SILVER SPRING, MD. – Lack of data on patients with refractory gout has scuttled for now any recommendation to approve the interleukin-1 inhibitor rilonacept.*
The Food and Drug Administration’s Arthritis Advisory Committee voted 11 to 0 that the safety and efficacy data on rilonacept did not support its approval for the prevention of gout flares during the initiation of uric acid-lowering therapy in adults with gout.
Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the 16 week pivotal trials, and that this length of time was not enough to evaluate safety because it was likely that the treatment would be used for longer periods of time.
Rilonacept, marketed as Arcalyst, was approved by the FDA in 2008 for the chronic treatment of familial cold autoinflammatory syndrome and Muckle-Wells syndrome (or cryopyrin-associated periodic syndromes), rare genetic disorders. Preclinical and clinical data indicate that interleukin-1 (IL-1) plays a role in triggering gout flares during the initiation of uric acid–lowering therapy, according to Regeneron Pharmaceuticals, which makes the drug. The dose for which Regeneron was seeking approval was a loading dose of 160 mg followed by a weekly dose of 80 mg for 16 weeks.
The manufacturer presented data to the FDA panel from two studies of almost 500 largely middle-aged men with moderate to severe gout. Their gout’s severity was characterized by a serum uric acid level of at least 7.5 mg/dL and at least two gout flares during the previous year. Patients were randomized to a dose of 80 mg subcutaneously, a dose of 160 mg administered once a week (after a 320-mg loading dose) given subcutaneously, or placebo. At the same time, all the participants initiated uric acid–lowering treatment with allopurinol. The prophylactic use of NSAIDs, glucocorticoids, or colchicine was not allowed. One study was conducted in the United States and Canada; the other was conducted in Germany, India, Indonesia, South Africa, and Taiwan.
Over a period of 16 weeks, treatment with the 80-mg dose was associated with a statistically significant reduction in the mean number of gout flares – the primary end point – compared with placebo. Those on the 80-mg dose had a mean of 0.29-0.35 gout flares per patient, compared with a mean of about one gout flare per patient on placebo, with no significant differences between the two rilonacept doses. In the two studies, 19% and almost 26% of those on the 80-mg dose had at least one gout flare, compared with almost half of those on placebo. Several panelists raised the issue of whether it was worth exposing patients to a biologic therapy when they had a 50% chance of not having a flare.
In a pooled database of the two pivotal studies and two other gout studies comparing the effectiveness of the 160-mg dose of rilonacept in about 1,000 patients to placebo in almost 400 patients, no significant increase in serious infections was observed in patients treated for 16 weeks. However, six malignancies were diagnosed during treatment with rilonacept, compared with none among those on placebo. FDA reviewers noted that while this number was low and the types of malignancies were not unusual for the typical gout patient, the lack of any malignancies among those on placebo and the biologic plausibility for an increased malignancy risk with a biologic immunosuppressant was a concern and suggested it would be useful to have data on a period longer than 16 weeks.
Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the pivotal trial, and that 16 weeks was not long enough to evaluate safety because it was likely that the treatment would be used for longer periods of time.
Several panel members questioned why the company did not compare rilonacept to an active control, such as colchicine, which is one of the main drugs used to prevent gout flares during the initiation of uric acid–lowering therapy.