CI‐1 Introduction and Regulatory History Beth‐Anne Knapp Vice President Global Regulatory Affairs, Marketed Products CI‐2 Agenda for Today Introduction Beth-Anne Knapp Vice President Global Regulatory Affairs, Marketed Products Gout Disease Background Michael A. Becker, MD and Treatment Landscape Professor Emeritus University of Chicago CARES and Cardiovascular Safety of William B. White, MD Febuxostat Professor of Medicine, Cardiology Center University of Connecticut School of Medicine Efficacy Lhanoo Gunawardhana, MD, PhD Senior Medical Director Clinical Science, Marketed Products Benefit/Risk Assessment John Affinito, MD Executive Medical Director Global Patient Safety & Evaluation, Marketed Products Clinical Perspective N. Lawrence Edwards, MD, MACP, MACR Professor and Vice Chairman Department of Medicine, University of Florida CI‐3 Consultants Kevin J. Carroll, PhD Managing Director and Statistical Consultant KJC Statistics Ltd, UK Andrew Whelton, MD Professor of Medicine, Adjunct Johns Hopkins University School of Medicine CI‐4 ULORIC (febuxostat) Prescribing Information Summary ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia. • Approved February 2009 • 40 mg and 80 mg • 85 countries; >15 million patient‐years of exposure • Ex‐US – Other indications – Doses 10 to 120 mg CI‐5 Rationale and Benefit of Febuxostat for the Treatment of Gout • Urate‐lowering therapy is central to long‐term management of gout – Febuxostat meets ACR recommendations to reduce and maintain serum urate • Reduces body urate pool and dissolve crystals • Decreases acute flares and reduces tophus size • Important treatment option • No dose adjustment for mild or moderate renal impairment – 40 mg for patients with severe renal impairment CI‐6 Febuxostat Clinical Development Program Phase 2 Trials Phase 3 Trials Study 004 APEX FACT CONFIRMS n=153 n=1072 n=760 n=2269 1 month 6 months 1 year 6 months FOCUS EXCEL Open‐Label Open‐Label Extension Study Extension Study n=1086 n=116 3 years 5 years Adjudicated Major CV Eventsa: CI‐7 Pooled Analysis of Phase 3 Randomized Controlled Studies CONFIRMS, APEX, FACT Events, n (rate per 100 subject‐years) 95% CI Febuxostat Allopurinol n=2690 n=1277 All APTC events 10 (0.74) 4 (0.60) 0.36, 1.37 0.16, 1.53 CV death 3 (0.22) 2 (0.30) 0.05, 0.65 0.04, 1.08 Nonfatal MI 5 (0.37) 2 (0.30) 0.12, 0.87 0.04, 1.08 Nonfatal stroke 2 (0.15) 0 0.02, 0.54 0.00, 0.55 a Adjudication was done prospectively in CONFIRMS and retrospectively in APEX and FACT. CI‐8 Brief Regulatory History • November 2008: Arthritis Advisory Committee recommended approval – Yes=12, No=0, Abstain=1 – Adequate evidence to support efficacy, safety, and quality – Cardiovascular safety risk not fully elucidated – Post‐approval study to assess CV safety • February 2009: ULORIC (febuxostat) approved – USPI included Warnings & Precautions for cardiovascular events – Post‐marketing requirement for a randomized, controlled CVOT CI‐9 Febuxostat Clinical Program Phase 2 Trials Phase 3 Trials Study 004 APEX FACT CONFIRMS n=153 n=1072 n=760 n=2269 1 month 6 months 1 year 6 months FOCUS EXCEL Open‐Label Open‐Label Extension Study Extension Study n=1086 n=116 3 years 5 years Post‐Marketing Requirement CARES (CVOT) n=6190 7 years CI‐10 What You Will Hear Today • CARES – Primary endpoint of adjudicated MACE: febuxostat is noninferior to allopurinol • Comparable rates in non‐fatal CV events • Higher rate of CV death – Comprehensive assessment • Totality of evidence – Development program: clinical and nonclinical – Literature – Post‐marketing surveillance • Informing physicians with CARES – Label: Warnings & Precautions, Patient Information Leaflet – Dear Healthcare Provider Letter • Febuxostat is an important treatment option CL‐1 Gout: Disease Burden, Background & Treatment Landscape Michael A. Becker, MD Professor Emeritus The University of Chicago CL‐2 Gout Is a Painful, Chronic, and Disabling Inflammatory Disorder • Affects approximately 9 million people in the USa • Signs/Symptoms: flares, tophi, arthropathy, and urolithiasis • Saturating levels of urate in extracellular fluids may result in urate crystal formation and deposition in joints, bones, cartilage, tendons, and skinb – Hyperuricemia (sUA >6.8 mg/dL) reflects urate saturation and is necessary, but not sufficient, for the expression of gout – In the absence of urate crystal formation and tissue deposition and an inflammatory response to the crystals, the symptoms and signs of gout do not occur a Chen‐Xu M, et al. Arthritis Rheumatol. 2019; In Press; b Doherty M, et al. Ann Rheum Dis. 2012;71:1765‐1770. Gout Flares and Monosodium Urate Crystals in Synovial Fluid CL‐3 Neutrophils on Polarized Microscopy ABC A. Courtesy of Michael A. Becker, MD. B. American College of Rheumatology slide collection on Rheumatic Diseases, 1997. C. Courtesy of Michael A. Becker, MD. Gout Progression May Lead to Tophi, Joint Destruction, CL‐4 and Functional Impairment Urate deposition 3‐Dimensional Bone and joint within handsa CT imagea destructionb a Dalbeth N, et al. Arthritis Rheumatol. 2007;56(1):29. b Image courtesy of Dr. Fernando Perez‐Ruiz. Serious Comorbidities Frequently Accompanying CL‐5 Hyperuricemia and Gout (NHANES 2007‐2008) 100% Gout 90% % No Gout 80% 70% n=5707 60% comorbidities, 50% of 40% 30% 20% Prevalence 10% 0% Hyper‐ CKD Obesity Diabetes Nephro‐ CKD MI Heart Stroke tension Stage ≥2 lithiasis Stage ≥3 failure Zhu Y, et al. Am J Med. 2012;125(7):679‐687. CL‐6 Increased Risk of CV Death Associated With Gout Risk of death Outcome Lower Higher HR (95% CI) All‐cause mortality 1.28 (1.15, 1.41) All‐cardiovascular death 1.38 (1.15, 1.66) Fatal coronary heart disease 1.55 (1.24, 1.93) 0.5 1 2 Relative risk (95% CI) Choi HK, et al. Circulation. 2007;116(8):894‐900. CL‐7 Current Treatment Landscape in Gout • Nonpharmacologic therapy: Adjunct therapy – Lifestyle adjustments and risk reduction measures (eg, weight loss, alcohol avoidance, replacement of hyperuricemia‐promoting meds) • Pharmacologic therapy – Anti‐inflammatory agents: Short‐term symptom control (not urate lowering) • NSAIDs, glucocorticoids, colchicine, IL‐1β antagonists – Urate‐Lowering Pharmacotherapy (ULT): Long‐term management • Majority of gout patients will ultimately fulfill criteria for urate‐lowering pharmacotherapy CL‐8 Urate‐Lowering Pharmacotherapy: Rationale and Support • Urate‐Lowering Pharmacotherapy (ULT): Long‐term management – Reduce the body soluble urate pool – Dissolve deposited urate crystals – Prevent/reverse gout symptoms and progression to disability & impaired QOL • Support for urate‐lowering pharmacotherapya – 3 mechanistically distinct urate‐lowering therapeutic strategies that are disease modifyinga a. Li‐Yu J, et al. J Rheumatol. 2001;28(3);577‐580; Perez‐Ruiz F, et al. Arthritis Rheum. 2002;47(4):356‐360; Sundy JS, et al. JAMA. 2011;306(7):711‐720; Becker MA, et al. J Rheum. 2009;36(6):1273‐1282; Shoji A, et al. Arthritis Rheum. 2004;51(3):321‐325. ACR 2012 Recommendations for CL‐9 Urate‐Lowering Pharmacotherapy First‐line Second‐line Third‐line Xanthene oxidase Uricosuric agents Biologic uricolytic therapy inhibitors • Decrease uric acid production • Increase uric acid renal • Converts uric acid to a soluble • Available agents excretion product – Allopurinol • Available agents • Available agent – Febuxostat – Probenecid – Pegloticase – Lesinurad Khanna D, et al. Arthritis Care Res. 2012;64(10):1431‐1467. CL‐10 ACR 2012 Gout Oral Urate‐Lowering Treatment Guidelines • Treat to serum urate (sUA) target – sUA <6.0 mg/dL in most patients – sUA <5.0 mg/dL with persistent symptoms and/or tophi • Treatment initiation and dose titration – Initiate ULT at lowest dose of the chosen agent – Stepwise up‐titration guided by sUA determinations • Lower initiation and incremental doses in renal impairment (same goal urate levels) Khanna D, et al. Arthritis Care Res. 2012;64(10):1431‐1467. CL‐11 Xanthine Oxidase Inhibitors Allopurinol Febuxostat • Purine analog and non‐selective XOI • Not a purine analog but is a selective XOI • Approved in 1966 at daily doses of 100 to 800 mg • Approved in 2009 at daily doses of 40 and 80 mg • Mainstay of urate‐lowering therapy • Renal excretion <10% of dose • Excreted primarily as active metabolite oxypurinol – No need to dose reduce in mild or moderate via kidney renal impairment – 40 mg approved for patients with severe renal impairment Allopurinol Oxypurinol Febuxostat De Vera MA, et al. Arthritis Care Res. 2014;66:1551‐1559. Reduction of Flares Following Treatment With Febuxostat CL‐12 vs Placebo Over 2 Years in Early Gout TMX‐67‐204 45 45 % 41.4 Placebo 40 40 Febuxostat flare, 35 35 * gout 29.3 30 30 27.9 one 25 25 21.7 least 20 20 17.2 16.5 at ** 15 15 13.4 13.5 * 10.3 with 10 10 * 5.9 5 5 Subjects 0 0 Overall M0‐M6 M6‐M12 M12‐M18 M18‐M24 Time interval P values for difference between treatment groups are from Fisher's exact test. *, ** indicate statistical significance at the 0.05 or 0.01 level, respectively. Dalbeth N, et al. Arthritis Rheumatol. 2017;69(12):2386‐2395. CL‐13 Lowering Serum Urate Increases Rates of Tophus Size Reduction Allopurinol 8 Benzbromarone Combined 6 mg/dL 4 urate, 2 Serum 0 0.0 0.5 1.0 1.5 2.0 2.5 Velocity of tophus reduction, mm/month Perez‐Ruiz F, et al. Arthritis Rheum. 2002;47(4):356‐360. CL‐14 Limited Urate‐Lowering Therapeutic Options in Gout With Many Treatment Challenges XO Inhibitors Uricosuric Agents Pegloticase (pegylated