FDA Briefing Document ARTHRITIS ADVISORY COMMITTEE AND DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE MEETING January 11, 2019 NDA 21856 Febuxostat Xanthine oxidase (XO) inhibitor for the chronic management of hyperuricemia in patients with gout Takeda 1 of 169 DISCLAIMER STATEMENT The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We bring the supplemental new drug application (sNDA) for Uloric (febuxostat) NDA# 21856 which includes the results from the post-marketing safety trial required by FDA to evaluate the cardiovascular (CV) safety of febuxostat - the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial to this Advisory Committee to gain the Committee’s insights and opinions. The background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2 of 169 1 Table of Contents 1 Division Memorandum ……………………………………………………………………………….... 6 2 Draft Points to Consider …………………………………………………………………………………. 17 3 Clinical and Statistical Review ………………………………………………………………………….. 18 4 Division of Cardiovascular and Renal Products Consult ……………………………………. 99 5 Office of Surveillance and Epidemiology Review …………………………………………….. 108 6 Office of Surveillance and Epidemiology – Sentinel Memo ……………………………… 138 3 of 169 Table of Tables Table 1 Primary Analysis of MACE – On Study Analysis................................................................ 11 Table 2 Analysis of CV Death and All Cause Death in CARES ........................................................ 12 Table 3: Treatments for the Management of Hyperuricemia ...................................................... 22 Table 4 Summary of Major Safety Results from First Cycle Review of Febuxostat ..................... 26 Table 5: All-Cause Mortality in Febuxostat Safety Database by Patient-Years of Exposure (Data Cut-off 08 February 2006) ............................................................................................................. 27 Table 6: Clinical Trials Relevant to this NDA ................................................................................. 31 Table 7 – Tabular Summary of Major Inclusion and Exclusion Criteria for Study 301 ................. 35 Table 8 - Tabular Summary of Assessments and Procedures for Study 301 ................................ 38 Table 9: Cardiovascular Endpoint Definitions Used to Adjudicate Deaths Reported in Study 301 .... 40 Table 10. Subjects Follow-up Until Trial Discontinuation (FAS) ................................................... 48 Table 11. Exposure Time in Subjects Exposed to Study Treatment (FAS) .................................... 49 Table 12. Disposition of Subjects by Vital Status .......................................................................... 50 Table 13 Follow-up Time and Treatment Exposure in Subjects Who Prematurely Discontinued Study Treatment ........................................................................................................................... 50 Table 14 Follow-up Time and Treatment Exposure in Subjects Who Prematurely Discontinued Study Visits .................................................................................................................................... 51 Table 15: Summary of Protocol Violations/Deviations for Study 301 .......................................... 51 Table 16: Baseline Demographics of Subjects Enrolled in Study 301 ........................................... 52 Table 17: Comorbid Disease Risk Factors for Subjects Enrolled in Study 301 .............................. 53 Table 18: Summary of Subjects' Gout History, Disease Status and Treatment History for Study 301 ................................................................................................................................................ 54 Table 19: Summary of Subjects' Cardiovascular History in Study 301 ......................................... 55 Table 20: Subjects' Compliance with Randomized Study Medication for Study 301 .................. 56 Table 21: Summary of Study Drug Dose Adjustments for Study 301 (All Subjects) ..................... 57 Table 22: Prophylactic Gout Medication Use and Dose Adjustments for Study 301 ................... 57 Table 23: Concomitant Medications Taken by > 10% of Subjects in Study 301 ........................... 58 Table 24 Primary Analysis of MACE – Number of Events ............................................................ 60 Table 25. Secondary Analysis of Cardiovascular Endpoints – Number of Events ......................... 62 Table 26. Number Needed to Harm in Study TMX-301 ................................................................ 63 Table 27. Number of Event by the Windows of Time after Treatment Discontinuation ............. 64 Table 28. Analysis of CV Death and All-Cause Death – Number of Events ................................... 65 Table 29. Sensitivity Analysis by Renal Function Status and Final Dose of Treatment Drug ........ 66 Table 30. Additional 199 deaths by Windows of Time after Treatment Discontinuation............ 67 Table 31. Follow-up Time and Treatment Exposure Time for Additional 199 Deaths ................. 68 Table 32. Follow-up Time in 821 Subjects with Unknown Vital Status ........................................ 68 Table 33. Primary and Secondary Analyses of Cardiovascular Endpoints .................................... 72 Table 34: Summary of Subjects by Treatment Group Who Experienced Treatment Emergent Adverse Events and Deaths During Study 301.............................................................................. 74 Table 35: Treatment Emergent Adverse Events Leading to Death by MedDRA System Organ Class and Preferred Term by Treatment Group for Study 301 ..................................................... 75 4 of 169 Table 36: Causes of Adjudicated Cardiovascular Deaths Reported in Study 301 by Various Time Windows ....................................................................................................................................... 79 Table 37: Summary of Adjudicated Non-Cardiovascular Deaths by MedDRA Preferred Term by Treatment Group for Study 301 ................................................................................................... 80 Table 38: Abridged Summary of Treatment-Emergent Serious Adverse Events (SAEs) by MedDRA System Organ Class and Preferred Term Occurring in >1% of Subjects by Randomized Treatment Group for Study 301 ................................................................................................... 81 Table 39: Treatment Emergent Adverse Events Leading to Discontinuation of Randomized Study Medication by MedDRA System Organ Class/Preferred Term Occurring in > 0.1% of Subjects by Randomized Treatment Group for Study 301 .............................................................................. 85 Table 40: Summary of Severe Treatment Emergent Adverse Events (TEAEs)1 by MedDRA System Organ Class in Study 3012 ............................................................................................................. 87 Table 41: Treatment Emergent Adverse Events1 (TEAEs) by MedDRA System Organ Class by Treatment Group for Study 3012 .................................................................................................. 88 Table 42: Summary of Common Treatment Emergent Adverse Events1 by Preferred Term Occurring in >5% of Subjects by Treatment Group in Study 3012,3 .............................................. 89 Table 43: Proportion of Subjects with Serum Uric Acid Levels <6.0 mg/dL and <5.0 mg/dL by Visit by Treatment Group in Study 301 (Full Analysis Set) ........................................................... 90 Table 44: Proportion of Subjects with Gout Flares Requiring Treatment During Study 301 (Full Analysis Set) .................................................................................................................................. 91 Table of Figures Figure 1 Schema of Study 301 ...................................................................................................... 35 Figure 2.Disposition of Subjects in Trial TMX-301 ........................................................................ 47 Figure 3. Discontinuations from Study Visits ................................................................................ 48 Figure 4. Study Follow-up Until Trial Discontinuation .................................................................. 49 Figure 5. Kaplan-Meier Cumulative Probability of Primary MACE by Treatment ........................ 60 Figure 6. Kaplan-Meier Plot for Cardiovascular Death ................................................................. 61 Figure 7. Kaplan-Meier