FDA panel votes against approval of a supplemental BLA application
By Sy Schlager, MD, PhD
Gout flares occurring during the early months of urate-lowering therapy are thought to result from the release of urate crystals from deposits softened by the treatment. These crystals trigger the release of interleukin (IL)-1, thus leading to a cascade of inflammation and flares of acute joint pain. Traditionally, the vast majority of gout flares have been managed with nonsteroidal anti-inflammatory drugs (NSAIDs), colchicines, or steroids.
A recent phase 2 study showed that gout attacks occurring during the first few months of urate-lowering therapy can be nearly eliminated by adding the IL-1 inhibitor rilonacept (Arcalyst) at the initiation of allopurinol (Zyloprim; Schumacher HR, et al. Arthritis Rheum. 2012;64:876-884). In this double-blind study, 83 adult patients with hyperuricemia and gout were randomized to receive rilonacept (loading dose of 320 mg followed by 160 mg weekly) or placebo administered subcutaneously and were started on allopurinol (300 mg daily, titrated to a serum urate level of <6 mg/dL).
The mean number of gout flares per patient through week 12 was significantly lower in the rilonacept group than in the placebo group (6 flares vs 33 flares, respectively; P = .001), and the proportion of patients experiencing a gouty flare during the 12 weeks was also significantly lower in the rilonacept group than in the placebo group (14.6% vs 45.2%, respectively; P = .003). At week 16, no rebound in the flare rate was observed for 6 weeks after discontinuation of rilonacept or placebo. Adverse events (AEs) were similar in the rilonacept and placebo groups, with the most common reported AEs being infections and musculoskeletal disorders. A higher percentage of patients receiving rilonacept than placebo controls completed the 12-week evaluation period (98% vs 79%, respectively; P = .015).
Although the findings of this study indicate that rilonacept can reduce the frequency of gouty flares during the initial period of treatment with urate-lowering therapy, inhibiting IL-1 is probably not the only factor involved in the flares; rilonacept prevented most, but not all, flares. In the real-world setting, rilonacept is likely to be used when conventional therapy (ie, NSAIDs, colchicines, steroids) has failed or is not well tolerated.
Despite these recent findings, the US FDA Arthritis Advisory Committee voted on May 8, 2012, against the approval of a supplemental Biologic License Application (BLA) for rilonacept to prevent gout flares.
The supplemental BLA asked for approval of the use of rilonacept as an 80-mg subcutaneous injection once weekly for 16 weeks after a 160-mg loading dose for the prevention of gout flares during initiation of uric acid–lowering therapy in patients with gout.
The main objections to the application centered around the supporting clinical data, which the majority of panel members said had failed to adequately demonstrate the safety of the drug and its improved efficacy over current standard therapy.