Novel Gout Drug Passes Mid-Stage Test

An investigational non-purine xanthine oxidase inhibitor for gout treatment, called tigulixostat, appeared effective enough in a phase II trial that a pivotal study is now getting underway.

Depending on the dose, 45% to 62% of patients receiving the oral drug met the serum urate target of <5.0 mg/dL after 12 weeks, compared with 2.9% of a placebo group (P<0.0001), reported Kenneth Saag, MD, MSc, of the University of Alabama at Birmingham, and colleagues.

This degree of urate lowering compares favorably to that seen with optimal treatment with other xanthine oxidase inhibitors such as allopurinol and febuxostat (Uloric). Efficacy did not seem impeded in participants with mild kidney disease, and no obvious safety concerns were seen with the drug, the authors reported in Arthritis & Rheumatology.

Developer LG Chem, based in South Korea, hopes to position tigulixostat as a first-line treatment for gout. Allopurinol now holds that distinction, but its use is complicated by the need to titrate dosing to achieve full effectiveness. In practice, Saag and colleagues noted, the titration is considered too complicated for many patients, who instead simply received fixed doses from the start — the result being that most never reach the recommended serum urate target. Dosing is further complicated in patients with severe renal impairment.

Febuxostat, meanwhile, is now indicated strictly as second-line therapy for patients not responding or intolerant to allopurinol, after a long-term safety study found increased risk for cardiovascular events and death. The FDA required in 2019 that the drug carry a boxed warning about this risk.

Tigulixostat is chemically distinct from both drugs, such that LG Chem believes it can avoid the attendant problems.

For the current study, the researchers randomized 143 patients in approximately equal numbers to placebo or one of three tigulixostat doses: 50, 100, or 200 mg/day. (Originally, the trial was to include a febuxostat group as well, but the 2019 label change came through just as the trial was getting underway, which made use of the drug under the trial’s design unethical. Consequently, that arm was terminated after 13 patients were enrolled.)

Mean patient age was about 54, and almost all were men. Gout duration averaged more than 12 years. Roughly one-quarter had tophi and mean serum urate at baseline stood at just over 9.0 mg/dL. All patients also received colchicine to prevent gout flares. The trial’s primary endpoint was reduction in serum urate to less than 5.0 mg/dL at week 12.

There appeared to be a dose-response effect with tigulixostat, such that the degree of urate lowering increased with the higher doses. Patients assigned to 200 mg/day saw an average 56% decrease at week 12, while it was down 44% and 41% with 100 and 50 mg/day, respectively. Encouragingly, urate reductions were similar irrespective of whether estimated glomerular filtration rates were above or below 90 mL/min/1.73 m².

Rates of treatment-emergent adverse events were similar across all study arms. At the 200-mg/day dose, three of 37 patients developed creatine kinase elevations, and three also showed increases in liver enzymes, neither of which occurred with placebo. Three patients across the active drug groups stopped treatment as a result of transaminase elevations. No new-onset cardiac disorders were seen.

Over the course of the study, gout flares occurred at roughly equal rates in the four arms, affecting about 15% of participants. Oddly, about 10% of patients in each of the three tigulixostat groups developed flares during weeks 4-8, while none occurred with placebo. But this pattern flipped during weeks 8-12.

The report described the study as “dose-finding,” but it didn’t actually succeed in that if taken literally. In the phase III study that is just getting started, with recruitment expected to begin this month, doses of 100, 200, and 300 mg/day are to be tested in some 2,500 patients for 12 months.

Assuming the efficacy findings in the current study are confirmed, the next big question is whether tigulixostat can avoid the cardiovascular risk seen with febuxostat. The phase III trial may not answer it, insofar as the safety problems with febuxostat became apparent with a study enrolling almost 6,200 patients and with median follow-up of 32 months.