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AB0880 Pharmacodynamic effects and safety of verinurad (RDEA3170) in combination with allopurinol versus allopurinol alone in adults with gout: a phase 2a, open-label study
  1. R Fleischmann1,
  2. P Winkle2,
  3. JN Miner3,
  4. X Yan3,
  5. L Hicks3,
  6. S Valdez3,
  7. J Hall3,
  8. M Hernandez-Illas4
  1. 1University of Texas, Southwestern Medical Center, Metroplex Clinical Research Center, Dallas, TX
  2. 2Anaheim Clinical Trials, Anaheim, CA
  3. 3Ardea Biosciences, Inc., San Diego, CA
  4. 4QPS MRA (Miami Clinical Research), Miami, FL, United States

Abstract

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

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