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

Abstract

Background Dotinurad, a novel selective urate reabsorption inhibitor (SURI) that has a future potential for the treatment of hyperuricemia, reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1). We evaluated the efficacy and safety of dotinurad in hyperuricemic Japanese patients with or without gout. Methods The study design was an exploratory, early phase 2 study that ran for 8 weeks. It was a randomized, multicenter, double-blind, placebo-controlled, parallel-group study, and performed in a dose escalation manner. There were four study arms consisting of dotinurad 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 A total of 80 hyperuricemic patients with or without gout were enrolled and randomly assigned to the dotinurad or placebo groups. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad 1, 2, 4 mg, and placebo groups was 37.03%, 50.91%, 64.37%, and 0.85%, respectively. The percentages of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit in each group were 75.0%, 89.5%, 95.2%, and none, respectively. The incidence of adverse events was comparable among all groups. Conclusion Dotinurad has a substantial serum uric acid lowering effect in patients with hyperuricemia. No serious adverse event was found. ClinicalTrials.gov Identifier NCT02344862

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.…”

“…Hyperuricemia, defined as a serum uric acid level > 7 mg/dl, is associated with an increased risk of urate deposition diseases, namely gout, uric acid nephrolithiasis, and urate neuropathy [1]. Additionally, an increased prevalence of chronic kidney disease (CKD), diabetes mellitus (DM), and hypertension (HTN) exist in patients with increased serum uric acid levels [2]. The global burden of hyperuricemia and gout is rising, projecting that gout mortality may increase by 55% in 2060 [3].…”

“…The global burden of hyperuricemia and gout is rising, projecting that gout mortality may increase by 55% in 2060 [3]. The third edition of Japanese guidelines classifies hyperuricemia as under-excretion, combined, and renal load type [2]. The renal load type encompasses the overproduction and extra-renal under-excretion hyperuricemia [2].…”

“…The third edition of Japanese guidelines classifies hyperuricemia as under-excretion, combined, and renal load type [2]. The renal load type encompasses the overproduction and extra-renal under-excretion hyperuricemia [2]. The latter is due to reduced intestinal urate excretion caused by ATP-binding cassette transporter, sub-family G, member 2 (ABCG2) dysfunction [4].…”

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.…”