Background Two replicate, randomized, core Phase III trials (CLEAR 1 and 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 ALLO+placebo (PBO) (P<0.0001). The safety profile of LESU200+ALLO was comparable to ALLO+placebo, except for higher rates of predominantly reversible serum creatinine (sCr) elevation.
Objectives Assess long-term safety and efficacy of LESU+ALLO therapy in subjects enrolled in the CLEAR 1and 2 extension study (NCT01808131).
Methods Efficacy was assessed for those completing the core study and either 1) continuing core LESU+ALLO treatment (200CONT, 400CONT) or 2) crossing over from core ALLO+PBO to either 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 proportions of subjects with target sUA <6.0 mg/dL and mean sUA levels (ITT–observed cases). Treatment-emergent adverse events (TEAEs) were calculated as exposure-adjusted incidence rates (EAIRs; events per 100 person-years [100-PY]).
Results For efficacy, the 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. Proportions 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 the core studies, and 5.71 (1.80), 6.68 (1.57), 5.06 (1.94) and 6.68 (1.38) at the end of the 12-month core studies. After 12 months in the extension study when all patients received lesinurad, mean (SD) sUA was 5.75 (1.77), 5.78 (1.92), 5.01 (1.95), and 5.25 (1.77), respectively.
For safety, pooled analysis on a total of 405 and 401 subjects (LESU200, LESU400 respectively), from the core studies and 239 and 232 (200CONT, 400CONT, respectively) from the extension studies, was conducted. EAIRs (per 100-PY) of TEAEs and serious TEAEs at any time during core or extension studies 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 incidence rates were 0.5 and 2.0 per 100-PY for LESU200 and LESU400, respectively. EAIRs of sCr elevations ≥1.5x baseline was 7.8 and 17.0 per 100-PY for LESU200 and LESU400, respectively; resolution of sCr elevations by analysis cutoff occurred in 91.7% and 87.8% of cases, respectively.
Conclusions Subjects treated with LESU+ALLO therapy through 2 years continued to be at sUA target; those crossing over from ALLO monotherapy had increased proportions reach target. Safety during continued treatment was consistent throughout the core and extension studies.
Acknowledgement This study was funded by Ardea Biosciences/AstraZeneca.
Disclosure of Interest K. Saag Grant/research support from: Ardea Biosciences, Inc., a member of the AstraZeneca Group; Crealta, Takeda, Consultant for: Ardea Biosciences Inc., a member of the AstraZeneca Group; AstraZeneca; Takeda, M. Becker Consultant for: Ardea Biosciences Inc., a member of the AstraZeneca Group; AstraZeneca; Takeda; Crealta; CymaBay; BioCryst; Pfizer, C. Storgard 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, J. Hu Employee of: Ardea Biosciences, Inc., a member of the AstraZeneca Group, T. Bardin Grant/research support from: Ipsen; Menarini, Consultant for: AstraZeneca; Ipsen; Menarini; Novartis; Savient; Sobi; Takeda