Takeda will focus its initial marketing effort for Uloric (febuxostat) - the first new treatment for gout in more than 40 years - on health care providers whose patients have highly elevated uric acid levels or continue to experience painful flares despite being on treatment.

FDA approved Takeda's Uloric for the chronic management of hyperuricemia in patients with gout Feb. 13, despite some concerns with cardiovascular safety. The approval came just about a month after the drug's Jan. 18 PDUFA date.

"Right now our efforts are focused on communicating to the physicians who have patients who need better control, patients who have hyperuricemia and gout, who are still having elevated uric acid levels who might still be flaring or ... who have some level of mild to moderate renal impairment or can't tolerate existing therapies," said Director of Uloric Marketing Heather Dean.

Takeda is gearing up to launch Uloric in March, targeting primary care physicians, rheumatologists and nephrologists. The Japanese drug maker said it expects Uloric to generate "meaningful revenue" for Takeda in the next five years, noting that by 2013, the market for urate treatment is expected to pass 16.5 million prescriptions.

Uloric Takes On Generic Allopurinol

Uloric, a xanthine oxidase inhibitor, will be competing against a generic from the same class, allopurinol, which has been available since 1964. Uloric was shown in clinical trials to be statistically significantly more efficacious at the higher 80 mg dose at lowering uric acid levels versus allopurinol, which also requires dose adjustment and can lead to hypersensitivity and renal insufficiency.

"For new patients, it would be up to the physician to look at that patient, how they're presenting, to give them the choice between allopurinol and Uloric," explained Nancy Joseph-Ridge, President, Takeda Global Research & Development Center. "Where we see Uloric working is in those patients who present with higher elevations, very high levels of uric acid."

Takeda will need to win managed care support for Uloric, a challenge given the presence of a long-marketed generic. "From the managed markets perspective ... while it won't be at the same co-pay tier, we are doing everything that we can to make sure that patients have unrestricted access to the product," Dean said. Takeda declined to comment on pricing.

Only 1.5 Million On Chronic Uric Acid Therapy

An estimated 5.1 million people in the U.S. have gout, a painful chronic inflammatory condition triggered by elevated levels of uric acid in the blood, or hyperuricemia, according to Takeda. 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.

However, only about 1.5 million patients are currently taking chronic uric acid-lowering treatment, Dean noted.

Uloric addresses the underlying cause of gout by helping to prevent uric acid production, which, in turn, lowers elevated levels of serum uric acid. In gout, the acid builds up in the blood, forming crystals that collect in the joints and soft tissue, causing 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 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 received an FDA "approvable" letter related to the cardiovascular safety profile of the drug. A re-analysis of existing data did little to appease FDA, which issued another approvable letter.

Takeda ultimately conducted 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 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 the clinical trials (¹ Also see "Takeda Febuxostat Benefits Outweigh CV Risk; Will Other Gout Drugs Follow?" - Pink Sheet, 1 December, 2008., p. 5).

The committee's support stemmed from the efficacy of the drug and the unmet medical need for a gout treatment.

Post-marketing Commitment Includes CV Study

In keeping with the advisory committee's recommendation, FDA is requiring a post-marketing study to evaluate cardiovascular outcomes. Takeda must submit a final protocol to FDA by Aug. 31 and initiate the trial by Jan. 31, 2010, according to the FDA approval letter. Takeda will need to submit a final report to FDA by Jan. 31, 2015.

"We are committed to the post-marketing study to further evaluate the CV safety of Uloric," the firm said, although the company declined to provide further details on the trial design or size.

The agency has also requested a drug-drug interacttion trial to evaluate the effect of Uloric on the pharmacokinetics of a single, oral dose of theophylline, with a final report required by May 31, 2010.

"Since Uloric is a xanthine oxidase inhibitor and theophylline is a xanthine oxidase substrate, co-administration of Uloric with theophylline may result in elevated theophylline exposure and associated serious adverse events," FDA said. Theophylline is a drug used to treat respiratory conditions, like asthma.

CV, Gout Flare Warnings Included In Label

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, labeling notes.

The approval gives Takeda 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).

Neither Uloric nor Kapidex are expected to be sufficient to replace the upcoming losses. The company does, however, have another near-term opportunity pending at FDA with the dipeptidyl peptidase IV inhibitor alogliptin for diabetes. The drug currently has a June 26 action date at FDA after the agency missed the original Oct. 27 deadline (³ Also see "FDA Offers Up Revised PDUFA Date In June For Takeda’s Alogliptin" - Pink Sheet, 29 December, 2008.).

Savient also is seeking to bring a new gout treatment to market, although the company is seeking an indication for treatment-failure gout. Questions about cardiovascular safety have also been linked to Savient's drug, pegloticase.

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 (⁴ 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 Positions Uloric To Gout Patients In Need Of Better Control

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