Urate Inhibitor Shows Promise in Gout

June 3, 2011 (London, United Kingdom) — Lesinurad added to allopurinol achieves rapid, sustained reductions in urate levels in patients with gout who have a suboptimal response to allopurinol alone. No safety concerns were raised in the randomized phase 2 trial reported here at the European League Against Rheumatism (EULAR) Congress 2011.

The beneficial effects of this novel URAT1 inhibitor were seen across normal and mild levels of impaired renal function and in patients receiving 200 mg or 300 mg of allopurinol.

Patients who fail to reach the uric acid target level on allopurinol and who develop longstanding hyperuricemia are at risk for recurrent acute inflammation, chronic synovial inflammation, and progressive joint destruction, explained lead author Fernando Perez-Ruiz, MD, from the Hospital de Cruces, Baracaldo, Vizcaya, Spain.

"If hyperuricemia is untreated, gout becomes more severe. Only 1 new drug has been approved for gout in the last 40 years. Lesinurad, a URAT1 inhibitor that increases the urinary excretion of uric acid, is a potential treatment option for patients with gout," he said.

The Spanish investigators enrolled 208 gout patients who had serum urate levels above target (≥6 mg/dL) for at least 6 months while receiving stable doses of allopurinol. Patients continued on allopurinol and were randomized to receive either placebo or lesinurad at 200 mg, 400 mg, or 600 mg for 4 weeks. The percentage of patients who achieved the target level of serum urate (<6 mg/dL) after treatment was 28% in the placebo group, 71% in the 200 mg group, 76% in the 400 mg group, and 87% in the 600 mg group (all 3 active treatment groups were significantly better than placebo; P < .0001).

Consistent reductions in serum urate were observed across a range of renal function, Dr. Perez-Ruiz said. After 4 weeks of treatment, 115 patients entered an extension phase, most of them treated with lesinurad 200 mg. In the first 30 evaluable patients at week 28, 83% were at target serum urate levels. No serious adverse events or dose-related adverse effects were reported.

EULAR guidelines for the treatment of gout recommend treating to target levels of uric acid. This can be done 1 of 2 ways, said Maxime Dougados, MD, professor at René Descartes University in Paris, France — decrease the synthesis of uric acid or increase its excretion.

Febuxostat (an oral nonpurine selective inhibitor of xanthine oxidase), an agent that decreases the synthesis of uric acid, is approved by the US Food and Drug Administration for the treatment of hyperuricemia in patients with gout, but agents developed to increase uric acid excretion have thus far had a high risk for liver toxicity. Lesinurad is a potentially important drug without this problem, he said.

"It's fantastic that we now have 2 new compounds for gout. These drugs, if both are approved, will probably lead to the revision of the EULAR guidelines, which were last published in 2006," Dr. Dougados said. "We are not at the end of the story."

European League Against Rheumatism (EULAR) Congress 2011: Abstract OP0111. Presented May 26, 2011.