BARCELONA, Spain—Data from the first phase III trial of tocilizumab (Actemra®, Roche Pharmaceuticals) show that the anti-interleukin-6 (IL-6) monoclonal produces quick improvement in rheumatoid arthritis (RA) signs and symptoms, including remission within 4 weeks in nearly 28% of patients treated at the higher dose level tested.¹ Lead investigator Josef Smolen, MD, presented results of the study at the 2007 EULAR meeting. Dr. Smolen is with the department of rheumatology at University Clinic for Internal Medicine, in Vienna, Austria. The phase III trial is known as the OPTION (TOcilizumab Pivotal Trial in Methotrexate Inadequate Responders) study.

"The efficacy of IL-6 receptor inhibition in this study confirms the critical role of IL-6 in the causal pathways of rheumatoid arthritis," Dr. Smolen said.

Tocilizumab is a humanized antihuman IL-6 receptor monoclonal antibody and was tested in a trial of 623 patients with moderate-to-severe RA that remained active despite long term treatment with methotrexate (MTX). In the double-blind, randomized, controlled, phase III study, all patients continued MTX (oral or parenteral) at their prestudy dose (10-25 mg/wk) and were randomized to also receive either placebo (n = 204), or tocilizumab 4 mg/kg (n = 213), 8 mg/kg (n = 205). All treatments were administered IV every 4 weeks for six cycles and all other DMARDs were discontinued at study entry.

The primary study endpoint was the proportion of patients who met American College of Rheumatology (ACR) 20 response criteria at week 24, which was 4 weeks after the last infusion. Dr. Smolen reported ACR20 responses in 26.5% of MTX/placebo patients, 47.9% of MTX/tocilizumab 4 mg/kg patients, and 58.5% of MTX/tocilizumab 8 mg/kg patients. The response differences were statistically significant for tocilizumab at both dose levels versus placebo (P <.0001) and also for ACR50 and ACR70 responses.

"A reduction in DAS28 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] versus placebo [-1.55, P <.0001]," Dr. Smolen said.

The investigators were impressed by the speed of therapeutic effect with tocilizumab. Dr. Smolen said that the 8 mg/kg tocilizumab dose reflected DAS28 improvements apparent as early as week 2 and ACR20 responses as early as week 4. "Overall, DAS28 improved significantly in two of every three patients treated with tocilizumab," Dr. Smolen said.

The rate of good/moderate response at 24 weeks also was higher in both tocilizumab groups compared with placebo (P <.0001), as seen in 79.5% of patients receiving tocilizumab 8 mg/kg, 61.9% receiving tocilizumab 4 mg/kg, versus 34.8% on placebo, Dr. Smolen reported.

The overall frequency of adverse events was similar in all three groups, with serious infections (requiring hospitalization or treatment with IV antibiotics) reported in six patients in the 8 mg/kg tocilizumab group, three patients in the 4 mg/kg tocilizumab group, and two in the placebo group. There were no cases of tuberculosis.

Cholesterol levels increased in the tocilizumab groups, but there were no significant changes in the atherogenic index. Dr. Smolen attributed the cholesterol rise to the anti-inflammatory effects of the drug, pointing out that inflammation is often accompanied by a decrease in lipid levels. There were transient rises in alanine transaminase in some patients on tocilizumab, but Dr. Smolen reported no cases of clinical hepatitis or hepatic failure. He said that hepatic function is an area likely to come under further investigation, however.

Table: Responses to MTX Plus Tocilizumab in RA at 24 Weeks

Response Criterion (%)	MTX + Placebo	MTX + Tocilizumb 4 mg/kg	MTX + Tocilizumab 8 mg/kg
ACR20	26.5	47.9	58.5
ACR50	10.8	31.5	43.9
ACR70	2	12.25	22.0
DAS28 remission (<2.6)	0.8	13.5	27.5

Source: Smolen J. EULAR 2007.

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Reference

1. Smolen J, Beaulieu A, Rubbert-Roth A, et al. Tocilizumab, a novel monoclonal antibody targeting IL-6 signaling, significantly reduces disease activity in patients with rheumatoid arthritis. Presented at: EULAR 2007 Meeting; June 13-16, 2007; Barcelona, Spain. Abstract OP0117.