Background/Purpose: Verinurad (RDEA3170) is a high-affinity URAT1 inhibitor in development for the treatment of gout and asymptomatic hyperuricemia. This Phase 2a, randomized, open-label, single-site study investigated the multiple-dose pharmacodynamics (PD), pharmacokinetics (PK), and safety of oral verinurad in combination with febuxostat versus febuxostat alone and verinurad alone in Japanese male adults with gout or asymptomatic hyperuricemia (NCT02317861).

Methods: Japanese male patients aged ≥20 and ≤70 years with gout or asymptomatic hyperuricemia and serum uric acid (sUA) ≥8 mg/dL were randomized to 1 of 6 cohorts to receive febuxostat (10 mg, 20 mg, and 40 mg) alone; febuxostat in combination with verinurad (dose range 2.5 mg to 10 mg); verinurad (2.5 mg to 15 mg) alone; or benzbromarone (50 mg) alone (4 treatment periods per cohort, each treatment period 7 days). The study drugs were administered once daily in the morning after breakfast. Serial blood and urine samples were measured at preset intervals on Days -1, 1, 2, 7, 8, 14, 15, 21, 22, 28 and 29 for PD and PK endpoints. Safety assessments included adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters.

Results: Seventy-two patients with gout (n=37) or hyperuricemia (n=35) were randomized in this study. Addition of verinurad (2.5 mg to 10 mg) to febuxostat (10 mg, 20 mg, or 40 mg) decreased sUA in dose-dependent manner (Figure). Verinurad coadministered with febuxostat increased the amount of uric acid recovered in urine (Aeur), compared with baseline and the same dose of febuxostat administered alone, yet comparable with benzbromarone. Plasma Cmax and AUC exposures of verinurad and febuxostat exhibited dose proportional increases within the investigated dose range. No clear PK drug-drug interaction of verinurad and febuxostat with each other was observed. Verinurad at doses from 2.5 mg to 15 mg was well tolerated, with no serious AEs or withdrawals due to AEs. One treatment-emergent AE (diarrhea) was considered possibly related to both verinurad and febuxostat. Laboratory values and vital signs indicated no clinically meaningful changes.

Conclusion: Verinurad coadministered with febuxostat dose-dependently decreased sUA while maintaining Aeur comparable to benzbromarone. All dose combinations of verinurad and febuxostat in this study were generally well tolerated.