SAN DIEGO—After a 40-year lag, 2 new, investigational gout treatments have shown efficacy in reducing uric acid levels, even causing resolution of tophi. Farthest along in development is febuxostat (Tap Pharmaceuticals), a nonpurine selective inhibitor of xanthine oxidase. At the annual meeting of the American College of Rheumatology, Ralph Schumacher, MD, of the University of Pennsylvania and the VA Medical Center in Philadelphia, reported results of Febuxostat vs Allopurinol and Placebo in Subjects with Hyperuricemia and Gout: The 28-Week APEX study.

This trial involved 1067 patients with gout, many with comorbidities, such as hypertension, hyperlipidemia, moderate renal impairment, or obesity. After an 8- to 10-week run-in period of prophylaxis with colchicine, 0.6 mg/day, or naproxen (Aleve, Anaprox), 250 mg twice daily, patients were randomized to febuxostat, 80, 120, or 240 mg/day, or to allopurinol (Zyloprim), 300 or 100 mg/day, in the presence of renal impairment, or to placebo, in a double-blind manner. The primary efficacy end point was the proportion of patients with the last 3 serum urate measurements of <6.0 mg/dL (Figure).

“This is an effective treatment that compares favorably to the sort of standard doses of allopurinol that are being used," Dr Schumacher said. "It looks like it's going to be easier to use in patients with kidney disease, be­cause it's not excreted by the kidney, and [is beneficial] in patients who have been allergic to allopurinol." He noted that febuxostat should expand the population of patients who can successfully be treated for gout.

Higher baseline serum urate levels required higher doses of febuxostat to achieve the target urate level. The drug was equally effective in patients with mild renal impairment.

Tophi decreased in size over time. By the end of the study, tophi were reduced by >40% for patients with serum urate levels <6.0 mg/dL and by >30% for those with levels >=6.0 mg/dL. The reduction in size of tophi was not significantly different among the treatment groups, but febuxostat, at 120 mg/day, was more effective in reducing tophi of the hands and feet compared with allopurinol. "It looks like if you make a cutoff of 6 [mg/dL] you're likely to be getting the uric acid low enough to dissolve away the crystals and eventually prevent the flares and get rid of the tophi," Dr Schumacher said.

Data presented by Tap Pharma­ceuticals suggest that the majority of patients receiving allopurinol do not achieve target serum urate levels, regardless of mean daily dose. In those treated with febuxostat, disease impact was greatest among patients who were younger, newly diagnosed, and had tophi or higher serum urate levels. "If we treat patients appropriately, aggressively, and early enough we can prevent a lot of that chronic disability that can come with gout," Dr Schumacher commented.

The incidence of flares was high in the study. "It seems that the more dramatically you lower the uric acid, the more flares you get," Dr Schumacher said. "You probably need to cover for a longer period, and maybe even with slightly higher doses, when you start dealing with potent drugs like this…maybe 6 months." Febuxo­stat appeared safe and well tolerated. Ad­verse events were mainly digestive disturbances, headache, and liver abnormalities, and were similar for all treatment arms.

The only serious event related to febuxostat was serum creatinine elevation, which occurred in those receiving the 240-mg dose —a dose that was twice the recommended highest dose of 120 mg.

Dr Schumacher suggested that this drug would help primary care physicians to treat gout and prevent the flares, emphasizing that the goal is not just to treat acute flares of gout but to keep uric acid below the 6-mg/dL target level.

The second treatment for gout, now in phase 2 clinical trials, is the intravenous (IV) PEG-uricase (Savient), a pegylated form of the porcine enzyme urate oxidase. John Sundy, MD, PhD, of Duke University, Durham, NC, presented new data showing that IV treatment every 2 weeks reduced plasma urate levels from a mean of 9.1 mg/dL to 1.4 mg/dL during a 12-week period in patients with severe gout who were unresponsive to or intolerant of conventional therapy. Tophi were reduced in 2 of the 41 patients during this short period.