Dotinurad Demonstrates Superiority to Febuxostat for the Treatment of Gout

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Among a cohort of Chinese patients with gout, dotinurad 4 mg demonstrated superiority to febuxostat 40 mg in lowering serum uric acid (sUA), according to data presented at the 2024 European Congress of Rheumatology (EULAR).¹ Additionally, dotinurad 2 mg was non-inferior to febuxostat and the drug was well tolerated.

“Gout is increasingly common disease in China,” explained a team of international investigators.

Dotinurad, a novel, selective urate reabsorption inhibitor, was approved for the treatment of hyperuricemia and gout in Japan in 2020. The drug works by reducing serum uric acid levels by selectively inhibiting the urate transporter. Febuxostat, a nonpurine xanthine oxidase inhibitor, is a commonly used urate lowering treatment.

Previous research has evaluated the safety and efficacy of dotinurad in patients with hyperuricemia with or without gout. The systematic review and meta-analysis used an electronic database search to identify eligible randomized controlled trials. Results revealed significant improvements in sUA levels among patients with hyperuricemia treated with dotinurad, which was comparable to other commonly available anti-hyperuricemic drugs, and was effective at doses 1 mg, 2 mg, and 4 mg.²

In the current multicenter, double-blind, active-controlled, parallel-group, phase 3 study assessed the safety and efficacy of dotinurad compared with febuxostat among a cohort of patients with gout. Eligible patients had sUA levels >7.0 mg/dL. Subjects were randomized 1:1 to receive either dotinurad 1 mg/day for 4 weeks, followed by 2 mg/day for 8 weeks, and 4 mg/day for 12 weeks; or febuxostat 20 mg/day for 4 weeks followed by 40 mg/day for 20 weeks. The randomization was stratified by baseline sUA levels (<9; 9 – <10; 10 – <11; and ≥11 mg/dL) as well as baseline body mass index (<25 and ≥25 kg/m²).

The primary outcome was the proportion of subjects who were able to achieve ≤ 6.0 mg/dL in sUA level at week 24 and the secondary outcome was the proportion of patients with ≤ 6.0 mg/dL in sUA at week 12. The non-inferiority margin was -10%. For subjects with missing sUA values, the last available post-baseline data were used for efficacy analysis purposes.

In total, 451 patients were included in the study, of which 225 were placed in the dotinurad cohort and 226 were placed in the febuxostat cohort. Among these patients, 220 receiving dotinurad and 221 receiving febuxostat were included in the full analysis set (FAS). Baseline characteristics were similar across treatment groups. Most (98.2%, n = 433) were male, the median age was 38 years, and 72.8 (n = 321) had a baseline body mass index of ≥ 25 kg/m². The mean sUA at baseline was 9.66 mg/dL and the mean time since gout diagnosis was 5.34 years. Most (95.9%) had previously reported gouty arthritis.

A significantly larger proportion of patients in the dotinurad group (73.6%; 95% confidence interval [CI] 67.8-79.5) met the primary endpoint compared with 38.1% (95% CI 31.6-44.5) in the febuxostat group at week 24. The 4 mg dose of dotinurad demonstrated superiority to febuxostat 40 mg, with a treatment difference of 35.87% (P <.001). Additionally, 2 mg proved non-inferiority to febuxostat, with a difference of 5.24% (55.5% vs 50.5%, respectively).

The most reported treatment-emergent adverse events were gouty arthritis (43.5%), COVID-19 (25.6%), and abnormal hepatic function (10.8%) in the dotinurad cohort and gouty arthritis (34.7%), COVID-19 (25.3%), and increased alanine aminotransferase (12.4%) among those in the febuxostat cohort. The safety profile was comparable across treatment arms and no new safety concerns were described in either cohort.

References

1. ^{Sun J, Wang Y, Zhang X, Guo D, et al. A Randomized Multicenter, Double-Blind, Phase 3 Study Comparing Efficacy of Dotinurad and Febuxostat for the Treatment of Gout in Chinese Subjects.Presented at: EULAR. Vienna, Austria. June 12 – 15, 2024.}
2. ^{Iqbal A, Iqbal K, Farid E, et al. Efficacy and Safety of Dotinurad in Hyperuricemic Patients With or Without Gout: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus. 2021;13(4):e14428. Published 2021 Apr 12. doi:10.7759/cureus.14428}