SILVER SPRING, MD. — Approval of a long-awaited alternative to allopurinol for people with gout is likely now that febuxostat has received a nearly unanimous vote for support by a federal advisory panel.
The Food and Drug Administration's Arthritis Drugs Advisory Committee voted 12-0, with 1 abstention, recommending approval of the xanthine oxidase inhibitor febuxostat for the treatment of chronic gout, but recommended that studies further evaluating the drug's cardiovascular safety be conducted after approval.
The panel agreed that the available data on febuxostat at doses of 40 mg/day and 80 mg/day provided evidence that it would be useful as a treatment for patients with gout and would meet an unmet need for treating hyp-eruricemia in patients who are intolerant to or allergic to allopurinol and in those patients with renal impairment, who have to take a reduced, less-effective dose of allo-purinol. The panel met last month.
Panelist Dr. John Cush, director of clinical rheumatology, Baylor Research Institute, Baylor College of Medicine, Dallas, said febuxostat would be a useful addition to the available treatments because of its potent urate-lowering effect. The drug requires less dose adjustment than does allopurinol and has been easier to tolerate than is allopurinol.
Like other panelists, he did not believe the issue regarding the potential cardiovascular safety signal seen in the two initial phase III studies of febuxostat had been completely resolved. That could be addressed with postmarketing studies, he said, adding it should not hold up approval.
Because of new legislation, the FDA now has more clout in getting companies to adhere to their postmarketing study commitments, which influenced some panelists to vote for approval. The FDA usually follows the recommendations of its advisory panels, which are not binding.
The manufacturer, Takeda Pharmaceuticals, has proposed that febuxostat, taken orally, at a dosage of 40 mg/day or 80 mg/day, be approved for treating hyperuricemia in patients with gout. The higher dosage would be recommended for patients with higher serum uric acid levels and for patients with tophi. If approved, febuxostat, a nonpurine selective inhibitor of xanthine oxidase that reduces the formation of uric acid, would be the second xanthine oxidase inhibitor approved for gout in the United States. Allopurinol, available since 1964, is a nonselective xanthine oxidase inhibitor.
Takeda presented the results of the phase III study of 2,269 mostly male patients with hyperuricemia, who had had gout for a mean of 11 years, conducted to prospectively evaluate the cardiovascular safety of febuxostat. Their mean age was 53 years; about 20% were older than 65 years, 53% had hypertension, 42% had hyperlipidemia, and 12% had atherosclerotic disease. Patients with mildly or moderately impaired renal function (about 66%) were also enrolled. At 6 months, the rates of cardiovascular events, blindly adjudicated by an independent expert committee, were similar in those on 40 mg/day or 80 mg/day of febuxostat and those on allopurinol (200-300 mg/day).
The FDA asked the company to conduct this study after the agency's review of the two phase III trials that were initially submitted to it for approval in 2004 suggested there was a cardiovascular safety signal associated with the 80-mg and 120-mg doses of febuxostat, compared with allopurinol. In the studies, the rates of cardiovascular thromboembolic events were higher in patients treated with 80 or 120 mg of febuxostat daily, compared with those on allopurinol or placebo, though the number of events was small. The company dropped development of the 120-mg dose and focused on the two lower doses.
The FDA held the panel meeting to review the drug's safety; efficacy was not an issue. In the three phase III studies, which enrolled patients with a diagnosis of gout and a baseline serum uric acid of 8.0 mg/dL or more, the 80-mg dose of febuxostat was significantly more effective than allopurinol, and the 40-mg dose was as effective as allopurinol, in lowering and maintaining serum uric acid below 6.0 mg/dL. Patients in all three groups experienced flares, which were higher in patients on the higher febuxostat doses but gradually decreased over time, said Takeda. The two doses of febuxostat were also effective in patients with renal impairment, who require a lower, usually suboptimal dose of allopurinol, and no safety signal was seen in this population. Febuxostat had no effects on blood pressure, glucose, lipids, or weight.
In two open-label extension studies that followed patients in phase II and the initial phase III studies for 3-5 years, gout flares fell to almost zero, said Takeda.
A cardiologist on the panel, Dr. Robert Harrington, professor of medicine, Duke University, Durham, N.C., said the database on febuxostat was insufficient to draw an inference about cardiovascular risk in patients with cardiovascular disease and that some of the issues regarding cardiovascular risk “still need to be better clarified.” He noted that most of the subjects were middle-aged, overweight men, and that 6 months was not enough time to detect a cardiovascular risk for a drug that will be taken for a lifetime. He said his vote in favor of approval was influenced by the FDA's increased authority in requiring companies to meet their postmarketing study commitments.