New phase III data show that febuxostat, a next-generation nonpurine selective xanthine oxidase inhibitor and the first new agent for gout in 40 years, is significantly more effective than standard doses of allopurinol for lowering serum uric acid levels to <6.0 mg/dL, according to a study published in the December 8, 2005, issue of the New England Journal of Medicine.¹

According to the Febuxostat versus Allopurinol Controlled Trial (FACT), a randomized, double-blind, 52-week, multicenter study, 53% of patients receiving >e;80 mg/day of febuxostat, 62% of patients receiving 120 mg/day of febuxostat (P <.001), and 21% of patients receiving 300 mg/day of allopurinol achieved their target uric acid levels of <6.0 mg/dL at the last three monthly measurements.

New agent may provide niche for patients with allopurinol hypersensitivity syndrome

If approved, febuxostat, which is currently under review by the US Food and Drug Administration for managing hyperuricemia in patients with chronic gout, would become the first new medication for gout in more than 40 years.

Despite its long-term use, allopurinol is associated with side effects known collectively as "allopurinol hypersensitivity syndrome," reactions that are more prevalent in patients with renal insufficiency.

"Ultimately, febuxostat will be used for people who have allopurinol reactions and patients with renal insufficiency," says lead study author Michael A. Becker, MD, professor of medicine at the University of Chicago in Illinois. "I am optimistic that [febuxostat] will be approved."

The FACT trial comprised 762 gout patients with serum urate concentrations of >8.0 mg/dL who were administered either 80 mg or 120 mg doses of febuxostat or the standard 300 mg dose of allopurinol once daily for 52 weeks. Prophylactic use of naproxen or colchicine was permitted between weeks 1 and 8 to prevent gout flares.

Similar reductions in gout flares and tophus area occurred in all treatment groups

Although the incidence of gout flares diminished with continued treatment, the overall incidence between weeks 9 and 52 was similar in all groups. Specifically, 64%, 70%, and 64% of patients in the 80 mg and 120 mg febuxostat groups and the allopurinol group, respectively, suffered gout flares. The median reduction in tophus area was 83% in patients receiving 80 mg of febuxostat, 66% in those receiving 120 mg of febuxostat, and 50% in patients receiving allopurinol, the FACT study showed.

The study had a high dropout rate, however. More patients in the high-dose febuxostat group than in the allopurinol group or the low-dose febuxostat group withdrew from the trial due to greater incidence of gout flares.

The study also showed an increased risk of acute gout flares early in the course of urate-lowering treatment, which "clearly documents a role for more sustained prophylaxis during the initiation of urate therapy than was provided here," Dr. Becker and colleagues write.

Four of the 507 patients in the two febuxostat groups died during the course of the trial, fatalities the investigators deemed unrelated to the study drug.

In an editorial accompanying the study,² Larry W. Moreland, MD, a rheumatologist at the University of Alabama at Birmingham School of Medicine in Alabama, acknowledges that while a new therapy that optimally lowered uric acid levels would be a welcome addition to the rheumatologist's armamentarium for the management of gout, the currently available drugs, including allopurinol, have limits in terms of efficacy and toxicity.

Dr. Moreland also points out that the new study has some limitations, such as the fact that the investigators used a fixed dose of allopurinol. "Allopurinol should be used at the lowest dose that reduces the serum urate level to <6.0 mg/dL," he writes. "Although this level is most often achieved with the dose used in this study, doses as high as 800 to 1000 mg per day may be needed."

If the FACT study design had provided for adjustments in allopurinol doses, then febuxostat may not have been superior to allopurinol in lowering uric-acid levels, he adds.
Dr. Becker agrees. "Had it been possible to titrate the dose, allopurinol probably would have performed better, but that is not possible in a double-blind study," he tells CIAOMed, adding that "there have been no randomized controlled trials looking at the safety and efficacy of higher doses of allopurinol, and 300 mg is a dose that very few physicians exceed."

In his editorial, Dr. Moreland also points out that although febuxostat was more effective than allopurinol at lowering uric acid, a large percentage of patients did not meet the primary endpoint of serum urate levels of <6.0 mg/dL. "We need to know whether higher doses of febuxostat that can be given safely will achieve this outcome," he says.

Dr. Moreland also notes that more information is needed about the high dropout rate in the study and the reported toxicity of febuxostat, including liver-function abnormalities, diarrhea, and headaches. "In particular, more details about the degree, duration, and reversibility of the elevation of liver enzymes would be helpful," he says. In FACT, the most common adverse event leading to withdrawal was abnormal liver function tests, which accounted for the withdrawal of five patients in the 80 mg febuxostat group, seven patients in the 120 mg febuxostat group, and one patient receiving allopurinol.

Regarding the impact of the hepatotoxicity side effects associated with febuxostat in the current trial, Dr. Becker asserts that "the toxicity was reversible. As far as the high dropout rate, in a study of a drug that increases the likelihood of acute attacks, which are painful—[the same condition for which these] patients are being treated—you can expect a high dropout rate."

The bottom line, according to Dr. Moreland, is that other studies are needed to better define the long-term safety profile of febuxostat, especially when administered in patients with renal insufficiency and other coexisting conditions or in those who are receiving medications that may cause hepatotoxicity. The relative costs of the two agents should also be weighed, he writes.

References

1. Becker MA, Schumacher RS, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450-2461.
2. Moreland LW. Febuxostat—treatment for hyperuricemia and gout? N Engl J Med. 2005;353:2505-2507.