Placebo-Controlled Pilot Study of Arcalyst (rilonacept) a Long Acting IL-1 Inhibitor, in Refractory Chronic Active Gouty Arthritis

Transcription

1 Placebo-Controlled Pilot Study of Arcalyst (rilonacept) a Long Acting IL-1 Inhibitor, in Refractory Chronic Active Gouty Arthritis Allen Radin 6, Robert Terkeltaub 1, H. Ralph Schumacher, Jr. 2, John Sundy 3, Frederick Murphy 4, Stephen Bookbinder 5, Stephanie Biedermann 6, Ke Yang 6, Scott Mellis 6 1 VAMC/UCSD, San Diego, CA; 2 University of Pennsylvania, VA Medical Center, Philadelphia, PA; 3 Duke University Medical Center, Durham, NC; 4 Altoona Center for Clinical Research, Duncansville, PA; 5 Ocala Rheumatology Research Center, Ocala, FL; 6 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.

2 Role of IL-1 in Gout Monosodium urate crystals internalized by monocytes activate the NLRP3 inflammasome which leads to the processing and release of IL-1b IL-1b induces the expression of adhesion molecules and chemokines which are critical for the recruitment of PMNs into the site of acute inflammation Preclinical studies and a clinical case series (Martinon 2006, Chen 2006, So 2007,Torres 2007) suggest that blockade of the NLRP3 (cryopyrin) inflammasome IL-1 pathway may offer a new treatment strategy for gout patients either intolerant of, not good candidates for, or refractory to currently-available medications

3 Arcalyst (rilonacept) IL1R-AcP IL1R Type 1 IgG 1 Fc On the cell surface, IL-1 is tightly bound by dual-point interaction between IL-1R1 and its accessory protein (AcP) Rilonacept, is a dimeric fusion protein made from human AcP, IL-1R1, and Fc which binds with high affinity, similar to the natural receptors. Fc enables dimerization and confers a long circulating half-life

4 Single-Blind, Placebo Run-In Study in Subject s with Chronic Active Gout S D0 W2 W4 W6 W8 W14 dosexx xx xx x x x x x Two week Placebo run-in Loading dose of rilonacept at Week 2 (2X 160 mg SC) Five weekly 160 mg SC injections of rilonacept Evaluations every 2 weeks, then follow-up 6 weeks after the last dose (Subjects Pain and Global VAS, Physician s Global VAS, Joint Assessment, and hs-crp)

5 A Single-Blind Design Was Used To Distinguish Active from Placebo Treatment Two weeks of treatment with Placebo and six weekly doses of rilonacept was planned in order to capture: Placebo effect (if any) Effect of treatment with rilonacept in each study subject over time in comparison to their own Baseline and to their own Placebo results

6 Inclusion Criteria Physician diagnosed chronic gouty arthritis for at least 6 months Male or female 18 years of age At least 1 continuously inflamed joint due to gout for at least 4 weeks VAS 10-cm Pain Scale Score of 3 due to joint pain Subjects for whom standard therapies are less than effective or associated with risks related to side effects

7 Baseline Demographics Demographic Trait All Subjects (N =10) Age (years) Mean (min-max) Male (%) 62 (50 78) 8 (80%) Caucasian (%) 9 (90%) Weight (kg) Mean (min-max) ( ) Height (cm) Mean (min-max) Gout duration (years) 171 ( ) 13 (3 26)

8 Median Screening and Baseline Measures Subject s Pain VAS Patient s Global VAS Physician s Global VAS Screening (Day -14 to -3) Baseline (Day 0) Serum uric acid (mg/dl) hs-crp (nl < mg/dl) Number of affected joints Severity & Symptom-adjusted joint score (Max 9 per joint)

9 Subject s Pain VAS Score Improved on Rilonacept Therapy, but not on Placebo (0 = normal/none to 10 = severe) (LOCF; N = 10) Screening Placebo Rilonacept Off Treatment ns* P<0.02** * - Wk 2 v D0 ** - Wk 8 v Wk 2

10 Rilonacept Therapy Achieved At Least 75% Improvement in Subject s Pain VAS (LOCF; N = 10) Proportion of Responders Placebo ns* Rilonacep t P<0.01** Off Treatment Study Week or more improvement in Pain 75% * - Wk 2 v D0 ** - Wk 8 v Wk 2

11 Improvement in Severity & Symptom- Adjusted Joint Score (median) (LOCF; N = 10) Screening Placebo Rilonacept Off Treatment ns* P < 0.04** * - Wk 2 v D0 ** - Wk 8 v Wk 2 Each joint is counted once for each symptom: swelling tenderness erythema Counts are weighted: 1 = mild 2 = moderate 3 = severe

12 Subject s Global Score (median) (0=normal/none to 10=severe) (LOCF; N =10) Screening Placebo Rilonacept Off Treatment P = ns* P<0.06** * - Wk 2 v D0 ** - Wk 8 v Wk 2

13 Rilonacept Decreases hs-crp (median) (nl < mg/dl) Screening Placebo Rilonacept Off Treatment P = ns** P < 0.004** * - Wk 2 v D0 ** - Wk 8 v Wk 2

14 Efficacy of Rilonacept in Chronic Gouty Arthritis Six of 10 subjects on rilonacept showed at least 50% improvement in Subject s Self-reported Pain VAS (P < 0.001) Five of 10 subjects showed at least 75% improvement (P <0.01) No subjects met these endpoints during Placebo run-in Severity & Symptom-adjusted joint scores improved within 2 weeks of rilonacept treatment (P <0.04) hs-crp (median) decreased 59% (P<0.004) by Week 8 trend towards return to Baseline by Week 14 (6 weeks off rilonacept)

15 Safety and Tolerability of Rilonacept in Chronic Gouty Arthritis Injection site reactions of mild to moderate severity were the most common drug-related adverse events There were no reported serious adverse events (SAEs) No serious or opportunistic infections One subject withdrew due to an injection site reaction which was rated as severe

16 Conclusions Rilonacept was generally well tolerated Decreases in clinical activity and hs-crp were seen after blinded switch from placebo run-in to active treatment with rilonacept These results support the hypothesis that IL-1 blockade may offer a new therapeutic option for patients with chronic gouty arthritis Further investigation of rilonacept for the treatment of gout is in progress

17 Back-Up Slides

18 Physician s Global Score (median) (0 = normal/none to 10 = severe) (LOCF; N =10) Screening Placebo Rilonacept Off Treatment P<0.09* P = ns** * - Wk 2 v D0 ** - Wk 8 v Wk 2