OP0108 TREATMENT OF MODERATE TO SEVERE RHEUMATOID ARTHRITIS WITH IL1-TRAP
C.O. Bingham III, M. Genovese, L. Moreland, J. Papadopoulos, M.V. Parsey; United States

Kineret^® is currently the only approved therapy aimed at the inhibition of IL-1, a cytokine involved in the pathogenesis of rheumatoid arthritis (RA). Its efficacy is modest, however, perhaps due to its short half-life. In this study, Bingham et al investigate the efficacy and safety of a new IL-1 inhibitor, IL-1 Trap. IL-1 Trap is a specific, high affinity inhibitor of IL-1 consisting of the Fc portion of human IgG1 and the extracellular domains of both IL-1 receptor components (the Type I receptor and receptor accessory protein) administered subcutaneously once weekly.

Methods: 201 patients with moderate to severe RA (>10 swollen and tender joints) were randomized to one of four treatment groups: 25mg, 50mg, or 100mg weekly subcutaneous injections of IL-1 Trap, or placebo. Patients had to have failed at least one prior DMARD and were allowed to continue current therapy at stable doses, including prednisone, methotrexate, and NSAIDS. No other biologic therapy, such anti-TNF inhibitors, was permitted. ACR 20 at 12 weeks was as the primary endpoint.

Results: The majority of patients in all groups were on background DMARDs (60-68%). The mean baseline DAS28 scores ranged from 5.47-5.77. The ACR 20 scores at week 12 using a LOCF analysis were 46.0%, 20.8%, 34.8%, and 30.9% in the 100mg, 50mg, 25mg, and placebo groups, respectively (pNS).

ESR and CRP decreased in a dose-dependent fashion with statistical significance reached at 12 weeks for the 100 mg dose compared to placebo: CRP (mean change -1.3 mg/dL vs. -0.1 mg/dL, p<0.001) and ESR (LS mean change 7.8 vs. 1.0, p=0.044). The AUC for DAS28 of the 100mg dose was significantly different compared to placebo for the active treatment period (p = 0.008, ANOVA). Also, the change in DAS 28 at the 100mg dose was significantly different from placebo at nearly all time points tested.

Injection site reactions (burning) were the most common adverse event and occurred with similar frequency (34%) in both the 100mg IL-1 Trap and placebo groups. No increased incidence of infections was found. Antibodies to IL-1 occurred in <5% of patients treated with IL-1 Trap and the occurrence was not dose-related.

Conclusion: Although the ACR 20 response to IL-1 Trap treatment was not significantly higher compared to placebo, the 100mg dose showed some clinical and biological efficacy as evidenced by the significantly enhanced reduction in ESR and CRP levels, as well as the significant reduction in DAS28 score. Given the apparent safety at these doses of IL-1 Trap and trends towards efficacy, further study at higher doses is warranted.

Editorial Comments: IL-1 exhibits potent pro-inflammatory properties and is believed to be an important mediator of bone and joint destruction in RA. The failure of anakinra to have a profound effect in RA has called the role of IL-1 in RA somewhat into question. But the short half-life and relatively low potency of anakinra makes it a less than ideal agent for a definitive proof-of-concept study of IL-1 in RA.

IL-Trap, an IL-1 inhibitor with high (picomolar) affinity and long duration of action, was a hopeful new agent for this long awaited proof-of-concept study. The current results are disappointing. Despite its high potency and affinity, the clinical response to this agent was dismal, although it is true that a high enough dose may not have been employed in this Phase II study. We may have to finally accept the fact that TNF, but not IL-1, drives the inflammatory processes in the rheumatoid joint.

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