Background/Purpose: Two replicate, randomized, core Phase III trials (CLEAR 1 & 2) reported significantly more subjects treated with lesinurad 200 mg (LESU200) or 400 mg (LESU400), combined with allopurinol (ALLO), achieved target sUA <6.0 mg/dL at 6 and 12 months than with ALLO alone (P<0.0001).^1,2 The safety profile of LESU200+ALLO was comparable to ALLO alone, except for higher incidences of predominantly reversible serum creatinine (sCr) elevations. Objectives: Assess long-term safety and efficacy of LESU+ALLO therapy in subjects enrolled in the CLEAR 1 and 2 extension study (NCT01808131).

Methods: Efficacy was assessed for those completing the core study and either continuing core LESU+ALLO treatment (200CONT, 400CONT) or crossing over into extension studies from core ALLO alone to ALLO+LESU200 (200CROSS) or LESU400 (400CROSS). Core LESU200+ALLO or LESU400+ALLO subjects and 200CONT and 400CONT extension groups are reported for safety. Efficacy endpoints included proportion of subjects with target sUA <6.0 mg/dL and mean sUA levels. Treatment-emergent adverse events (TEAEs) were calculated as exposure-adjusted incidence rates (EAIRs; subjects with events per 100 person-years).  

Results: For efficacy, 200CONT (n=239) and 400CONT (n=232) groups receiving treatment for up to 24 months, and 200CROSS (n=121) and 400CROSS (n=122) groups, receiving treatment for up to 12 months, were analyzed. Proportion of subjects with sUA <6.0 mg/dL during core and extension are shown (Figure). Mean (SD) sUA (mg/dL) for 200CONT, 200CROSS, 400CONT and 400CROSS groups, respectively, were 6.96 (1.14), 6.92 (1.33), 6.80 (1.20) and 6.99 (1.14) at baseline of core studies, and 5.71 (1.80), 6.68 (1.57), 5.06 (1.94) and 6.68 (1.38) at end of 12-month core studies. After 12 months in the extension study when all patients received LESU, mean (SD) sUA (mg/dL) was 5.75 (1.77), 5.78 (1.92), 5.01 (1.95) and 5.25 (1.77), respectively. For safety, a pooled analysis on a total of 405 (LESU200) and 401 (LESU400) subjects receiving lesinurad in combination with ALLO from the core studies was conducted. During the core and extension study period, EAIRs of TEAEs and serious TEAEs at any time were 54.2 and 5.8 for LESU200 and 57.2 and 8.3 for LESU400. EAIRs of renal-related TEAEs and serious renal-related TEAEs were 7.4 and 0.5 for LESU200 and 14.2 and 0.8 for LESU400. EAIRs of kidney stone TEAEs were 0.5 and 2.0 for LESU200 and LESU400, respectively. EAIRs of sCr elevations ≥1.5x baseline was 7.8 and 17.0 for LESU200 and LESU400, respectively. The majority of elevations (91.7% and 87.8%, respectively) were resolved by analysis cut-off.

Conclusion: Subjects treated with LESU+ALLO therapy through 2 years continued to be at sUA target; those crossing from ALLO monotherapy had increased proportions reach target. Safety during continued treatment in the extension studies was consistent with the profile observed in the core studies.