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Tocilizumab Monotherapy Tops Methotrexate Monotherapy for Patients With Rheumatoid Arthritis: Presented at EULAR

By Jill Stein

PARIS -- June 15, 2008 -- Tocilizumab monotherapy is superior to methotrexate monotherapy in patients with active rheumatoid arthritis (RA) who have not failed earlier treatment with methotrexate or biologics, according to phase 3 results released on June 13 at EULAR 2008, the Annual Congress of the European League Against Rheumatism.

Tocilizumab is an anti-interleukin (IL)-6 receptor antibody that inhibits IL-6 signalling. IL-6 has been implicated in the pathogenesis of RA and is thought to play a role in synovial inflammation and in the damage to periarticular bone and cartilage.

"Importantly, our results demonstrate for the first time that treatment with a biologic agent as monotherapy outperformed methotrexate monotherapy at the 6-month assessment point," reported Graeme Jones, MD, University of Tasmania, Hobart, Tasmania, Australia. Prof. Jones is the principal investigator of the trial, known as Actemra Versus Methotrexate Double-Blind Investigative Trial in Monotherapy (AMBITION).

The trial evaluated the noninferiority and subsequent superiority of tocilizumab monotherapy in patients treated with tocilizumab alone compared with methotrexate alone at 24 weeks.

"Although anti-TNF [anti-tumour necrosis factor] treatments like tocilizumab are more effective than methotrexate before 24 weeks, none of these agents has demonstrated superiority with longer-duration therapy, Prof. Jones observed.

According to the study protocol, 673 patients were randomised to treatment with either a tocilizumab infusion 8 mg/kg every 4 weeks plus placebo capsules weekly or placebo infusions every 4 weeks plus methotrexate 7.5 to 20 mg weekly.

All patients had moderate to severe RA for at least 3 months, were methotrexate-naive or had not received methotrexate for at least 6 months before randomisation, and had not previously failed methotrexate or biologic treatment.

The primary endpoint was noninferiority followed by superiority of tocilizumab in American College of Rheumatology (ACR) response at week 24 compared with methotrexate.

Overall, 70%, 44%, and 28% of patients in the tocilizumab 8 mg/kg-arm achieved ACR20 (P < .001), ACR50 (P = .0023), and ACR70 (P = .0002), respectively, after 24 weeks of treatment versus 53%, 34%, and 15%, respectively, of patients treated with methotrexate alone.

Moreover, 34% of tocilizumab patients achieved a 28-joint disease activity score (DAS28) of <2.6, which indicates disease remission, versus 12% of methotrexate patients. "This amounts to a 3-fold difference," Prof. Jones said.

A larger percentage of patients achieved a good to moderate EULAR response as early as the second week (64% for tocilizumab and 19% for methotrexate), with rates reaching 82% versus 65%, respectively, at week 24.

C-reactive protein normalised by the second week of the trial, with mean changes from baseline at week 24 of -2.6 mg/dL for tocilizumab compared with -1.9 mg/dL for methotrexate.

The researchers also documented a rapid improvement in haemoglobin levels in the tocilizumab cohort, with adjusted mean changes from baseline at week 24 of +1.2 g/dL for tocilizumab compared with +0.1 g/dL for methotrexate.

Tocilizumab-treated patients also had larger improvements in quality-of-life measures, including fatigue, pain, and physical and mental functions compared with methotrexate-treated patients.

Adverse events occurred in about 80% of patients in both treatment groups, but adverse events necessitating premature withdrawal from the trial occurred in more methotrexate patients (3.8% for tocilizumab vs 5.3% for methotrexate). The most common adverse events reported more frequently in the tocilizumab arm of the trial were upper respiratory tract infections, headache, and nasopharyngitis.

Overall, the results demonstrated tocilizumab's superior efficacy to methotrexate for ACR20, ACR50, and ACR70, a EULAR good-to-moderate response, and DAS28 remission, Prof. Jones said. In addition, treatment was associated with a rapid onset of action (within 2 weeks) and a safety profile consistent with the mechanism of action and immunomodulatory properties of IL-6 receptor inhibition.

Roche provided funding for the study.

[Presentation title: Tocilizumab Monotherapy Is Superior to Methotrexate Monotherapy in Reducing Disease Activity in Patients With Rheumatoid Arthritis: The AMBITION Study. Abstract OP-0131.]

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