................................................56 8.4.3. Electrocardiograms (ECGs) .....................................................................................58 8.4.4. QT ...........................................................................................................................59 8.4.5. Immunogenicity......................................................................................................59 8.5. Analysis of Submission-Specific Safety Issues ................................................................59 8.5.1. Impulse Control Disorder........................................................................................59 8.5.2. Dizziness, Hypotension, Orthostatic Hypotension..................................................61 8.5.3. Falls.........................................................................................................................62 8.5.4. Effects on Ability to Drive .......................................................................................62 8.5.5. Cardiac Safety .........................................................................................................63 8.5.6. Suicide.....................................................................................................................64 8.5.7. Neutropenia and Neutropenic Sepsis.....................................................................66 8.5.8. Drug-Drug interactions ...........................................................................................67 8.6. Safety Analyses by Demographic Subgroups .................................................................67 CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 44827364484018 Clinical Review Natalie Branagan, MD NDA 022075 Nourianz/istradefylline 8.7. Specific Safety Studies/Clinical Trials .............................................................................80 8.8. Additional Safety Explorations.......................................................................................80 8.8.1. Human Carcinogenicity or Tumor Development ....................................................80 8.8.2. Human Reproduction and Pregnancy.....................................................................83 8.8.3. Pediatrics and Assessment of Effects on Growth ...................................................84 8.8.4. Overdose, Drug Abuse Potential, Withdrawal, and Rebound.................................84
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