SAT0329 Lesinurad, A Novel Selective Uric Acid Reabsorption Inhibitor, in Combination with Febuxostat, in Patients with Tophaceous Gout: the Crystal Phase III Clinical Trial
Authors: N. Dalbeth, G. Jones, R. Terkeltaub, D. Khanna, J. Kopicko, N. Bhakta, M. Fung, C. Storgard, S. Baumgartner, F. Perez-Ruiz
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Lesinurad (LESU; RDEA594) is a selective uric acid reabsorption inhibitor (SURI) being investigated for the treatment of gout in combination with a xanthine oxidase inhibitor. <h3>Objectives</h3> The CRYSTAL study is a multinational, randomized, double-blind, placebo-controlled, phase III clinical trial of LESU in combination with febuxostat (FBX) to determine efficacy and safety of combination therapy compared with FBX monotherapy in patients with tophaceous gout (NCT01510769). <h3>Methods</h3> Patients with gout, ages 18-85 yrs, with serum uric acid (sUA) ≥8 mg/dL (≥6 mg/dL on urate lowering therapy) and ≥1 tophus were given FBX 80 mg qd for 3 weeks before randomization to LESU (200 mg or 400 mg oral, qd) in combination with FBX or placebo (PBO) + FBX. Primary endpoint was proportion of patients with sUA &lt;5.0 mg/dL by Month 6. Secondary endpoints included proportion of patients with complete resolution of ≥1 tophus and percent reduction in tophus area by Month 12. Safety assessments included adverse events and laboratory data. <h3>Results</h3> Patients (N=324) were white (79.9%) and male (95.4%) with mean ± SD age of 54.1±11.0 yrs and 14.7±10.9 yrs since gout diagnosis. sUA was 8.7±1.6 mg/dL at screening and 5.3±1.6 mg/dL on FBX at randomization (28% with sUA ≥6 mg/dL). More patients achieved sUA levels &lt;6, &lt;5 (primary endpoint), &lt;4, and &lt;3 mg/dL with LESU+FBX (Figure). Percentage of patients with complete resolution of ≥1 tophus by Month 12 was 21.1%, 25.5% and 30.3% for FBX+PBO, FBX+LESU200 and FBX+LESU400, respectively. Percent decrease in tophus area by Month 12 was 55.8% and 57.9% for FBX+LESU200 and FBX+LESU400, respectively, vs. 31.3% for FBX + PBO (both p&lt;0.05). Safety data are reported in the Table. More serum creatinine (sCr) increases were observed with LESU+FBX; most resolved at last study visit (Table). Kidney stones were lower with LESU. <h3>Conclusions</h3> In patients with tophaceous gout, LESU (200 or 400 mg) in combination with FBX increased the proportion of patients achieving sUA &lt;5 mg/dL at 6 months compared with FBX alone. LESU in combination with FBX resulted in greater tophus area resolution compared with FBX alone, as well as a dose-ordered numerical increase in the proportion of subjects having complete tophi resolution. LESU was generally well tolerated, except for higher incidence of predominately reversible sCr elevations. Combination therapy with LESU+FBX may represent a future treatment option for patients with tophaceous gout on FBX who warrant additional therapy. <h3>Acknowledgements</h3> Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca. <h3>Disclosure of Interest</h3> N. Dalbeth Grant/research support from: AstraZeneca, Fonterra, Novartis, Speakers bureau: Savient, Menarini, Novartis, Takeda, and Advisory Boards for AstraZeneca, Fonterra, Takeda, Metabolex, G. Jones Grant/research support from: Abbvie, Ardea, Novartis, Auxilium, Consultant for: Pfizer, Roche, Hospira and Janssen, Speakers bureau: UCB, Roche, Janssen, Abbvie, Novartis, Mundipharma, Amgen, BMS, Pfizer, R. Terkeltaub Consultant for: AstraZeneca, Takeda, Revive, Relburn, UCB, D. Khanna Grant/research support from: AstraZeneca, Consultant for: AstraZeneca, Takeda, J. Kopicko Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, N. Bhakta Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, M. Fung Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, C. Storgard Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, S. Baumgartner Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, F. Perez-Ruiz Grant/research support from: Spanish Health Ministry, Spanish Rheumatology Foundation, and Cruces Hospital Rheumatologists Association, Consultant for: AstraZeneca, Menarini, Metabolex, Novartis, Pfizer, and SOBI, Speakers bureau: AstraZeneca and Menarini