OP0117   TOCILIZUMAB, A NOVEL MONOCLONAL ANTIBODY TARGETING IL-6 SIGNALLING, SIGNIFICANTLY REDUCES DISEASE ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS

J. Smolen1, A. Beaulieu2, A. Rubbert-Roth3, E. Alecock4, R. Alten5, T. Woodworth4
1Clinical Department of Rheumatology, University Clinic for Internal Medicine I, Vienna, Austria, 2Faculty of Medicine, Laval University, Quebec, Canada, 3Medical Clinic I, University of Cologne, Cologne, Germany, 4Pharma Development, Roche Products Ltd., Welwyn, United Kingdom, 5Department of Internal Medicine II, Rheumatology, Schlosspark Clinic, University of Medicine, Berlin, Germany

Background: IL-6 is a cytokine involved with the pathogenesis of rheumatoid arthritis (RA). Therefore, targeted blockade of IL-6 signalling may represent a novel and attractive approach to the treatment of RA.
Objectives: To investigate the efficacy and safety of tocilizumab, a new humanised anti-human interleukin-6 (IL-6) receptor monoclonal antibody, in patients with RA.
Methods: In this double-blind, randomised, controlled phase III study, 623 patients with moderate to severe active RA despite long term treatment with methotrexate (MTX) were randomly allocated to receive tocilizumab 8 mg/kg, tocilizumab 4 mg/kg, or placebo i.v. every 4 weeks. All three groups received MTX (oral or parenteral) at their pre-study dose throughout the study (10-25 mg weekly), with all other disease modifying anti-rheumatic drugs (DMARDs) discontinued at study entry.
Results: A 20% improvement according to the American College of Rheumatology Criteria (ACR20 response) at 24 weeks (primary endpoint) was observed in a significantly higher proportion of patients receiving tocilizumab 8 mg/kg (58.5%) and tocilizumab 4 mg/kg (47.9%) compared with placebo (26.5%, p<0.0001). In the tocilizumab 8 mg/kg group, significantly more patients achieved ACR50 (43.9%) and ACR70 (22.0%) responses compared with placebo (10.8% and 2.0% respectively, p<0.0001). A reduction in Disease Activity Score (DAS) using 28 joint counts was observed from week 2 onwards in both tocilizumab groups, with significant change from baseline to week 24 for both tocilizumab 8 mg/kg (-3.43) and 4 mg/kg (-2.68) vs. placebo (-1.55, p<0.0001). A significantly higher proportion of patients achieved a good/moderate EULAR response at 24 weeks in both tocilizumab groups compared with placebo (p<0.0001). Good/moderate response was seen in 79.5% of patients receiving tocilizumab 8 mg/kg, 61.9% receiving tocilizumab 4 mg/kg and 34.8% on placebo.
Tocilizumab was generally well tolerated, with adverse event profile consistent with data reported in previous studies.1 The overall frequency of adverse events was similar in all 3 groups, with serious infections reported by 6 patients in the 8 mg/kg tocilizumab group, 3 patients in the 4 mg/kg tocilizumab group and 2 patients in the placebo group.

Conclusion: This large phase III study demonstrates that tocilizumab, a novel monoclonal antibody targeting IL-6 signalling, is a highly effective therapy in patients with RA, with good safety and tolerability profile.
References: 1 Maini RN, Taylor PC, Szechinski J et al., on behalf of the CHARISMA Study Group. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006 Sep;54(9):2817-29.