FRI0367 BCX4208 added to allopurinol increases response rates in patients with GOUT who fail to reach goal range serum uric acid on allopurinol alone: A randomized, double-blind, placebo-controlled trial

Abstract

Background BCX4208, a novel purine nucleoside phosphorylase inhibitor, blocks uric acid production at a step preceding xanthine oxidase and synergistically reduces serum urate concentration (sUA) in gout patients when combined with allopurinol1. Objectives To assess the sUA response to the addition of placebo or one of 4 doses of BCX4208 to 300 mg/d allopurinol in gout patients with sUA ≥6.0 mg/dL on allopurinol alone. Primary endpoint was the proportion of BCX4208-treated subjects achieving sUA goal range (<6.0 mg/dL) at 12 weeks compared with placebo. Methods 278 adult subjects (M:F =266:12) with gout and sUA ≥6.0 mg/dL despite allopurinol 300 mg/d for at least 2 weeks were randomized and received oral placebo or BCX4208 5, 10, 20, or 40 mg/d for 12 weeks while continuing allopurinol 300 mg/d. On-study assessments were performed at 2, 4, 8, and 12 weeks of treatment. Subjects received colchicine 0.6 mg/d or naproxen 220 mg to 250 mg BID for gout flare prophylaxis. Data from subjects who received >1 dose of study drug and had at least one on-study sUA assessment (modified intention-to-treat [mITT] population) were analyzed. Missing data were imputed using the last observation carried forward method. Results Demographic, comorbid, and gout characteristics of the study population were evenly distributed in the study arms. Mean (SD) age was 49 (10) years and BMI was 36 (7) kg/m2 in the predominantly white (73%) population, with high prevalences of hypertension (58%), diabetes (16%), and hypercholesterolemia (39%). BCX4208 added to allopurinol 300 mg/d brought more patients to goal range sUA compared with placebo (Table). Table 1. Percent Goal sUA Attainment at 12 Weeks (mITT) ParameterAllopurinol 300 mg/d BXC4208 Placebo5 mg/d10 mg/d20 mg/d40 mg/d Subjects, n5556555653 % Subjects with sUA <6.0 mg/dL18%45%33%39%49% P value compared with placebo–0.0040.1250.021<0.001 Overall treatment effect, P=0.009 vs placebo. Differences between the BCX4208 5, 20, and 40 mg/d arms and placebo were significant. Five to 11% of subjects per arm experienced ≥1 gout flare during treatment. Frequency and severity of adverse events, including infections, were evenly distributed across dose groups. Conclusions Addition of BCX4208 to allopurinol 300 mg/d allows a significantly greater proportion of gout patients to achieve goal range sUA than addition of placebo. Twelve weeks of BCX4208 daily dosing is generally safe and well-tolerated when combined with allopurinol. References Hollister AS, et al. Ann Rheum Dis 2011; 70 (Suppl 3): 183 Disclosure of Interest M. Becker Consultant for: BioCryst, Takeda, Savient, URL/Pharma, Ardea, Regeneron, Metabolex, Isis, A. Hollister Employee of: BioCryst Pharmaceuticals, Inc., R. Terkeltaub Consultant for: BioCryst, Ardea, Regeneron, Novartis, A. Waugh Employee of: BioCryst Pharmaceuticals, Inc., A. Flynt Consultant for: BioCryst Pharmaceuticals, Inc., D. Fitz-Patrick Grant/Research support from: BioCryst Pharmaceuticals, Inc., W. Sheridan Employee of: BioCryst Pharmaceuticals, Inc.

Treatment of hyperuricemia in gout: current therapeutic options, latest developments and clinical implications

“…An initial 12-week RCT comparing four different doses of ulodesine (5, 10, 20 and 40 mg/day) with allopurinol 300 mg/day to allopurinol monotherapy showed a significantly greater proportion of patients achieving the SU goal, with a safe profile and adequate tolerance to the combination [Becker et al 2013]. The 24-week extension which included 160 patients from the original study showed that by the end of trial, 40%, 50%, 46% and 55% of the patients receiving the 5, 10, 20 and 40 mg/day of ulodesine, respectively, achieved a goal SU less than 6 mg/dl [Hollister et al 2013].…”

Investigational drugs for hyperuricemia

“…Two Phase II clinical trials have shown promising results regarding urate-lowering effect in both as monotherapy and in combination with allopurinol ( Table 5) [90]. In the 12-week randomized controlled trial, in 82 gout patients, the response rates to 5, 10, 20 and 40 mg ulodesine (BCX4208) compared with allopurinol 300 mg were 45, 33, 39 and 49%, respectively [91]. In the 24-week extension study, response rates for doses 5, 10 and 20 mg were found to be 40, 50, 45 and 65%, respectively, compared with placebo response of 25% [92].…”

Modulation of Urate Transport by Drugs

“…Hypoxanthine is the precursor of xanthine and a substrate of xanthine oxidase ( Figure 1 ). Ulodesine, a PNP inhibitor, was effective as single agent [ 86 ] and in combination with allopurinol [ 87 ]. In the combination treatment arm, 40–55% of patients achieved the target urate level, which compared favorably to 25% in the allopurinol arm [ 88 ].…”