BOSTON — A new, long-acting interleukin-1 inhibitor being tested for multiple inflammatory conditions substantially decreased disease activity and pain associated with chronic active gout in a placebo-controlled pilot study.
If the findings are validated in larger investigations, the drug, rilonacept, may offer much-needed relief to patients with severe gouty arthritis who are refractory to other therapies, Dr. Robert Terkeltaub said in a late-breaking poster presentation at the annual meeting of the American College of Rheumatology.
Studies have shown that gout-associated uric acid crystals activate the NALP3 (cryopyrin) inflammasome, resulting in the production of active interleukin-1 (IL-1). Rilonacept, a fusion protein that is given by subcutaneous injection, attaches to and neutralizes IL-1 before the proinflammatory cytokine attaches to cell surface receptors and generates inflammation-triggering signals. Unlike some of the IL-1 blocking agents currently on the market, rilonacept is described as an IL-1-specific cytokine trap: Once the IL-1 attaches to rilonacept, it cannot bind to the cell surface receptors and is eliminated from the body with the rilonacept.
Based on data from preclinical studies and a clinical case series suggesting that blockade of the NALP3 inflammasome IL-1 pathway may be an effective treatment strategy for gout, as well as the promising results of a phase III trial of the drug in patients with cryopyrin-associated periodic syndrome (CAPS) arising from NALP3 mutations, Dr. Terkeltaub, professor of medicine at the University of California, San Diego, and colleagues, sought to assess the utility of the drug in chronic active gout in a multicenter, nonrandomized phase III trial.
The single-blind, placebo-controlled study enrolled 10 patients with severe chronic gout, mean age 62 years, with a mean disease duration of 13 years. Inclusion criteria were a diagnosis of chronic gouty arthritis for at least 6 months, at least one active joint for a minimum of 4 weeks, and a self-reported pain visual analog scale (VAS) of 3 or higher. The study protocol included a run-in period of 2 weekly subcutaneous injections of placebo, followed by 6 weekly injections of rilonacept. Gout activity was assessed using the Subject Pain VAS, Subject and Physician Global VAS, joint count, and serum levels of high-sensitivity C-reactive protein (hs-CRP).
At baseline, the mean and median Subject Pain VAS scores were 5.1 and 5.0, respectively. The mean and median changes in Subject Pain VAS from baseline to week 2 with placebo treatment were 0.25 and −0.25, respectively, and from week 2 to week 8 with rilonacept treatment were −3.2 and −2.25, respectively, Dr. Terkeltaub reported. During the active treatment period, 7 of the 10 subjects showed at least 50% improvement in Subject Pain VAS, and 6 of the 10 showed at least 75% improvement. By treatment week 8, serum CRP levels decreased by 59%, he said. At week 14, which was 6 weeks after the last dose of rilonacept, a trend toward baseline hs-CRP levels was observed.
Rilonacept treatment was not associated with deaths or severe adverse events. It generally was well tolerated with the most common adverse events being mild to moderate injection site reactions, Dr. Terkeltaub said.
The drug might be particularly useful in the treatment of “increasingly complex, refractory cases of gout,” said Dr. Terkeltaub. Advanced age, comorbidities such as chronic kidney disease, and concomitant medications complicate management decisions, he noted, as does the lack of new Food and Drug Administration-approved treatment options for “difficult gout.” The drug's ability to interfere with the IL-1 inflammatory process suggest it could be useful as an adjunct to uric acid-lowering drugs in gout, which sometimes lead to disease flares, he said.
Dr. Terkeltaub disclosed that he has had financial or other relationships with multiple companies, including TAP Pharmaceutical Products Inc., Savient Pharmaceuticals, ISIS Pharmaceuticals Inc., BioCryst Pharmaceuticals Inc., Novartis AG, and Regeneron Pharmaceuticals Inc., maker of rilonacept.