Despite concerns about cardiac safety, FDA approved Takeda's Uloric (febuxostat) for the chronic management of hyperuricemia in patients with gout Feb. 13. The approval marks the first new FDA-approved treatment for gout in more than 40 years.

The drug will be targeted to the estimated 5.1 million people in the U.S. who have the painful chronic inflammatory condition triggered by elevated levels of uric acid in the blood, or hyperuricemia. It is the most common inflammatory arthritis in men over the age of 40, Takeda said, citing data from the National Health and Nutrition Examination Survey.

Uloric is a xanthine oxidase inhibitor that helps prevent uric acid production, thereby lowering elevated levels of serum uric acid that can build up in the blood. When uric crystals are deposited in the joints and soft tissue, it causes inflammation. The disease is characterized by "flares," periods of intense pain, redness and swelling in the affected joints.

Uloric is not recommended for the treatment of asymptomatic hyperuricemia, labeling notes.

A long road that ends with FDA approval

The FDA approval marks a regulatory achievement for Takeda, which submitted the NDA for febuxostat in 2004 with then-partner Abbott (through the TAP Pharmaceutical joint venture, since dissolved). The original application was based on two pivotal trials, but was met with an FDA "approvable" letter related to the cardiovascular safety profile of the drug. A re-analysis of existing data did little to appease FDA, and likewise was met with an approvable letter.

Takeda ultimately went on to conduct a third trial, the 2,269-patient CONFIRMS study, to address FDA's outstanding concerns. That trial studied the efficacy and safety of febuxostat compared to allopurinol, a generic drug that is the current standard of care for chronic gout, over six months. CONFIRMS included a lower 40 mg dose of febuxostat, pre-specified cardiovascular endpoints and three times the number of subjects per arm than the previous two trials.

The trial was at the heart of an FDA Arthritis Drugs Advisory Committee debate in November, with the panel voting in favor of approving febuxostat, despite the potential cardiovascular signal detected in clinical trials (¹ Also see "Takeda’s Febuxostat Gets Advisory Committee Nod for Gout; Cardio Risk Remains A Concern" - Pink Sheet, 24 November, 2008.).

The committee's support stemmed from the strong efficacy of the drug and the unmet medical need for a gout treatment. Allopurinol, also an XO inhibitor, often is prescribed at suboptimal doses, and many patients are intolerant to therapy. It was approved in 1964.

Warnings included for cardiovascular safety

Labeling for Uloric includes a Warning on cardiovascular safety. "In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions and non-fatal strokes) in patients treated with Uloric [0.74 per 100 patient years] than allopurinol [0.60 per 100 patient years)," labeling states. "A causal relationship with Uloric has not been established. Monitor for signs and symptoms of myocardial infarction and stroke."

Uloric also carries a Warning for gout flare, which states that an increase in flares frequently is observed following treatment initiation, as the reduction of serum uric acid levels results in the mobilization of urate from tissue deposits. Concurrent prophylactic treatment with a non-steroidal anti-inflammatory or colchicine is recommended. Labeling also includes a warning on liver enzyme elevations.

The recommended starting dose for Uloric is 40 mg once daily. For patients who do not achieve a serum uric acid less than 6 mg/dL after two weeks with the 40 mg tablet, an 80 mg dose is recommended. No dose adjustment is needed for treating patients with mild to moderate renal or hepatic impairment.

For Takeda, the approval gives the firm yet another new drug to add to its armamentarium as it prepares to march into a new era without blockbusters like the proton pump inhibitor Prevacid , set to lose exclusivity later this year, and the diabetes drug Actos , facing patent expiration in 2011. The news comes just weeks after FDA approved Takeda's Prevacid follow-on Kapidex (dexlansoprazole) for heartburn (² Also see "PPI Market Snapshot: Kapidex Joins The Party Fashionably Late" - Pink Sheet, 9 February, 2009., p. 7).

Nonetheless, neither Uloric nor Kapidex are expected to be large enough launches to replace the upcoming losses.

Saviant also is seeking to bring a new gout treatment to market, although its drug would be for treatment-failure gout. The company recently submitted major amendments to its BLA for pegloticase, one month prior to a scheduled advisory committee hearing, including a proposed Risk Evaluation and Mitigation Strategy (³ Also see "Savient Suggests More Restrictive REMS Plan For Pegloticase In BLA Amendment" - Pink Sheet, 13 February, 2009.).

-Jessica Merrill (j.merrill@elsevier.com)

Takeda Uloric Cleared For Gout Indication

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