Dotinurad Outperforms Febuxostat in Reducing Uric Acid Levels in Gout Patients, EULAR 2024 Reports

Gout is a painful arthritis caused by high uric acid levels, leading to joint inflammation. Dotinurad is a novel, selective urate reabsorption inhibitor approved in 2020 for treating hyperuricemia and gout in Japan. The drug lowers serum uric acid levels by selectively inhibiting the urate transporter. Febuxostat, a non-purine xanthine oxidase inhibitor, is a widely used treatment for urate reduction.

Previous research has evaluated the efficacy and safety 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, comparable to other commonly available anti-hyperuricemic drugs, and was effective at doses 1 mg, 2 mg, and 4 mg.

The current multicenter, double-blind, active-controlled, parallel-group, phase 3 study evaluated the safety and efficacy of dotinurad compared to febuxostat in patients with gout. Eligible participants had serum uric acid (sUA) levels greater than 7.0 mg/dL. Subjects were randomly assigned in a 1:1 ratio to receive either dotinurad, starting at 1 mg/day for four weeks, then 2 mg/day for eight weeks, and finally 4 mg/day for 12 weeks, or febuxostat, which was administered at 20 mg/day for four weeks followed by 40 mg/day for 20 weeks. Randomization was stratified based on baseline sUA levels (<9, 9–<10, 10–<11, and ≥11 mg/dL) and body mass index (BMI) categories (<25 and ≥25 kg/m²).

The primary outcome was the percentage of participants achieving serum uric acid (sUA) levels of ≤ 6.0 mg/dL by week 24, while the secondary outcome focused on those reaching this level by week 12. The non-inferiority margin was set at -10%. For participants with missing sUA values, the most recent post-baseline data were utilized for efficacy analysis.

A total of 451 patients were included in the study, of which 225 were in the dotinurad cohort, and 226 in the febuxostat cohort. The full analysis set (FAS) included 220 receiving dotinurad and 221 receiving febuxostat. Baseline characteristics were comparable across treatment groups. The majority (98.2%) 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.

The study led to the following findings:

• A significantly larger proportion of patients in the dotinurad group (73.6%) met the primary endpoint compared with 38.1% 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%.
• 2 mg proved non-inferiority to febuxostat, with a difference of 5.24% (55.5% versus 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; there were no new safety concerns in either cohort.

"The findings showed that dotinurad 4 mg is superior to febuxostat 40 mg for gout treatment," the researchers concluded. "Also, dotinurad 2 mg was non-inferior to febuxostat, and the drug was well-tolerated."

Reference:

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.