Clinical efficacy and safety of dotinurad, a novel selective urate reabsorption inhibitor, in Japanese hyperuricemic patients with or without gout: randomized, multicenter, double-blind, placebo-controlled, parallel-group, confirmatory phase 2 study

Abstract

Background Dotinurad, a novel selective urate reabsorption inhibitor (SURI), reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1) for the treatment of hyperuricemia with or without gout. We confirmed the serum uric acid lowering effect and safety of dotinurad. Methods This was a confirmatory, 12-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose escalation, late phase 2 study. The study arms were dotinurad 0.5, 1, 2, or 4 mg and placebo. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. The secondary endpoint was the percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit. Results The study drugs were administered to 200 Japanese hyperuricemic patients with or without gout. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad 0.5, 1, 2, and 4 mg groups and the placebo group was 21.81%, 33.77%, 42.66%, 61.09%, and − 2.83%, respectively. The percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit in each group was 23.1%, 65.9%, 74.4%, 100%, and none, respectively. Regarding safety, the incidence of adverse events did not increase with dose escalation in the dotinurad groups. No significant differences were observed in the incidence of gouty arthritis in each group. Conclusion The serum uric acid lowering effect and safety of dotinurad were confirmed in hyperuricemic patients with or without gout. ClinicalTrials.gov Identifier NCT02416167Keywords Hyperuricemia · Gout · Selective urate reabsorption inhibitor · URAT1 inhibitor · Dotinurad · FYU-981Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Efficacy and Safety of Dotinurad in Hyperuricemic Patients With or Without Gout: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…After removing duplicates and screening titles and abstracts, 30 full-text articles were reviewed. Finally, four RCTs (684 patients) were eligible for inclusion in the study (Figure 1) [2,7,8,10]. All the included studies assessed the efficacy and safety of dotinurad in hyperuricemic patients with or without gout.…”

“…All the included studies assessed the efficacy and safety of dotinurad in hyperuricemic patients with or without gout. Two trials compared dotinurad with placebo, while the rest of the two used active control, i.e, benzbromarone and febuxostat as a comparator [2,7,8,10].…”

“…These asymptomatic patients do not exhibit clinical features of gout [6]. Japanese guidelines for the management of hyperuricemia and gout recommend drug therapy for asymptomatic hyperuricemic patients with comorbidities like DM, HTN, and CKD when serum uric acid level is ≥ 8 mg/dl [7]. The pharmacological therapy aims to reduce and maintain a serum uric acid level at ≤ 6 mg/dl [7].…”

“…Allopurinol and febuxostat inhibit xanthine oxidase, reducing the conversion of xanthine to uric acid [1]. However, despite being the first-line urate-lowering drug, allopurinol carries a risk of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity syndrome of allopurinol [7]. While severe hepatotoxicity, including fulminant hepatitis, is associated with benzbromarone [8].…”

Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment

“…Completed phase 2 studies of dotinurad demonstrated a potent uric acid lowering effect as well as a favorable safety profile [10,11]. In a phase 1 study in healthy adults, PK parameters of dotinurad showed a linear C max and its time to C max (T max ) and elimination half-life (T 1/2 ) were approximately 3 and 10 h, respectively, which were nearly constant irrespective of the dose level.…”