PARIS — The investigational long-acting interleukin-1 inhibitor rilonacept showed potential as an important new treatment option in patients with severe refractory chronic active gout in a small pilot study, according to a rheumatologist whose research focus is chronic gout.
Five of 10 patients in the single-blind nonrandomized study showed at least a 75% improvement in pain scores after 6 weekly subcutaneous injections of rilonacept at a fixed dose of 160 mg.
These were patients with severe refractory pain and disability at baseline, and none of them responded to 2 weeks of placebo injections, commented Dr. John S. Sundy, the director of rheumatology and allergy research at the Duke Clinical Research Institute, Duke University, Durham, N.C.
He disclosed that he is a consultant to Regeneron Pharmaceuticals Inc., which sponsored the pilot study.
Rilonacept is a soluble dimeric fusion protein and high-affinity blocker of the interleukin-1 receptor type 1 and the IL-1 accessory protein. Its therapeutic efficacy in this multicenter proof-of-concept study reinforces preclinical evidence and a small case series suggesting that IL-1 plays an important role in gouty inflammation, and that blockade of the IL-1 pathway represents a new treatment strategy in gouty arthritis.
The pathophysiologic sequence involves the engulfing of monosodium urate crystals by monocytes, which activates the cryopyrin inflammasome with resultant release of IL-1 into surrounding tissues.
The IL-1β induces expression of chemokines and adhesion molecules, which draw polymorphonuclear leukocytes to the site of acute inflammation, thereby making the inflamed joint even hotter, he explained.
The 10 participants in the pilot study had a mean age of 62 years, a 13-year history of gout, and a mean visual analog scale pain score of 5.1 at enrollment.
The patients had a mean of nearly three actively inflamed joints for at least the past month at enrollment.
Standard gout therapies were either ineffective or laden with unacceptable side effects in this overweight/obese population with numerous comorbid conditions.
High-sensitivity C-reactive protein levels (a measure of disease activity) dropped by an average of 59% after 6 weeks of rilonacept, then trended back up toward baseline during 6 weeks of follow-up off the drug. The number of affected joints decreased during active treatment, a trend that just missed statistical significance in this small study.
The same was true for physicians' global ratings.
Rilonacept was generally well tolerated. The most common reported side effect consisted of mild to moderate injection site reactions.
Speaking at the annual European Congress of Rheumatology, Dr. Sundy said that in addition to much larger and longer-term placebo-controlled trials of rilonacept in refractory chronic active gout, other trials are planned or underway to evaluate the IL-1 inhibitor for prevention of acute flares in patients with chronic gout, as well as in other inflammatory diseases in which the IL-1 pathway is believed to figure prominently.
These include juvenile idiopathic arthritis, familial Mediterranean fever, and rheumatoid arthritis.
Earlier this year, rilonacept received Food and Drug Administration marketing approval for the treatment of two rare cryopyrin-associated periodic syndromes: Muckle-Wells syndrome and familial cold autoinflammatory syndrome.
One audience member indicated that he wasn't bowled over by the 50% response rate reported by Dr. Sundy.
He questioned the merits of developing a sophisticated and costly new therapy for a familiar disease for which far simpler alternatives—including intra-articular corticosteroid injections—are often highly effective.
Dr. Sundy replied that rilonacept is targeted at the minority of patients in whom tried-and-true therapies aren't effective or are intolerable.
Given that gout is the most common inflammatory arthritis in men and its incidence is climbing, that's not an insignificant number of patients.
“This is the severe end of the spectrum of gout. It's the small tail on the curve, not the typical everyday presentation of gout,” he stressed.