Formal publication of a positive Phase II study on the novel xanthine oxidase inhibitor febuxostat¹ combined with recent Phase III data showing that treatment with this agent resulted in significant reductions in serum urate levels versus allopurinol² provide further evidence of its potential to receive US Food and Drug Administration (FDA) approval.

"The results to date are very encouraging, and additional Phase III data are being analyzed," says the lead author on both studies, Michael A. Becker, MD, professor of medicine at the Pritzker School of Medicine at the University of Chicago in Illinois. "The bottom line is that so far, in the groups that have been studied, the drug looks good." TAP Pharmaceuticals, Inc, submitted a new drug application with the FDA for febuxostat in mid-December, 2004.

 

Phase II data show safety and efficacy

The Phase II study, originally presented at the 2004 European League Against Rheumatism meeting in Berlin, Germany, appears in the March issue of Arthritis & Rheumatism. The data show that at each doctor visit, a greater percentage of patients treated with febuxostat had achieved serum uric acid (sUA) levels <6 mg/dL than those on placebo. Moreover, target sUA levels were achieved in 56% of patients taking 40 mg of febuxostat, 76% taking 80 mg, and 94% taking 120 mg, compared with 0% taking placebo.

The mean sUA reduction from baseline at day 28 was 2% in the placebo group, 37% in the 40 mg, 44% in the 80 mg, and 59% in the 120 mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40 mg febuxostat (35%) groups, the study showed, with increased frequency in the higher dosage febuxostat groups (43% of those taking 80 mg; 55% of those taking 120 mg). Administration of colchicine prophylaxis largely prevented this effect, however.

The drug appeared safe and incidences of treatment-related adverse events were similar between the active and placebo groups, says Dr. Becker, who also is a consultant for TAP. "There were no [safety] signals except for one patient who developed Guillain-Barré syndrome that had not been seen before. The subject had delirium tremens and pneumonia, and the adverse event has to be reported as possibly related [to the study treatment]."

Phase III data compare efficacy of febuxostat and allopurinol

A 52-week randomized, double-blind Phase III trial of 760 patients found that 80 mg and 120 mg febuxostat performed better than allopurinol in achieving the study's primary end point of sUA <6 mg/dL. These results were presented at the 2004 American College of Rheumatology (ACR) Annual Meeting in San Antonio, Texas.

The data suggest that the efficacy of febuxostat is dose-related. Fifty-three percent of patients in the 80 mg febuxostat group, 62% of patients in the 120 mg febuxostat group, and 21% of those receiving allopurinol reached this target. Moreover, a greater number of patients in both febuxostat groups achieved sUA levels of <5 mg/dL or <4 mg/dL than their counterparts taking allopurinol, the study showed.

Subjects with an average sUA <6.0 mg/dL post-baseline had fewer flares of gouty arthritis than those above that threshold, 6% vs 14%, respectively. In addition, these patients had a greater median reduction in tophus area, the study showed.

"The data is consistent with the idea that if we lower serum urate, tophi get smaller," Dr. Becker tells CIAOMed. "Paradoxically, patients get acute attacks of gout in the beginning of treatment with anything that lowers urate."

Another, larger Phase III trial also shows positive results

A second Phase III study comprises five arms including patients taking placebo, allopurinol, and several doses of febuxostat. "This is a bigger study than what was presented at [the 2004 ACR meeting]," Dr. Becker says. The results will "confirm much of what we saw in the Phase II studies with placebo and in the Phase III with allopurinol." An open-label extension of the initial double-blind phase of this trial has followed patients for over 1 year.

Currently, allopurinol is the only commercially available xanthine oxidase inhibitor that effectively lowers uric acid and helps prevent recurrence of gout. Febuxostat, a nonpurine inhibitor of xanthine oxidase, is thought to be more selective, and therefore is expected to cause fewer side effects than allopurinol.

New option for patients with renal insufficiency and allopurinol hypersensitivity

While allopurinol has been used for 30 years, serious side effects can occur, and dose adjustment is often necessary in patients with renal insufficiency. According to preliminary data, normal doses of febuxostat appear to be safe in these patients.

So far, the data "look very good," Robert Terkeltaub, MD, chief of the rheumatology section of the Veteran Affairs Medical Center in San Diego, California, and TAP consultant, tells CIAOMed. "There has been nothing new for gout in a long time, and it has doubled in prevalence in the last 10 to 20 years," says Dr. Terkeltaub, also an associate division director at the University of California at San Diego's Rheumatology-Allergy-Immunology Division. "Many of these patients have renal insufficiency and are allergic or intolerant to allopurinol. We are in a bind on how to treat them and need new treatments," he emphasizes.

"[Febuxostat] will serve well patients with allopurinol hypersensitivity or intolerance," Dr. Becker says, adding, "We in the rheumatology community think this will be a very useful drug."

Reference

1. Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005 Mar 4;52:916-923.
2. Becker MA, Schumacher HR, Wortmann RL, et al. A Phase III study comparing the safety and efficacy of oral febuxostat and allopurinol in subjects with hyperuricemia and gout. Presented at: the Annual Meeting of the American College of Rheumatology; October 16-21, 2004; San Antonio, Texas; Abstract L18.