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Tocilizumab

A Review of its Use in the Management of Rheumatoid Arthritis

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Summary

Abstract

Tocilizumab (RoActemra® or Actemra®) is a recombinant humanized monoclonal antibody that acts as an interleukin (IL)-6 receptor antagonist. Intravenous tocilizumab 8 mg/kg (and no less than 480 mg), in combination with methotrexate, is approved in the EU for the treatment of moderate to severe active rheumatoid arthritis in adult patients with inadequate response to, or who are intolerant of, prior disease-modifying anti-rheumatic drug (DMARD) or tumour necrosis factor (TNF) antagonist therapy. It may also be administered as monotherapy in patients intolerant of methotrexate or in whom methotrexate therapy is inappropriate. Tocilizumab is also approved in Japan for the treatment of polyarticular-course juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and Castleman’s disease.

Intravenous tocilizumab was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in several well designed clinical studies in adult patients with moderate to severe rheumatoid arthritis. Tocilizumab-based therapy was consistently more effective than placebo, methotrexate or other DMARDs in reducing disease activity, and some trials also showed significant benefits with tocilizumab in terms of reducing structural joint damage and improving health-related quality of life (HR-QOL). Notably, tocilizumab-based therapy was effective in patients with long-standing disease in whom anti-TNF therapy had previously failed. More data are required to determine the comparative efficacy and safety of tocilizumab versus other biological agents and to establish their relative cost effectiveness. However, the present data suggest that tocilizumab is an important emerging treatment option in adult patients with moderate to severe rheumatoid arthritis.

Pharmacological Properties

Elevated levels of IL-6 in the serum and synovial fluid of rheumatoid arthritis patients contribute to the chronic inflammatory process characterizing this disease and correlate positively with disease activity. Tocilizumab binds selectively and competitively to soluble and membrane-expressed IL-6 receptors, blocking IL-6 signal transduction. In vivo, maximum (>90%) IL-6 receptor saturation was achieved when serum tocilizumab concentrations were >1 μg/mL. In dose-ranging studies, serum levels of inflammatory markers were normalized in rheumatoid arthritis patients who had detectable levels of tocilizumab in the serum. Tocilizumab displays dose-dependent, non-linear pharmacokinetics and has a long elimination half-life, allowing administration every 4 weeks.

Therapeutic Efficacy

Several well designed studies in patients with early or long-standing rheumatoid arthritis, including those with treatment-refractory disease, demonstrated the efficacy of intravenous tocilizumab 8 mg/kg every 4 weeks in improving disease activity, structural joint damage and/or HR-QOL.

Monotherapy with tocilizumab 8 mg/kg was noninferior to methotrexate for achievement of a clinical response in patients who had not experienced any prior treatment failures in the AMBITION study; subsequent superiority analyses in the intent-to-treat population demonstrated that significantly more tocilizumab than methotrexate recipients achieved American College of Rheumatology (ACR) clinical responses at week 24. Tocilizumab recipients also demonstrated significant improvements at week 24 in HR-QOL measures.

Among patients with early (mean disease duration <3 years) rheumatoid arthritis whose previous treatment with conventional DMARDs had failed, monotherapy with tocilizumab 8 mg/kg for 1 year was significantly more effective than treatment with DMARDs for achieving an ACR20 response, preventing radiographic disease progression and improving HR-QOL.

Patients with long-standing treatment-refractory disease achieved significantly better clinical responses with tocilizumab 8 mg/kg monotherapy than with placebo or methotrexate. These beneficial effects were maintained for up to 5 years with tocilizumab in a noncomparative extension of a placebo-controlled trial. Five studies of tocilizumab-based combination therapy for up to 52 weeks in patients with long-standing, treatment-refractory disease demonstrated better clinical responses with tocilizumab 8 mg/kg plus methotrexate or other DMARDs than with methotrexate or other DMARDs alone. Improvements in the levels of inflammatory markers were also observed, including serum C-reactive protein levels, which reduced as early as week 2. The mean changes from baseline in HR-QOL outcomes also favoured patients receiving tocilizumab-based combination therapy. The RADIATE trial found that generally better clinical responses were achieved with tocilizumab 8 mg/kg plus methotrexate than methotrexate alone in patients whose therapy with at least one anti-TNF agent had failed. In LITHE, significantly less radiographic disease progression was seen with tocilizumab plus methotrexate than with methotrexate alone.

Tolerability

Intravenous tocilizumab was generally well tolerated in adult patients with early or long-standing rheumatoid arthritis. The rates of withdrawal because of treatment-emergent adverse events among patients receiving tocilizumab 8 mg/kg monotherapy or in combination with DMARDs were generally low (≤12% of patients) and similar to those observed in active comparator groups. Most treatment-emergent adverse events were mild to moderate in intensity; upper respiratory tract infections, nasopharyngitis, headache, hypertension and ALT elevations were the most frequently reported adverse events in patients receiving tocilizumab monotherapy or combination therapy for up to 52 weeks. Mild infusion reactions were also common, but were generally transient.

Serious adverse events generally occurred with similar incidence among patients receiving tocilizumab, alone or in combination (with methotrexate or other DMARDs), and patients receiving methotrexate or other DMARDs alone. The incidence of serious treatment-emergent infections was generally low with tocilizumab (1–8% of patients) and similar to the incidence observed with methotrexate or other DMARDs.

Moderate, reversible increases in mean serum levels of total cholesterol, low-and high-density lipoprotein cholesterol and triglycerides occurred in tocilizumab recipients. No corresponding increases in vascular adverse events were observed with tocilizumab plus methotrexate versus methotrexate alone during 24 weeks of therapy and few changes were observed in the atherogenic index in patients receiving tocilizumab for up to 1 year. Dose-dependent increases in serum ALT and AST levels were also frequently observed in patients receiving tocilizumab, with elevations in ALT and AST generally occurring more frequently with tocilizumab monotherapy than combination therapy (with methotrexate or other DMARDs). Hypersensitivity reactions and the development of antibodies are uncommon with tocilizumab.

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Acknowledgements

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturers of the agent under review were offered an opportunity to comment on this article. Changes resulting from any comments received were made on the basis of scientific and editorial merit.

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Vicki Oldfield, Sohita Dhillon & Greg L. Plosker

  2. Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Vicki Oldfield, Sohita Dhillon & Greg L. Plosker

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  1. Vicki Oldfield
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Correspondence to Sohita Dhillon.

Additional information

Various sections of the manuscript reviewed by: R. Alten, Department of Internal Medicine II, Rheumatology, Schlosspark-Klinik Teaching Hospital, Charité University Medicine Berlin, Berlin, Germany; H. Bird, Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, England; J. Gomez-Reino, Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain; A.I. Sebba, Arthritis Research of Florida, Palm Harbor, Florida, USA; H. Yamanaka, Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘tocilizumab’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘tocilizumab’ or ‘R 1569’. Searches were last updated 2 April 2009.

Selection: Studies in patients with rheumatoid arthritis who received tocilizumab. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Tocilizumab, rheumatoid arthritis, monoclonal antibody, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Oldfield, V., Dhillon, S. & Plosker, G.L. Tocilizumab. Drugs 69, 609–632 (2009). https://doi.org/10.2165/00003495-200969050-00007

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