Ilaris Safety Data Inadequate For Gout Indication, FDA Panel Says

Arthritis Advisory Committee votes against approval of Novartis' biologic for treatment of gout attacks, citing the need for more data on long-term safety and retreatment, along with a narrower indication.

FDA's Arthritis Advisory Committee provided Novartis with a laundry list of necessary data and tasks before its biologic Ilaris (canakinumab) can be approved for treatment of gout.

At a June 21 review of the interleukin-1 beta inhibitor, the panel said more data were needed on long-term safety, particularly for retreatment of gout flares and in patients with significant co-morbidities.

The proposed indication should be narrowed and a Risk Evaluation and Mitigation Strategy developed to assure that the agent is used only in those patients suffering from chronic gout flares who cannot find relief from other treatments, the committee said.

The panel was enthusiastic about canakinumab's efficacy. By votes of 11-1 and 8-4, it found substantial evidence of efficacy for the treatment of gout attacks and for the additional claim of extending the time to next attack and reducing the frequency of subsequent attacks.

However, the impressive efficacy was outweighed by safety concerns. The committee voted 12-0 that the safety profile was not sufficient for approval as an acute recurrent treatment of gout flares in those patients who cannot obtain adequate response with non-steroidal anti-inflammatories or colchicine.

The safety concerns guided the ultimate votes on approval. The group voted 11-1 against approval for treatment of gout attacks and 12-0 against approval for the additional claim of extending the time to next attack and reducing the frequency of attack.

Priority Review Voucher Used

Ilaris is already approved for cryopyrin-associated periodic syndrome, an ultra orphan indication. The supplemental application for gout is undergoing a six-month review, with an August user fee deadline, because Novartis cashed in a priority review voucher that it obtained with the 2009 approval of its antimalarial Coartem.

The voucher program created by the 2007 FDA Amendments Act was designed to spur research and development of tropical disease treatments. A voucher allows the holder to secure priority review of a future new drug application in exchange for bringing a new tropical disease therapy to market. Novartis was the first company to receive a voucher under the program (Also see "FDA Awards First-Ever Priority Review Voucher To Novartis For Coartem Approval" - Pink Sheet, 8 Apr, 2009.).

However, it appears Novartis may ultimately reap little benefit from the shortened review timeframe given the safety concerns that FDA reviewers and the advisory committee have about canakinumab's use in the gout population.

In FDA briefing documents released ahead of the meeting, agency reviewers questioned whether the symptomatic relief provided by canakinumab outweighed the risk of serious infections and other adverse events, such as increases in uric acid levels and renal function declines, that could potentially worsen gout patients' condition (Also see "Novartis' Ilaris For Gout: FDA Questions Whether Symptom Relief Is Worth Risks" - Pink Sheet, 17 Jun, 2011.).

Novartis proposed a second-line indication: treatment of gouty arthritis attacks in patients who cannot obtain adequate response to NSAIDS or colchicine. It also requested an additional claim that Ilaris has been shown to extend the time to next attack and reduce the frequency of attacks. The company said the indication encompasses approximately 6% (or 300,000) of the U.S. patients diagnosed with gout.

However, even this narrowed indication was too broad for the committee.

Many panel members took issue with the proposal that patients had to first fail either NSAIDS or colchicine, preferring instead that patients be required to fail, or unable to take, both first-line therapies. Some committee members also believed that patients should be required to fail corticosteroids before receiving canakinumab treatment.

Not Enough Retreatment Data

Committee members were particularly concerned about potentially widespread use, including off-label treatment in less severe patients, given the dearth of long-term safety and retreatment data.

Only 43 patients in the Phase III program received three or more canakinumab injections, a number that many committee members deemed inadequate to assess whether safety risks increased with repeated exposure.

Canakinumab's risks warrant longer-term safety data beyond the six months provided in the clinical trials, particularly with regard to renal function, cardiovascular effects, infections, and the impact of uric acid level increases, committee members said. They also called for safety data in patients with significant co-morbidities.

"There's probably room for use of this drug in a specific population that could benefit, but I would like to see at least two, three years of data with respect to long-term safety," temporary voting member Maria Suarez-Almazor, MD Anderson Cancer Center, said.

"I think we need a lot more data on patients with co-morbidities that predispose to infection, particularly chronic kidney disease, diabetes," committee member Lenore Buckley, Virginia Commonwealth University, said. "There's a huge population of transplant patients who would be candidates for this drug that are already immunosuppressed and we don't know the effect of giving them additional immunosuppression."

Temporary voting member Allan Gibofsky, Cornell University, was the lone panelist who supported approval for treatment of gout attacks. He proposed a more limited indication combined with a "vigorous" REMS program with elements to assure safe use. "I would not want to see the population of patients who would benefit from this drug not get it because of the possibility of overuse by other individuals, and I think we can control that," he said.

-Sue Sutter ([email protected])