Background Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for the treatment of gout and asymptomatic hyperuricemia.
Objectives This Phase 2a, randomized, open-label, multicenter study investigated the multiple-dose pharmacodynamics (PD), pharmacokinetics (PK), and safety of oral verinurad in combination with allopurinol versus allopurinol alone in adults with gout (NCT02498652).
Methods Patients aged ≥18 and ≤75 years with gout and serum uric acid (sUA) ≥8 mg/dL were randomized to 1 of 2 cohorts to receive allopurinol (300 mg) in combination with verinurad (dose range 2.5 mg to 20 mg) and allopurinol 300 mg or 600 mg alone (each treatment period was 7 days). Medications were administered once daily ∼30 min after breakfast (for allopurinol 300 mg b.i.d. group, the second allopurinol dose was in the evening). Colchicine 0.6 mg for gout flare prophylaxis was initiated at approximately Day -14 (start of urate-lowering therapy [ULT]) washout) or Day -7 if not on ULT. Serial blood and urine samples were measured on Days -1, 1, 7, 14, 21, 28, and 35 for PD and PK endpoints. Safety assessments included adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters.
Results Forty-one patients were randomized (n=20–21 per cohort). Serum PD data pooled across cohorts demonstrated maximal % decrease in sUA from baseline (Emax)at 6–10 h after verinurad and allopurinol combination treatment. Addition of verinurad (2.5 mg to 20 mg) to allopurinol decreased sUA in dose-dependent manner (Figure). Greater sUA reductions were observed for dose combinations of verinurad ≥5 mg with allopurinol 300 mg versus allopurinol 600 mg alone, while allopurinol 600 mg once daily was equivalent to allopurinol 300 b.i.d. Emax was 46.9%, 58.9%, 59.9%, 67.1%, 68.4%, and 74.3% for verinurad at doses of 2.5, 5, 7.5, 10, 15, and 20 mg in combination with allopurinol 300 mg, versus 39.7%, 53.8%, and 54.4% with allopurinol 300 mg, allopurinol 600 mg, and allopurinol 300 mg b.i.d. alone. No drug-drug interaction on verinurad and allopurinol plasma PK parameters was observed.
Conclusions Verinurad coadministered with allopurinol dose-dependently decreased sUA. All dose combinations of verinurad and allopurinol in this study were generally well tolerated with no serious AEs or renal-related events during combination treatment.
Disclosure of Interest R. Fleischmann Grant/research support from: Ardea Biosciences, Inc., P. Winkle Employee of: Anaheim Clinical Trials, J. Miner Employee of: Ardea Biosciences, Inc., X. Yan Employee of: Ardea Biosciences, Inc., L. Hicks Employee of: Ardea Biosciences, Inc., S. Valdez Employee of: Ardea Biosciences, Inc., J. Hall Employee of: Ardea Biosciences, Inc., M. Hernandez-Illas: None declared