Dose-Finding Trial Showcases Promise of Tigulixostat in Gout with Hyperuricemia

Robert Terkeltaub, MD
Image Courtesy: American College of Rheumatology

Data from a dose-finding trial assessing use of tigulixostat in patients with gout with hyperuricemia suggest the nonpurine xanthine oxidase inhibitor shows promise for serum urate-lowering in this patient population.

Named the CLUE trial, results of the study, which included more than 140 patients, demonstrate use of the tigulixostat was associated with significantly lowered serum rate levels in gout patients with hyperuricemia across all 3 doses examined as part of the trial.

“In this randomized, placebo-controlled, dose-finding, phase II study conducted in gout patients with hyperuricemia, a significantly greater proportion of subjects in the tigulixostat dose groups achieved a pre-specified treatment target of serum urate levels of less than 5.0 mg/dL at week 12 compared with the placebo group," wrote investigators.

Led by Robert Terkeltaub, MD, and a multinational team of investigators, the CLUE trial was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding phase II trial designed with the intent of examining the safety and efficacy of tigulixostat in doses of 50 mg, 100 mg, and 200 mg relative to placebo therapy.¹

After screening, gout patients with hyperuricemia were randomized in a 1:1:1:1 ratio to daily oral administration of 50 mg, 100 mg, or 200 mg of tigulixostat or placebo for 12 weeks. Conducted in 42 centers in the US from October 2019-May 2021, the trial enrolled . Of note, the trial was originally designed as a double-dummy, active comparator study with febuxostat serving as an active compactor. This was revised following the US Food and Drug Administration’s addition of a boxed warning for cardiovascular safety risks with febuxostat. Investigators pointed out colchicine gout flare prophylaxis was administered to all trial subjects.

Overall, 751 patients were screened. Of these, 595 failed screening and 156 underwent enrollment in the study. Among this group, 143 underwent randomization, with 34, 38, 37, and 34 assigned to the tigulixostat 50 mg, tigulixostat 100 mg, tigulixostat 200 mg, and placebo groups. Investigators pointed out 12 patients were assigned to the febuxostat group prior to revisions in trial protocol.¹

The primary efficacy outcome of the trial was the achievement of a serum rate level less than 5.0 mg/dL at week 12. Gout flares served as a secondary outcome of interest for the trial, with investigators gout flares as subject-reported pain requiring rescue medication.

Results of the trial indicated a significantly greater proportion of subjects in the tigulixostat 50 mg (47.1%), tigulixostat 100 mg (44.7%), and tigulixostat 200 mg (62.2%) groups achieved a serum rate level lower than 5.0 mg/dL at week 12 compared to the placebo o group (2.9%; P <.0001). Further analysis of serum rate levels from baseline demonstrated mean perchance change was significantly greater in the tigulixostat groups, with mean changes ranging from -38.8% to -61.8%, compared to the placebo groups at all time points (P <.0001).¹

Analysis of secondary outcomes of interest revealed gout flares were experienced by 12.9%, 13.2%, 10.8%, and 9.4% in the tigulixostat 50 mg, 100 mg, 200 mg, and placebo groups, respectively. Additional analysis indicated treatment emergent adverse events were experienced by 50%, 50%, 56.8%, and 50.0%, in the tigulixostat 50 mg, 100 mg, 200 mg, and placebo groups, respectively.¹

“Tigulixostat at all 3 doses significantly lowered serum urate levels in gout patients with hyperuricemia compared to placebo. Tigulixostat was generally well tolerated at all dose levels without clinically noticeable safety issues,” wrote investigators.¹ “The efficacy and safety of tigulixostat in patients with chronic gouty arthritis warrant long-term clinical studies.”

References:

1. Terkeltaub R, Lee J, Min J, Shin S, Saag KG. Serum urate‐lowering efficacy and safety of tigulixostat in gout patients with hyperuricemia: A randomized, double‐blind, placebo‐controlled, dose‐finding trial. Arthritis & Rheumatology. January 2023. doi:10.1002/art.42447