Phase III Study Reveals Potential New Therapy for Gout

Newswise — Rilonacept (IL-1 Trap) may substantially decrease both disease activity and pain in patients with chronic active gout, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Boston, Mass.

Gout is a painful and potentially disabling form of arthritis that has been recognized since ancient times. Initial symptoms usually consist of intense episodes of painful swelling in single joints, most often in the feet, especially the big toe.

Rilonacept, a potential new therapy currently being tested in the treatment of inflammatory conditions, prevents interleukin-1 from attaching to cell-surface receptors " creating a flare in disease. Interleukin-1 is a protein secreted by many cells in the body; secreted in excess, IL-1 can trigger disease activity in gout.

To assess the safety and change in disease activity in patients with chronic, active, gouty arthritis after treatment with rilonacept, researchers followed 10 patients who participated in a multi-center, non-randomized, single-blind, placebo-controlled study.

The participants were on average 62 years old, had gout for an average of 13 years, and had suffered from chronic gout. Participants received twice-weekly subcutaneous injections of placebo followed by six weekly injections of rilonacept. Gout activity was assessed by the degree of pain reported by the patient, overall disease assessment, the number of joints experiencing joint pain, and a C-reactive protein blood test used to measure inflammation in the body.

There were no reported deaths or serious adverse events. Drug-related adverse events were most often associated with mild-to-moderate reactions at the injection site.

In the second through eighth week of treatment, 70 percent of participants had at least a 50 percent improvement in pain, and 60 percent of participants had at least a 75 percent improvement in pain. No participants on placebo showed improvement.

Inflammation levels detected in the blood decreased by 59 percent by the eight week of rilonacept therapy, and at week 14, a trend toward baseline levels was observed.

"The last two decades have seen a remarkable resurgence of gout in the USA, and practitioners are facing increasingly complex, refractory cases in which advanced age, co-morbidities including chronic kidney disease, and concomitant medications impose difficult management decisions," said Robert Terkeltaub, MD, section chief, rheumatology-allergy, VA Medical Center, San Diego; professor of medicine, University of California, San Diego; and an investigator in the study. "Practitioners are further limited by the lack of new FDA-approved therapeutic options for gouty inflammation and hyperuricemia management for patients who present with 'difficult gout' " particularly those who have extensive gouty skin and joint deposits of tophi and frequent or persistent inflammation of multiple joints. Experimental gouty inflammation is clearly IL-1beta-driven, and preliminary studies of gout patients suggest therapeutic benefit of IL-1 receptor antagonism, reinforced by this small pilot study of rilonacept in a group of refactory patients."

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.

Editor's Notes: Dr. Terkeltaub will present this research during the ACR Annual Scientific Meeting at the Boston Convention and Exhibition Center from 9:00 " 11:00 am ET on Friday, November 9, 2007, in the Exhibit Hall. Presentation Number: L2

Placebo-Controlled Pilot Study of Rilonacept (IL-1 Trap), A Long Acting IL-1 Inhibitor, In Refractory Chronic Active Gouty Arthritis

Robert Terkeltaub1, H. Ralph Schumacher, Jr.2, John Sundy3, Frederick Murphy4, Stephen Bookbinder5, Stephanie Biedermann6, Scott Mellis6, Ke Yang6, Allen Radin6. 1VAMC/UCSD, San Diego, CA; 2University of Pennsylvania, VA Medical Center, Philadelphia, PA; 3Duke University Medical Center, Durham, NC; 4Altoona Center for Clinical Research, Duncansville, PA; 5Ocala Rheumatology Research Center, Ocala, FL; 6Regeneron Pharmaceuticals, Inc., Tarrytown, NY

Background: Preclinical studies and a clinical case series suggest that blockade of the NALP3 (cryopyrin) inflammasome IL-1 pathway may offer a new treatment strategy for gout. Rilonacept, a soluble receptor-Fc fusion protein that blocks IL-1 showed rapid and sustained benefits in a Phase 3 study of subjects with cryopyrin-associated periodic syndrome (CAPS) arising from NALP3 mutations. This pilot study explored the potential utility of rilonacept in chronic active gout.

Objective: To assess the safety profile and change in disease activity in subjects with chronic, active gouty arthritis after treatment with rilonacept.

Methods: This was a multi-center, non-randomized, single-blind, placebo-controlled, monosequence crossover study. The study population included subjects with a diagnosis of ≥ 6 months of chronic gouty arthritis, ≥1 active joint for ≥ 4 weeks, and a self-reported pain visual analogue scale (VAS) of ≥ 3. A run-in period of 2 weekly subcutaneous (SC) injections of placebo (PBO) was followed by 6 weekly injections of rilonacept. Gout activity was assessed by Subject Pain VAS, Subject and Physician Global VAS, joint count, and hs-CRP.

Results: Ten subjects (8M/2F) with a mean age of 62 years (50-78), mean disease duration of 13 years (6-26), and Day 0 Subject Pain VAS of 5.1/5.0 (mean/median) were enrolled. There were no reported deaths or SAEs, and drug-related adverse events were most often associated with mild-to-moderate injection site reactions. Mean/median changes in Subject Pain VAS rating from Day 0 to Week 2 with PBO treatment were 0.25/-0.25 (ns), respectively, and -3.2/-2.25 (p=0.02) with rilonacept treatment from Week 2 to Week 8. During this period, seven of 10 subjects on rilonacept showed at least 50% improvement in Subject Pain VAS (p< 0.0001) and six of 10 subjects showed at least 75% improvement (p=0.0001), while no subjects showed improvement in this parameter while on PBO. Hs-CRP median decreased 59% (p = 0.004) by Week 8 after rilonacept therapy. At Week 14 (6 weeks after last dose of rilonacept) a trend towards baseline hs-CRP levels was observed.

Conclusion: Rilonacept was generally well tolerated. Substantial decrease in both clinical activity and hs-CRP was seen after blinded switch from treatment with PBO to rilonacept. These results support the hypothesis that IL-1 blockade may offer an important new therapeutic option in a subset of gout patients with chronically active inflammatory arthritis. Further studies are planned.

Disclosure Block: R. Terkeltaub, VA; NIH; TAP Pharmaceuticals; Regeneron; TAP; Savient; ISIS; BioCryst; Novartis; AR Scientific; H. Schumacher, Wyeth; TAP; CherryPharm; ACR/EULAR; NIH; Abbott; TAP; Savient; Ipsen; Regeneron; Pfizer; Merck; J. Sundy, Regeneron; Savient; Abbott; Novartis; Professional Postgraduate Services; Regeneron; Savient; F. Murphy, None; S. Bookbinder, None; S. Biedermann, Regeneron; Regeneron; S. Mellis, Regeneron; Regeneron; K. Yang, Regeneron; Regeneron; A. Radin, Regeneron; Regeneron.