LONDON – Prophylactic treatment with the potent interleukin-1 inhibitor rilonacept significantly reduced the incidence of acute gout flares triggered by the initiation of urate-lowering therapy, according to data from a global phase III study reported at the annual European Congress of Rheumatology.
Patients in the 16-week trial who were randomized to receive weekly subcutaneous injections of either 80 mg or 160 mg of rilonacept (Acralyst) at the outset of standard uric acid–reducing treatment with allopurinol had significantly fewer gout flares and significantly fewer days per flare than did patients randomized to placebo, said principal investigator Dr. Essack Mitha of Newtown Clinical Research in Johannesburg, South Africa.
Further, treatment with the fusion protein, which interrupts the inflammatory cascade by attaching to and neutralizing interleukin-1, demonstrated acceptable safety and tolerability, he said.
The findings are consistent with those of a sister phase III trial in North America reported at the 2010 annual meeting of the American College of Rheumatology, he said.
The phase III, double-blind Preventive Study Against Urate-Lowering Drug-Induced Gout Exacerbations (PRE-SURGE 2) was conducted in South Africa, Germany, and Asia, and included 248 patients with gout, serum uric acid levels of 7.5 mg/dL or higher, and a history of at least two gout flares in the prior year. All of the patients were initiated on 300 mg of allopurinol daily (except those with documented renal dysfunction, who were initiated on a lower dose), and subsequently titrated to achieve target urate levels of less than 6 mg/dL, Dr. Mitha stated.
After the initial allopurinol dose, which was continued for 20 weeks, including a 4-week safety follow-up period, patients were randomized to receive 16 weekly subcutaneous injections of placebo (82 patients), 80 mg of rilonacept with a double dosing on day 1 (82 patients), or 160 mg of rilonacept with a double dosing on day 1 (84 patients). During the study, nonsteroidal anti-inflammatory drugs and oral steroids were allowed for the treatment but not for prevention of gout flares, said Dr. Mitha.
"The primary end point was the mean number of gout flares per patient through week 16. The secondary end points were the proportion of patients experiencing two or more gout flares during this period and the number of flare-days per patient," he said, adding that safety and tolerability were also assessed.
At baseline, the characteristics of the predominantly male (93%) study population were similar across all three groups, with a mean age of 51 years, a mean serum uric acid level of 9.4 mg/dL, a mean of seven gout flares in the prior year, and a mean gout flare duration of 3.8 days. A similar number of patients in the placebo and rilonacept groups completed the treatment period, Dr. Mitha reported.
With respect to the primary end point, the mean number of gout flares per patient was 101 in the placebo group, 29 in the 80-mg rilonacept group, and 28 in the 160-mg rilonacept group, which represent a significant reduction in gout flares relative to placebo, said Dr. Mitha.
"Compared with placebo, the proportion of patients who experienced more than one gout flare through week 16 was reduced by 54% in the 80-mg group and 63% in the 160-mg group," he said. The respective reductions relative to placebo in the proportion of patients experiencing two or more flares were 74% and 82%. "The mean number of gout flare days per patient was also significantly lower in the rilonacept subjects, at 4.3 and 1.9 for the 80-mg and 160-mg groups, respectively, compared with 11.2 for placebo," and significantly fewer patients in the treatment arms had flares lasting 5 days or longer, he said.
In terms of adverse events, the overall incidence was similar across the groups, and although there were more injection-site reactions in the rilonacept groups, "the reactions were generally mild, and none of the patients withdrew for that reason," Dr. Mitha said. Three patients did withdraw from the higher-dose rilonacept group for other reasons – one each for neutropenia, gout flare, and gastric cancer – "but there were no deaths and no serious adverse events related to the product," he stressed.
Together with the results of the North American PRE-SURGE 1 trial, the findings of this study are an important step in the clinical development program for rilonacept, which the U.S. Food and Drug Administration approved in February 2008 for the treatment of cryopyrin-associated periodic syndromes and Muckle-Wells syndrome in adults and children older than 12 years.
"Our results suggest that concomitant use of rilonacept during the first several months of allopurinol therapy may help avoid the acute gout flares that make it difficult for patients to maintain urate-lowering therapy," according to Dr. Mitha. Currently, standard practice includes the use of colchicine or anti-inflammatory drugs to reduce the risk of flares associated with early allopurinol, but the gastrointestinal side effects associated with colchicine in particular can be prohibitive, he said.