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Dec 08, 2008
 |  BioCentury  |  Regulation

Seek, but not find

In voting to recommend approval of Uloric febuxostat to treat chronic gout, FDA's Arthritis Advisory Committee concluded that its benefits trumped an ambiguous cardiovascular safety signal.

The committee voted 12-0 with one abstention on Nov. 24 to recommend approval of Uloric, a non-purine inhibitor of xanthine oxidase from Takeda Pharmaceutical Co. Ltd.

The committee spent little time debating the efficacy of Uloric, which met the primary endpoint in three Phase III trials of a significant proportion of patients with blood levels of uric acid <6 mg/dL compared with allopurinol, another xanthine oxidase inhibitor.

However, the committee recommended postmarketing safety studies because the third Phase III trial, which the company and FDA both hoped would rule out a weak cardiovascular safety signal from earlier trials, ended up having fewer events than predicted.

The committee was divided over whether a long-term observational study, a double-blind placebo-controlled trial, or both would be the best way to collect long-term safety data.

Safety signal or not?

Gout is defined by uric acid concentrations in the plasma >=6.8 mg/dL. At about that point, uric acid precipitates out of solution to form urate crystals in the joints, leading to inflammation. Over time, these deposits lead to the formation of bulbous projections (tophi) around the joints.

Uloric selectively inhibits xanthine oxidase, the final enzyme in purine metabolism that converts xanthine to uric acid.

Standard of care is 300 mg allopurinol. But the purine analog is metabolized and excreted by the kidneys and can cause a hypersensitivity reaction in susceptible individuals. Physicians are therefore reluctant to prescribe higher doses in patients with kidney disease, even though it's approved at doses up to 800 mg.

By comparison, Uloric is metabolized by the liver and thus can be taken at effective doses by patients with renal impairment, and it does not cause hypersensitivity reactions.

Takeda sought approval of Uloric twice before, in 2004 based on the first two Phase III trials, and in 2006 based on a re-analysis of the same data.

Study 009, known as APEX, was a six-month trial in 1,072 patients randomized into five arms: 80 mg, 120 mg or 240 mg Uloric, allopurinol, or placebo. Study 010, known as FACT, was a 52-week trial in 760 patients randomized into three arms: 80 or 120 mg Uloric or 300 mg allopurinol.

In its original review, FDA found a cardiovascular safety signal in patients taking Uloric. In Studies 009 and 010, there were three CV-related deaths in patients who received Uloric (n=1,177) and none in the allopurinol groups (n=521) (see "APTC Events").

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