Background Lesinurad (RDEA594) is a selective uric acid reabsorption inhibitor (SURI) being investigated for treatment of gout in combination with xanthine oxidase inhibitors.
Objectives Investigate the efficacy and safety of lesinurad in combination with allopurinol (ALLO) in gout patients with inadequate response to standard of care (SOC) ALLO dosing (NCT01510158).
Methods CLEAR 1 was a 12-month, randomized, double-blind, US phase III trial to evaluate lesinurad (200 mg or 400 mg oral, qd) in combination with ALLO vs ALLO+placebo (PBO). Patients were ages 18-85 yrs on stable, medically appropriate SOC ALLO doses ≥300 mg (≥200 mg in moderate renal impairment), as determined by investigator, with serum uric acid (sUA) ≥6.5 mg/dL at screening and ≥2 gout flares in prior 12 months. Primary endpoint was proportion of patients meeting sUA target of <6.0 mg/dL (<360 μmol/L) by Month 6. Secondary endpoints included mean gout flare rate requiring treatment (GFRT; Months 6 through 12) and proportion of patients with complete resolution of ≥1 target tophus by Month 12. Safety assessments included treatment-emergent AEs and laboratory data.
Results Patients (N=603) were primarily male (94.0%), mean ± SD age was 51.9±11.3 yrs, and duration since gout diagnosis was 11.8±9.4 yrs. Most patients (90.5%) received ALLO 300 mg (range: 200-600 mg) daily; 14.3% had tophi at screening (measurable target tophi at baseline, 9.0%) and baseline sUA was 6.94±1.27 mg/dL. Lesinurad at both doses in combination with ALLO significantly increased proportions of patients achieving sUA targets (<6.0 mg/dL and <5.0 mg/dL) vs ALLO+PBO at all visits, with approximately twice as many patients achieving these targets at Month 6 (Figure). No significant differences were observed between groups in mean rate of GFRT (Month 6 to 12) or patients with complete target tophus resolution (by Month 12). Safety data are reported in the Table. Serum creatinine (sCr) elevations were observed, which resolved in most cases without interrupting study medication.
Conclusions Significantly greater proportions of patients responded to addition of lesinurad (200 or 400 mg), with approximately twice as many achieving sUA target at 6 months compared with patients treated with ALLO+PBO. Lesinurad was generally well tolerated, particularly at 200 mg, where AE profile was comparable to ALLO+PBO, with the exception of higher incidence of reversible 2.0x sCr elevations. Combination therapy with lesinurad+ALLO may represent a future option for gout patients who warrant additional therapy.
Acknowledgements Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca.
Disclosure of Interest K. Saag Grant/research support from: Ardea, Crealta, Takeda, Consultant for: Ardea/AstraZeneca, Takeda, D. Fitz-Patrick Grant/research support from: Takeda, CymaBay Therapeutics, Ardea, J. Kopicko Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, M. Fung Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, N. Bhakta Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca group, S. Adler Employee of: AstraZeneca Pharmaceuticals, 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, M. Becker Consultant for: Ardea /AstraZeneca, BioCryst, Metabolex, Savient, Takeda, Pfizer