FDA panel rejects rilonacept for treating gout flares

The FDA Arthritis Advisory Committee voted unanimously today that efficacy and safety data did not support the approval of interleukin-1 blocker Arcalyst to treat gout flares caused by uric acid-lowering therapy.

Regeneron Pharmaceuticals presented results from multiple randomized, double blind, placebo-controlled studies indicating a reduction in gout flares among patients receiving 80 mg or 160 mg of the drug subcutaneously. The drug (rilonacept), initially approved in 2008 and used as a treatment for cryopyrin-associated periodic syndromes (CAPS), was offered as an alternative to standard gout flare treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine, which can result in serious contraindications. The sponsor proposed a 160-mg subcutaneous loading dose followed by 80 mg administered once a week for 16 weeks, but would also distribute the drug through specialty pharmacies and establish a mandatory registry to identify and follow up with any patients prescribed the drug for longer periods.

While a narrow majority (6-5) agreed that the drug’s efficacy was supportive of an approval, members voiced concerns that the proposed indication was too broad for first-line use and that insufficient data had been collected from patients intolerant of other existing treatments who would be most likely to receive the drug. The committee also noted that the drug might be administered to patients who did not require it, as a large number of patients who received a placebo in the studies did not experience any flare-ups, but that in severe cases a 16-week regimen might be insufficient.

“My objections are those of a clinician,” David Blumenthal, MD, committee member and assistant professor of medicine at Case Western Reserve University Cleveland Veterans Affairs Medical Center in Cleveland, said during the hearing. “We all envision this as something we’d use in our worst gout patients, but once you stop this drug, the rate of flares spikes back up to where it was in the placebo group at 12-16 weeks. A lot of patients are going to require something to prevent gout flares longer than 16 weeks.”

Several members also said that a lack of comparative data between rilonacept and other gout treatments influenced their decisions.

“NSAIDs and colchicine are flawed agents and haven’t been extensively studied, and there is potential toxicity,” Blumenthal said. “[But] the speculation that this pharmaceutical might be the answer to that is just that: speculation. We don’t have head-to-head comparisons with current therapies to see if this would even be equivalent to what we are doing now.”

When asked if the presented safety data supported approval, three members voted yes and eight voted no, with most indicating a need for more long-term safety data beyond the 16-week studies presented. Of particular note was the incidence of six malignancies within a treatment-receiving study group compared with zero in the placebo group, which some members said was not sufficiently ruled out as insignificant by available data.

The committee recommended that further research be conducted with a focus on patients at high risk for flares, as well as larger, lengthier studies to ensure safe use beyond 16 weeks. Regeneron began an ongoing, 1-year safety study of the drug vs. placebo in November.

“I think there is a role for this drug, or this type of drug, in the treatment of patients initiating [uric acid-lowering therapy],” Lenore M. Buckley, MD, MPH, committee chair and professor of international medicine and pediatrics at Virginia Commonwealth University School of Medicine, said. “I’m looking forward to the availability of this drug. I just don’t think we have the data yet about the patient population in terms of safety.”

Although the FDA is not required to follow the recommendations of the advisory committee, it usually does.