Tocilizumab, A Novel Monoclonal Antibody Targeting Il-6
Background:
Interleukin-6 is a cytokine involved in the pathogenesis of rheumatoid arthritis (RA). This molecule is involved in the activation of many of the cells that participate in inflammatory arthritis and also affect levels of inflammatory markers such as C-reactive protein and the ESR. Tocilizumab (previously known as MRA) is a humanized monoclonal antibody directed against the receptor for IL-6. Targeted blockade of IL-6 using this antibody represents a new approach to treatment of RA. Two recent studies have also been published demonstrating efficacy of this compound (1. Maini RN, Taylor PC, Szechinski J, Pavelka K, Bröll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T; 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. 2 Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Murata N, van der Heijde D, Kishimoto T. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007 Sep;66(9):1162-7). We have previously reviewed studies presented at ACR 2006 of this medication in RA and JRA. Prior studies from Japan used a background of methotrexate of only 8 mg/week thus making the extrapolation of results to populations in the US and EU in which patients typically receive higher doses of MTX background therapy were needed. At EULAR2007, results from a large multricentered international phase III study were presented.
OP0117. TOCILIZUMAB, A NOVEL MONOCLONAL ANTIBODY TARGETING IL-6 SIGNALLING, SIGNIFICANTLY REDUCES DISEASE ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: J. Smolen, A. Beaulieu, A. Rubbert-Roth, E. Alecock, R. Alten, T. Woodworth
SAT0001. TOCILIZUMAB, A NOVEL MONOCLONAL ANTIBODY TARGETING IL-6 SIGNALLING, SIGNIFICANTLY IMPROVES QUALITY OF LIFE IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: R. Alten, C. Ramos-Remus, J. Rovensky, M. Lucero, T. Woodworth, J. Smolen
Methods:
This was a double-blind, randomized, controlled phase III study of 623 patients with moderate to severe active RA despite long term treatment with methotrexate (MTX). This study is also known as the OPTION1 study. Patients received tocilizumab 8 mg/kg, tocilizumab 4 mg/kg, or placebo intravenously every 4 weeks. All three groups received MTX (oral or parenteral) at their pre-study dose (10-25 mg weekly), with other disease modifying anti-rheumatic drugs discontinued. The primary endpoint was ACR20 response at 24 weeks.
Results:
Reductions in signs and symptoms as measured by ACR responses were seen with both doses of tocilizumab (see below). A reduction in Disease Activity Score (DAS) using 28 joint counts was also observed from week 2 onwards in both tocilizumab groups, with significant change from baseline to week 24 for 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 responses at 24 weeks (79.5% tocilizumab 8 mg/kg, 61.9% tocilizumab 4 mg/kg, 34.8% placebo, p<0.0001). 28% of patients achieved a DAS28 remission in the tocilizumab 8mg/kg group compared to only 1% of patients in the control group. Improvements were also seen in measures of function measured by the HAQ, physical and mental components of the SF-36 as well as in fatigue, measured by the FACIT scale. These changes were above generally accepted thresholds for minimally clinically important differences.
Treatment |
ACR20 |
ACR50 |
ACR70 |
HAQ |
FACIT |
SF36 Physical |
SF36 |
TCZ 4 mg/kg + MTX (n=204) |
47.9% |
31.5% |
12.2% |
-0.52 |
7.29 |
9.7 |
5.7 |
TCZ 8 mg/kg + MTX (n=214) |
58.5% |
43.9% |
22.0% |
-0.55 |
8.60 |
9.5 |
7.3 |
PBO + MTX group |
26.5% |
10.8% |
2.0% |
-0.34 |
4.01 |
5.0 |
2.7 |
Tocilizumab was generally well tolerated, with adverse event profile consistent with data reported in previous studies. 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 demonstrated that tocilizumab, a novel monoclonal antibody targeting IL-6 signaling, is a highly effective therapy in patients with RA, with good safety and tolerability profile.
Editorial Comment:
The studies presented at EULAR2007 continue to demonstrate that inhibition of the cytokine IL-6 using tocilizumab administered every 4 weeks in conjunction with background methotrexate results in clinical improvements in RA over 24 weeks. While these results are less robust than those previously reported, they are significant in demonstrating a role for IL-6 inhibition as another strategy for patients with RA. Longer term efficacy and safety data is needed, and information regarding possible structure modification with this compound is still awaited. Additional safety questions concerning lipid levels and atherosclerotic indices also need further clarification.