Abstract
BackgroundDotinurad, 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.MethodsThe 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.ResultsA 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.ConclusionDotinurad has a substantial serum uric acid lowering effect in patients with hyperuricemia. No serious adverse event was found.ClinicalTrials.gov IdentifierNCT02344862
Highlights
Hyperuricemia, defined as a serum uric acid level > 7.0 mg/dL in Japan, often causes gouty arthritis by deposition of urate crystals in the joints, tendons, and other connective tissues [1]
All patients were Japanese males, aged 30–64 years, and 85.0% were classified into the “underexcretion type”, while 96.3% had a history of gouty arthritis
In the phase 1 study of dotinurad for healthy adult subjects to date, we confirmed that dotinurad reduced serum uric acid levels and amount of urinary uric acid excretion increased in a dose-dependent manner [NCT02348307]
Summary
Hyperuricemia, defined as a serum uric acid level > 7.0 mg/dL in Japan, often causes gouty arthritis by deposition of urate crystals in the joints, tendons, and other connective tissues [1]. Recent clinical reports have shown that high serum uric acid levels were associated with the increased prevalence of chronic kidney disease (CKD), hypertension, and diabetes mellitus [2,3,4]. Japanese guidelines for the management of hyperuricemia and gout recommend uric acid lowering therapy for hyperuricemia without gout or gouty tophi (asymptomatic hyperuricemia) especially in cases where the serum uric acid level is ≥ 8.0 mg/dL in association with lifestyle diseases, such as CKD, hypertension, and diabetes mellitus. 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.
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