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209203Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209203Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Clinical Review Non-Clinical Review Clinical Pharmacology Review NDA 209203 Multi-disciplinary Review and Evaluation 505(b)(2) Duzallo (lesinurad/allopurinol) NDA/BLA Multi-disciplinary Review and Evaluation Application Type 505(b) Application Number(s) NDA 209203 Priority or Standard Standard Submit Date(s) October 20, 2016 Received Date(s) October 20, 2016 PDUFA Goal Date August 18, 2017 (actual August 20, 2017 Sunday) Division/Office DPARP Review Completion Date August 14, 2017 Established Name Lesinurad/allopurinol fixed dose combination drug product (Proposed) Trade Name Duzallo Pharmacologic Class Combination URAT1 inhibitor (lesinurad) and XOI (allopurinol) Applicant Ardea Bioscience Formulation(s) Tablets Dosing Regimen Once daily Applicant Proposed Treatment of hyperuricemia associated with gout in patients who Indication(s)/Population(s) have not achieved target serum uric acid (sUA) levels with allopurinol alone Recommendation on Approval Regulatory Action Recommended Treatment of hyperuricemia associated with gout in patients who Indication(s)/Population(s) have not achieved target serum uric acid levels with a medically (if applicable) appropriate daily dose of allopurinol alone. 1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4139576 NDA 209203 Multi-disciplinary Review and Evaluation 505(b)(2) Duzallo (lesinurad/allopurinol) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9 Additional Reviewers of Application ............................................................................................... 9 Glossary ......................................................................................................................................... 10 1 Executive Summary ............................................................................................................... 12 1.1. Product Introduction ...................................................................................................... 12 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 12 1.3. Benefit-Risk Assessment ................................................................................................ 14 2 Therapeutic Context .............................................................................................................. 16 2.1. Analysis of Condition ...................................................................................................... 16 2.2. Analysis of Current Treatment Options ......................................................................... 17 3 Regulatory Background ......................................................................................................... 19 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 19 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 19 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 21 4.1. Office of Scientific Investigations (OSI) .......................................................................... 21 4.2. Product Quality .............................................................................................................. 21 4.3. Clinical Microbiology ...................................................................................................... 23 4.4. Devices and Companion Diagnostic Issues .................................................................... 23 5 Nonclinical Pharmacology/Toxicology................................................................................... 24 5.1. Executive Summary ........................................................................................................ 24 5.2. Referenced NDAs, BLAs, DMFs ....................................................................................... 24 5.3. Pharmacology ................................................................................................................. 25 5.4. ADME/PK ........................................................................................................................ 25 5.5. Toxicology ....................................................................................................................... 27 5.5.1. General Toxicology .................................................................................................. 27 5.5.2. Genetic Toxicology .................................................................................................. 32 5.5.3. Carcinogenicity ........................................................................................................ 32 5.5.4. Reproductive and Developmental Toxicology ........................................................ 33 2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4139576 NDA 209203 Multi-disciplinary Review and Evaluation 505(b)(2) Duzallo (lesinurad/allopurinol) 6 Clinical Pharmacology ............................................................................................................ 36 6.1. Executive Summary ........................................................................................................ 36 6.2. Summary of Clinical Pharmacology Assessment ............................................................ 36 6.2.1. Pharmacology and Clinical Pharmacokinetics ........................................................ 36 6.2.2. General Dosing and Therapeutic Individualization ................................................. 37 6.3. Comprehensive Clinical Pharmacology Review ............................................................. 38 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................ 38 6.3.2. Clinical Pharmacology Questions ............................................................................ 38 7 Statistical and Clinical and Evaluation ................................................................................... 50 7.1. Sources of Clinical Data and Review Strategy ............................................................ 50 7.1.1. Table of Clinical Studies ........................................................................................ 50 7.1.2. Review Strategy ...................................................................................................... 52 7.2. Review of Relevant Individual Trials Used to Support Efficacy ...................................... 52 7.2.1. Studies RDEA594-301 and RDEA594-302 ............................................................... 52 7.2.2. Study Results ........................................................................................................... 52 7.3. Integrated Review of Effectiveness ................................................................................ 52 7.3.1. Assessment of Efficacy Across Trials ....................................................................... 52 7.3.2. Integrated Assessment of Effectiveness ................................................................. 52 7.4. Review of Safety ............................................................................................................. 54 7.4.1. Safety Review Approach ......................................................................................... 54 7.4.2. Review of the Safety Database ............................................................................... 54 7.4.3. Safety Results .......................................................................................................... 55 7.4.4. Analysis of Submission-Specific Safety Issues ......................................................... 55 7.4.5. Safety Analyses by Demographic Subgroups .......................................................... 55 7.4.6. Specific Safety Studies/Clinical Trials ...................................................................... 55 7.4.7. Additional Safety Explorations ................................................................................ 55 7.4.8. Safety in the Postmarket Setting ............................................................................ 55 7.4.9. Integrated Assessment of Safety ............................................................................ 56 SUMMARY AND CONCLUSIONS .................................................................................................... 56 7.5. Statistical Issues ............................................................................................................. 56 7.6. Conclusions and Recommendations .............................................................................. 56 8 Advisory Committee Meeting and Other External Consultations ......................................... 58 3 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4139576 NDA 209203 Multi-disciplinary Review and Evaluation 505(b)(2) Duzallo (lesinurad/allopurinol) 9 Pediatrics ............................................................................................................................... 58 10 Labeling
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