Background/Purpose: Gout can be effectively managed by inhibiting synthesis of uric acid. Tigulixostat is a novel non-purine selective xanthine oxidase inhibitor which lowers production of uric acid and was well tolerated up to the maximum dose of 800 mg/day for seven-day administration in healthy subjects in a first-in-human clinical study. This phase 2 study was conducted in the U.S. to assess the efficacy and safety of tigulixostat in gout patients with hyperuricemia and to find the appropriate doses for further development.

Methods: Gout patients with serum uric acid (sUA) ≥8.0 mg/dL to ≤12.0 mg/dL after a wash-out/prophylaxis period were randomized to one of tigulixostat 50 mg, 100 mg, 200 mg, or placebo groups and received the study treatment, once daily oral intake, for 12 weeks. The subjects took colchicine 0.6 mg once daily as a gout flare prophylaxis from the screening period and until the end of the treatment. The primary endpoint was the proportion of the subjects achieving sUA < 5 mg/dL at week 12. Non-responder imputation was applied to the subjects who discontinued the study. Secondary endpoints included the proportion of subjects meeting sUA < 6 mg/dL at week 12, and gout flare collected using eDiary. Safety was assessed throughout the study including a 2-week post-treatment follow-up visit.

Results: Subjects were randomized into one of the groups of tigulixostat 50 mg (n=34), tigulixostat 100 mg (n=38), tigulixostat 200 mg (n=37) or placebo (n=34), received at least one dose of the assigned treatment and analyzed for efficacy and safety. Primary and secondary endpoints are reported in the figure 1. Differences in the proportion to the placebo group were statistically significant at all tigulixostat dose levels at both sUA levels (P < 0.0001). The superiority of tigulixostat groups over the placebo group was demonstrated in the primary endpoint. Tigulixostat rapidly lowered sUA within 2 weeks from treatment initiation, and the sUA levels were well maintained throughout the study treatment period. Mean (SD) of maximum percent reduction in sUA was -46.67% (±13.560), -50.64% (±19.127) and -66.79% (±15.787) and -11.20 (8.814), respectively. Mean sUA at baseline and week 12 are reported in the table 1. Total 12.9%, 13.16%, 10.81%, and 9.38% of the subjects had gout flares which required rescue treatment, respectively. TEAEs were comparable across treatment and placebo groups, and no serious TEAEs were reported during the study period. There were three severe TEAEs, and all of them were resolved or resolved with sequelae and were not related to tigulixostat.

Conclusion: In this phase 2 study, tigulixostat significantly lowered sUA levels in gout patients with hyperuricemia compared to placebo at all dose levels, and sUA lowering effect of tigulixostat appeared to be dose-dependent. Treatment with tigulixostat at all 3 dose levels appeared to be well tolerated by study participants. These results and the observed safety profile support dose finding of tigulixostat and the continued development of tigulixostat in gout patients with hyperuricemia.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-2-study-results-from-a-randomized-double-blind-placebo-controlled-dose-finding-study-to-evaluate-efficacy-and-safety-of-tigulixostat-a-novel-non-purine-selective-xanthine-oxidase-inhibitor/