Strong efficacy data and a desperate need for new gout therapies outweigh the potential cardiovascular risk associated with Takeda's febuxostat, an FDA advisory committee determined in recommending approval of the drug during a Nov. 24 meeting.

Yet despite the near-unanimous vote (12-0 with one abstention), members of the Arthritis Drugs Advisory Committee expressed concern over a potential cardiovascular signal and encouraged FDA to use its post-approval authorities to require further study.

Febuxostat is a non-purine selective xanthine oxidase inhibitor; Takeda is seeking an indication for the management of hyperuricemia in patients with chronic gout. The user fee goal for the standard review is Jan. 16, 2009.

Will Takeda Succeed Where Others Have Failed?

Should FDA agree with the advisory committee and approve febuxostat - which Takeda hopes to market as Uloric - it would be the first new drug approved for gout in 40 years. Other gout drugs developed in recent years have been denied approval by FDA.

For example, Cardiome's Oxyprim (oxypurinol), an active metabolite of the only other available prescription treatment for gout - the purine non-selective xanthine oxidase inhibitor allopurinol - never made it past the Arthritis advisory committee (¹ Also see "Oxyprim Gout Therapy To Be Limited To Allopurinol Failures, Cardiome Says" - Pink Sheet, 7 June, 2004., p. 40).

Merck had held out hope that a gout indication for its COX-2 inhibitor Arcoxia (etoricoxib) would help it stand out from entrenched competitors, but an increased cardiovascular risk led FDA to reject the NDA (² Also see "FDA’s Arcoxia Decision Offers New Evidence Of Conservative Review Stance" - Pink Sheet, 7 May, 2007., p. 15).

In the case of febuxostat, FDA's post-approval authorities under the FDA Amendments Act may make the agency more comfortable in approving the drug. Those authorities seemed to placate advisory committee members, who questioned whether FDA had the resources to require sponsor follow-through with any post-marketing cardiovascular trials.

Curtis Rosebraugh, director of CDER's Office of Drug Evaluation II, assured the committee that under FDAAA, the agency "has a lot more authority than what we used to have" over post-marketing studies.

Bob Rappaport, director of the Division of Anesthesia, Analgesia & Rheumatology Products, added: "We do have some authorities now to put sponsors on a timeline. We can't drag our feet anymore."

A Long Regulatory Road For Febuxostat

The advisory committee review represented a major regulatory milestone for febuxostat. Since Takeda submitted the NDA in 2004 (with then-partner Abbott through the TAP Pharmaceutical joint venture), FDA has issued two "approvable" letters over the safety profile of the drug.

After the first letter, Takeda submitted a re-analysis of existing data from two long-term extension trials. That failed to placate FDA, which was concerned with the small number of events and subjects. A second "approvable" letter suggested that Takeda conduct a new study to further explore the safety signal ("³ Also see "TAP To Discuss Gout Treatment With FDA Following Second “Approvable” Letter" - Pink Sheet, 11 August, 2006..

It was that third trial, the 2,269-subject CONFIRMS study, that was the central issue on the table at the advisory committee meeting: FDA wanted to hear from the committee on whether those data adequately resolved febuxostat's safety profile.

In CONFIRMS, Takeda included a lower, 40 mg dose (previous doses were 80 mg and 120 mg). The study evaluated the efficacy and safety of febuxostat 40 mg and 80 mg compared with allopurinol, the standard of care for chronic gout, over six months.

The primary endpoint - serum uric acid levels below 6.0 mg/dL at the final visit - was met by 67 percent of patients in the 80 mg arm, 45 percent in the 40 mg arm, and 42 percent receiving allopuriol. The 80 mg results were statistically significant compared to the 40 mg arm and allopurinol; the 40 mg results were statistically non-inferior to allopurinol (10 percent NI margin).

Febuxostat 80 mg was also significantly more efficacious than 40 mg and allopurinol in subjects stratified by baseline tophi or sUA levels ³ 10 mg/dL, while both 40 mg and 80 mg were statistically superior to allopurinol in patients with mild or moderate renal impairment.

Cardiovascular events in the CONFIRMS study were few in number, FDA's Gilbert noted, and were approximately even among febuxostat (16) and allopurinol patients (17). The study did not demonstrate a pattern of increased risk, but "statistical analysis ... does not enable one to exclude that possibility," FDA's Gilbert said.

Lingering Doubts Over Cardiovascular Safety

The committee shared FDA's lingering doubts over febuxostat's cardiovascular safety - especially the cardiologists serving as temporary members on the Arthritis advisory committee.

Complicating the picture is the fact that gout patients are already at elevated risk for cardiovascular adverse events. Given the inherent risk in the population, a cardiovascular signal detected in the two pivotal trials supporting febuxostat's NDA was cause for concern.

Gout patients tend to have significant comorbidities, including hypertension, diabetes, chronic renal failure and metabolic syndrome, FDA clinical reviewer Jane Gilbert said. The risk of cardiovascular disease in the gout population is 1.5 times greater than in the normal population, she noted.

A major point of contention with committee members was CONFIRMS trial design. Temporary voting member Robert Harrington, a cardiologist at the Duke University Medical Center, took issue with the trial population and relatively short six-month timeframe.

High cardiovascular risk "is not driven by the things that are being measured" in the trial, Harrington said. He noted that most of the CONFIRMS patients were "overweight middle-aged men," rather than older individuals with overt coronary or vascular disease.

"The fact is, people who are 50 years old with a bunch of risk factors, they don't die. The only way you really see these effects - go back to the COX-2 story - is when you start exposing the 65-year-old with disease. But we don't have those patients, so I wonder if some discussion had taken place as to why not."

Harrington also questioned the six-month timeframe for the study, arguing that 180 days "is a very, very short period of time to uncover cardiovascular risk for a drug that's going to be taken for life."

Jeffrey Siegel, clinical team leader of FDA's arthritis review division, defended the trial design, noting that Takeda was not asked to conduct a cardiovascular outcomes study. "The purpose of the trial was to repeat the types of studies that were done before to see whether there was any signal," he said.

"That's the reason the study was carried out for six months as opposed to much longer, which is what you'd want to do if you were doing a CV outcomes study, and why we didn't particularly insist on having people at higher risk. A study that has more people at risk may have been more sensitive."

Rheumatologists on the panel argued that the unmet medical need superseded the potential cardiovascular signal, and would eventually result in lower risk of downstream consequences of hyperuricemia.

Voting member Nancy Olsen, a rheumatologist at UT-Southwestern Medical School, agreed that evidence "was iffy in both directions," but said she was "relatively impressed" with the efficacy in the CONFIRMS population.

Temporary voting member John Cush, Baylor Research Institute, said for most rheumatologists, "the first and most important indication would be as an alternative agent to allopurinol," which requires dose adjustment and can led to hypersensitivity and renal insufficiency.

Post-Marketing Trial May Call For Outcomes

The committee recommended that any remaining questions about febuxostat's cardiovascular safety profile be addressed by a randomized clinical trial and an observational study that would follow patients for cardiac adverse events.

Takeda had proposed a Phase IV clinical outcomes study focusing on prevention of gout flares and all aspects of safety, but said the design was "fluid" and had yet to be discussed with FDA.

Any decision on post-approval trials could affect several other gout therapies in the pipeline.

After febuxostat, the closest new product to the market is Savient's pegloticase, a pegylated mammalian urate oxidase. The company hopes to file the NDA before year-end, but the drug has run into trouble with cardiovascular adverse events and infusion reactions (⁴ Also see "FDA Febuxostat Review Could Boost Savient Gout Agent" - Pink Sheet, 20 October, 2008., p. 27).

Pfizer also jumped on the gout bandwagon, announcing it will submit its COX-2 inhibitor Celebrex for a different indication than the other pipeline products - treatment of acute gouty arthritis.

- Becky Jungbauer (r.jungbauer@elsevier.com)

Takeda Febuxostat Benefits Outweigh CV Risk; Will Other Gout Drugs Follow?

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