Background Lesinurad (RDEA594) is a selective uric acid reabsorption inhibitor (SURI) investigated for treatment of gout in combination with xanthine oxidase inhibitors (XOI).
Objectives Investigate efficacy as assessed by a composite endpoint of serum uric acid (sUA) target and no flares in gout patients with inadequate response to XOIs alone from three Phase 3 clinical trials examining treatment with lesinurad in combination with allopurinol (ALLO) or febuxostat (FBX).
Methods CLEAR 1 (NCT01510158), CLEAR 2 (NCT01493531) and CRYSTAL (NCT01510769) were 12-month, randomized, double-blind, Phase III trials to evaluate lesinurad (LESU; 200 mg or 400 mg oral, qd) in combination with ALLO vs ALLO + placebo (PBO) (CLEAR 1 and 2) or in combination with FBX vs FBX+PBO (CRYSTAL). A post-hoc composite endpoint defined as the proportion of patients reaching target sUA level (<6 mg/dL in CLEAR 1 and CLEAR 2 and <5 mg/dL in CRYSTAL) and no gout flares was assessed monthly starting at month 7 (after flare prophylaxis was to be discontinued) in each study and in a pooled analysis.
Results CLEAR 1 (N=603), CLEAR 2 (N=610), and CRYSTAL (N=324) patients, respectively, were primarily male (94.0%, 96.2%, and 95.4%); mean ± SD age was 51.9 ± 11.3, 51.2 ± 10.9, and 54.1 ± 11.0 years and duration since gout diagnosis was 11.8 ± 9.4, 11.5 ± 9.3, and 14.7 ± 10.9 years. Most CLEAR 1 and CLEAR 2 patients (90.5% and 84.1%) received ALLO 300 mg daily (range: 200–600 mg and 200–900 mg, respectively). For CLEAR 1 and CLEAR 2, LESU at both doses in combination with ALLO significantly increased proportions of patients achieving the composite endpoint (sUA target <6.0 mg/dL and no flares) vs ALLO+PBO at all visits, with approximately twice as many LESU patients achieving the composite endpoint (p<0.001). For CRYSTAL, LESU at both doses in combination with FBX increased proportions of patients achieving the composite endpoint (sUA target <5.0 mg/dL and no flares) vs FBX+PBO at all visits, with approximately 40% more LESU patients achieving the composite endpoint (p=0.374 to p=0.002). A pooled analysis of LESU at both doses in combination with ALLO or FBX significantly increased proportions of patients achieving the composite endpoint sUA target vs ALLO+PBO or FBX+PBO at all visits, with approximately twice as many LESU patients achieving the composite endpoint (p<0.001). Sensitivity analysis comparing gout flares requiring treatment (rather than all flares) and sustained achievement of composite endpoint were also carried out.
Conclusions Significantly greater proportions of patients responded to the combination of lesinurad (200 or 400 mg) + XOI, with approximately twice as many achieving the composite endpoint of sUA target and no flares compared with patients treated with XOI+PBO. Combination therapy with lesinurad + XOI represents an option for gout patients who warrant additional therapy
Acknowledgement Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca.
Disclosure of Interest P. Khanna Grant/research support from: AstraZeneca, S. Baumgartner Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, J. Robinson Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, E. Tafesse Employee of: AstraZeneca, R. Morlock Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group