Serum Urate–Lowering Efficacy and Safety of Tigulixostat in Gout Patients With Hyperuricemia: A Randomized, Double‐Blind, Placebo‐Controlled, Dose‐Finding Trial

Abstract

Objective. To evaluate the safety and efficacy of the nonpurine xanthine oxidase inhibitor tigulixostat for lowering serum urate level in gout patients with hyperuricemia.Methods. We conducted a multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding trial. After screening, gout patients with hyperuricemia were randomly assigned, after appropriate washout, to receive daily oral administration of 50 mg, 100 mg, or 200 mg of tigulixostat, or placebo for 12 weeks. Colchicine gout flare prophylaxis was administered to all patients. The primary end point was the proportion of patients with a serum urate level <5.0 mg/dl at week 12.Results. A total of 143 patients were randomized to receive tigulixostat 50 mg (n = 34), 100 mg (n = 38), or 200 mg (n = 37), or placebo (n = 34). A significantly greater proportion of patients in the tigulixostat groups achieved the target serum urate level <5.0 mg/dl at week 12 (47.1% in the 50 mg group, 44.7% in the 100 mg group, and 62.2% in the 200 mg group) compared to the placebo group (2.9%) (P < 0.0001). The mean percentage change in serum urate level from baseline was also significantly greater in the tigulixostat groups (−38.8% to −61.8%) than in the placebo group at all time points (P < 0.0001). The rate of gout flares requiring rescue treatment ranged from 9.4% to 13.2% in the tigulixostat and placebo groups. The incidence of adverse events was 50.0% to 56.8% across all groups, and their severity was mild or moderate.Conclusion. Tigulixostat significantly lowered serum urate compared to placebo at all doses studied with an acceptable safety profile.ClinicalTrials.gov identifier: NCT03934099.

Isocyanoalkene Addition–Cyclization–Decarboxylation Cascades

“…initial conjugate addition that constitutes a formal [4+1] addition to isocyanoalkenes. The reaction efficiently generates an array of synthetically valuable 2,3-dihydro-1H-pyrroles, 9 a valuable core found in bioactive heterocycles such as Tigulixostat (10), 10 which is a phase 3 clinical candidate for the treatment of gout (Scheme 1d). 11 Exploratory conjugate additions employed 1a as a prototype because the isocyanoalkene is readily prepared as a stable, free-flowing solid with virtually no odor (Scheme 2).…”

“…Described here is the first conjugate addition–isocyanide cyclization–decarboxylation sequence ( 1 → 9 , Scheme 1d ) based on an initial conjugate addition that constitutes a formal [4+1] addition to isocyanoalkenes. The reaction efficiently generates an array of synthetically valuable 2,3-dihydro-1 H -pyrroles, 9 a valuable core found in bioactive heterocycles such as Tigulixostat ( 10 ), 10 which is a phase 3 clinical candidate for the treatment of gout (Scheme 1d ). 11…”

Greetings from the editor 2023/2

“…We started with this activity last November in Philadelphia and will continue it this year in Milan on Friday afternoon. Each of the journal editors selects two recent papers that should highlight some of the many publication aspects in these two major societal journals, Arthritis & Rheumatology 13 14 and AR D 15 16. If you have time, please join us at this session for a direct discussion with the authors of these publications.…”