Background/Purpose: Three randomized, double-blind, Phase III trials reported that greater proportions of patients treated with lesinurad 200 mg (LESU200) or 400 mg (LESU400), combined with the xanthine oxidase inhibitor (XOI) allopurinol (ALLO; CLEAR 1 and 2) or febuxostat (FBX; CRYSTAL), achieved serum uric acid (sUA) targets at 6 months versus xanthine oxidase inhibitor (XOI) alone. This analysis evaluated the impact of long-term treatment with lesinurad + XOI on tophus and flares for at least 1 year and up to 2 years.

Methods: Patients completing 12 months in the core CLEAR and CRYSTAL studies could enroll in respective uncontrolled extension studies (NCT01808131; NCT01808144). Patients randomized to LESU200 + XOI or LESU400 + XOI in the core studies who continued on combination therapy in the extension studies were analyzed. Efficacy endpoints included: (1) proportion of patients with complete resolution (CR) of ≥1 target tophus (ie, measurable tophus on hands/wrists and/or feet/ankles 5–20 mm in longest diameter), (2) percent reductions in the total area of all target tophi, and (3) proportion of patients experiencing a gout flare requiring treatment (GFRT).

Results: A total of 239 (LESU200+ALLO) and 232 (LESU400+ALLO) patients continued in the CLEAR extension (n=32 and 33, respectively, with target tophi at baseline); 64 (LESU200+FBX) and 65 (LESU400+FBX) patients continued in the CRYSTAL extension. Proportion of patients with CR of ≥1 target tophus increased from end of core study (1 year) to 2 years: from 25.0% to 43.8% in LESU200+ALLO and 30.3% to 36.4% in LESU400+ALLO, and from 26.6% to 53.1% in LESU200+FBX and 35.4% to 58.5% in LESU400+FBX (LOCF). Percent reduction in the total area of all target tophi versus baseline changed from end of core study to 2 years: from 11.6% to 41.8% in LESU200+ALLO and 42.7% to 49.3% in LESU400+ALLO, and from 54.8% to 68.3% in LESU200+FBX and 58.6% to 72.4% in LESU400+FBX (LOCF). Proportion of patients with a GFRT per month decreased during continued combination treatment in both extension studies (Figure). The proportion of patients with a GFRT during Months 1, 12, and 24 were, respectively, 16.3%, 7.9%, and 5.6% in LESU200+ALLO; 18.1%, 6.9%, and 3.0% in LESU400+ALLO; 26.6%, 10.9%, and 6.3% in LESU200+FBX; and 36.9%, 4.6%, and 1.9% in LESU400+FBX. Extended treatment with LESU + XOI did not result in increased exposure-adjusted incidence rates of adverse events (AEs), AEs leading to discontinuation of lesinurad, serious AEs, or clinical laboratory abnormalities.  

Conclusion: The CLEAR and CRYSTAL extension studies showed that patients treated with lesinurad + XOI for up to 2 years exhibited continued increases in the rate of complete resolution of tophi and reduction in tophus area, as well as decreased rates of gout flares.