The novel uricosuric drug arhalofenate significantly reduced the incidence of gout flares, compared with allopurinol alone and placebo, and also modestly lowered serum urate levels in a phase IIb trial.
However, arhalofenate alone did not lower serum uric acid levels as much as did allopurinol plus colchicine, potentially making it “better suited for a combination regimen with a xanthine-oxidase inhibitor,” first author Dr. Jeffrey Poiley of Arthritis Associates in Orlando, and his coauthors at CymaBay Therapeutics in Newark, Calif.
The double-blind, randomized, placebo- and active-drug controlled trial of 239 gout patients showed that arhalofenate at a dose of 800 mg daily significantly reduced gout flares over 12 weeks by 46% versus allopurinol at a dose of 300 mg daily (0.66 flares vs. 1.24; P = .0056) and by 41% versus placebo (0.66 vs. 1.13; P = .049).
The 12-week incidence of flares with the 800-mg dose was no better than the combination of allopurinol 300 mg with 0.6 mg colchicine a day (0.40), but the study was not powered to detect this comparison. “The clinical utility of arhalofenate 800 mg will have to be judged in the context of the respective risk/benefit ratio of each flare treatment,” the study authors said (Arthritis Rheumatol. 2016 Mar 18. doi: 101002/art.39684).
The flare rate for arhalofenate at a lower daily dose of 600 mg was not significantly different from allopurinol 300 mg without flare prophylaxis (1.04 vs. 1.24, respectively).
Secondary outcomes of the study revealed that arhalofenate had modest effects on serum urate levels, compared with allopurinol on its own and in combination with colchicine. The average percentage change in serum uric acid levels from baseline to week 12 were –12.5% with 600 mg of arhalofenate; –16.5% with 800 mg; –28.8% with allopurinol 300 mg, and –24.9% for allopurinol plus colchicine, and –0.9% with placebo.
Arhalofenate lowers serum urate by blocking its reabsorption by the proximal tubules of the kidney via inhibition of the urate transporter 1. In animal studies of urate crystal–induced inflammation, arhalofenate suppressed the release of proinflammatory cytokines and prevented the movement of neutrophils to the site of inflammation. Prior studies of arhalofenate in gout patients treated with colchicine suggested that the drug could prevent flares, but this was impossible to prove definitively because of the simultaneous use of colchicine, the authors wrote.
The study authors will now confirm their findings in a phase III trial with a treatment regimen that combines arhalofenate with febuxostat.
Patients involved in the study had more than three flares in the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum urate level of 7.5-12 mg/dL.
They were randomized in a 2:2:2:2:1 fashion to one of five treatment groups: daily arhalofenate 600 mg or 800 mg, allopurinol 300 mg, allopurinol 300 mg together with 0.6 mg of colchicine, or placebo.
The researchers said there were no meaningful differences in adverse events between treatment groups. There were no significant changes in estimated creatinine clearance in any treatment group, including no declines in any group receiving arhalofenate.
The study was sponsored by CymaBay Therapeutics. Dr. Poiley was an investigator in the study, and five other authors are employees of CymaBay.