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Fresh from the Pipeline: Tocilizumab

Nature Reviews Drug Discovery 8, 273-274 (April 2009) | doi:10.1038/nrd2863
http://www.nature.com/nrd/journal/v8/n4/full/nrd2863.html


Abstract

In January 2009, tocilizumab (RoActemra; Chugai/Roche), a humanized monoclonal antibody that binds to the interleukin-6 receptor, was granted marketing authorization by the European Commission for the treatment of moderate to severe rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterised by pain, swelling and progressive destruction of joints, resulting in disability1. In the past decade, the introduction of biologic disease-modifying antirheumatic drugs (DMARDs) that target the underlying immuno-inflammatory process and can retard joint destruction has greatly improved treatment outcomes for patients with RA1. Nevertheless, a substantial proportion of patients do not respond to, or have an unsustained response to, available DMARDs1.

Basis of discovery

The success of biologic DMARDs that target the pro-inflammatory cytokine tumour-necrosis factor- (TNF-) in the treatment of RA — as well as recognition of their limitations — stimulated extensive research on the involvement of other cytokines in the disease process. Among these is interleukin-6 (IL-6), a pleiotropic cytokine that has important roles in a range of biological processes, including regulation of the immune response and inflammation.

Signalling by IL-6 is mediated by a receptor system that consists of the ligand-binding membrane protein IL-6R (mIL-6R) and the signal-transducing membrane protein gp130 (Ref. 2). A soluble form of IL-6R (sIL-6R) that lacks the cytoplasmic domain can also bind to gp130 following IL-6 binding and thus trigger downstream signalling events2.

Several lines of evidence indicated the involvement of IL-6 in the pathogenesis of RA, including increased expression of IL-6 in the synovium of patients with RA and a correlation between elevated IL-6 levels in serum or synovial fluid and measurements of disease. Furthermore, studies in mice showed that IL-6 is required for the development of collagen-induced arthritis (CIA), and that an antibody against IL-6R inhibited CIA development2.

Drug properties

Tocilizumab is a humanized monoclonal antibody that binds specifically to both sIL-6R and mIL-6R, and inhibits sIL-6R and mIL-6R-mediated signalling2, 7, 8. It was first granted regulatory approval in 2005 in Japan for the treatment of Castleman's disease, a rare lymphoproliferative disorder, and was approved for RA and juvenile idiopathic arthritis in Japan in 2008.

Clinical data

The safety and efficacy of tocilizumab in alleviating the signs and symptoms of RA were assessed in five randomised, double-blind trials (I–V) involving patients 18 years of age with active disease diagnosed according to the American College of Rheumatology (ACR) criteria and who had at least eight tender and six swollen joints at baseline8, 9, 10, 11, 12, 13. The primary endpoint for each of the studies was the proportion of patients who achieved a 20% improvement in disease activity according to the ACR criteria (ACR 20) at week 24 (Ref. 8). In all studies, tocilizumab was administered every 4 weeks intravenously.

Study I involved 673 patients who had not been treated with the standard small-molecule DMARD methotrexate (MTX) within the 6 months prior to randomisation and who had not discontinued previous MTX treatment as a result of toxic effects or lack of response8, 9. Tocilizumab (8 mg per kg) demonstrated superiority over weekly MTX, with 70% of patients in the tocilizumab group achieving an ACR 20 response at week 24 compared with 53% of patients in the MTX group.

Study II involved 1,196 patients who had an inadequate clinical response to MTX8, 10. Doses of 4 or 8 mg per kg of tocilizumab or placebo were given every 4 weeks as blinded therapy for 52 weeks in combination with stable MTX8, 10. A co-primary endpoint in this study was prevention of joint damage, assessed radiographically at week 52 (Ref. 8). Inhibition of joint structural damage was shown, with significantly less radiographic progression in patients receiving tocilizumab compared with patients in the control group8.

Study III involved 623 patients who had an inadequate clinical response to MTX, and compared tocilizumab (4 or 8 mg per kg) in combination with stable MTX8, 11. Study IV involved 1,220 patients who had an inadequate response to their existing therapy, including one or more DMARDs, and evaluated tocilizumab (8 mg per kg) or placebo in combination with stable DMARDs8, 12. Study V involved 499 patients who had an inadequate clinical response or were intolerant to one or more TNF inhibitor therapies and evaluated tocilizumab (4 or 8 mg per kg) or placebo in combination with stable MTX8, 13.

In all studies, patients treated with tocilizumab (8 mg per kg) had statistically significant higher ACR 20, 50 and 70 response rates at 6 months compared with controls8. The time to response onset was rapid (as early as week 2) and the magnitude of response continued to improve with duration of treatment8. Continued durable responses were seen for more than 24 months in the ongoing open-label extension studies I, III, IV and V8. Pooled analysis of the studies indicated that the 8 mg per kg dose of tocilizumab was superior to the 4 mg per kg dose8.

Patients in studies I–V had a mean Disease Activity Score (DAS28) of 6.5–6.8 at baseline8. A significant reduction in DAS28 from baseline (mean improvement) of 3.1–3.4 was observed in tocilizumab-treated patients compared with control patients (1.3–2.1)8. The proportion of patients achieving a DAS28 clinical remission (DAS28 <2.6) was significantly higher in patients receiving tocilizumab (28–34%) than control patients (1–12%) at 24 weeks.

Tocilizumab-treated patients also showed an improvement in all patient-reported outcomes.

Indications
Tocilizumab, in combination with MTX, is approved by the European Commission for the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more DMARDs or TNF antagonists8. In these patients, tocilizumab can be given as monotherapy in the case of MTX intolerance or when continued treatment with MTX is inappropriate.

Biologics for rheumatoid arthritis

Analysing issues for biologics for RA are Clemens Scheinecker, M.D., and Josef Smolen, M.D., Professor of Medicine and Chairman, Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Austria.

At present, available therapies for RA allow 20% of patients to meet stringent remission criteria and a further 40% to attain low disease activity14. Nevertheless, the remaining 40% of patients still have moderate to high disease activity, indicating a substantial need for improved therapies.

With the approval of the anti-IL-6R antibody tocilizumab in Europe, a new class of therapy has now joined the growing family of biologics for RA, which target the cytokines TNF- and IL-1, T-cell co-stimulation and B cells1. The details of the actions of tocilizumab are not yet clear. IL-6 affects B cells, T cells, monocytes and osteoclasts — cell populations that are thought to be important in RA pathogenesis — and it also induces the hepatic acute phase response2. Tocilizumab might interfere with some or all of these pathways and thereby exert broader effects than other biologics2.

The safety issues are mostly related to the mode of action: an increased risk of infections (as with other biologics), increases in lipid levels — probably due to its anti-inflammatory activity, although long-term observation for potential cardiovascular risks is needed — and increases in liver enzyme levels, particularly in combination with MTX, although there is no evidence of drug-induced hepatitis to our knowledge.

Tocilizumab is active across a broad spectrum of RA populations. In combination with MTX, it is effective in patients with active disease, despite previous treatment with MTX, other synthetic DMARDs11, 12, or anti-TNF-inhibitors13. In addition, tocilizumab was found to be superior to MTX as a monotherapy in patients with early RA9.

Interestingly, across these trials, as with trials of other biologics, the response rates decreased with increasing preceding disease duration or therapeutic experience. Good control of disease activity is of paramount importance clinically, functionally and in order to interfere with the progression of joint damage15. In general, attaining low disease activity (or at least 70% improvement) translates to a very good response. However, this level of response is only achieved in 20–25% of MTX-treated (and 30–40% of anti-TNF plus MTX-treated) patients with early MTX-naive RA, 20–25% of patients with active disease, previously treated with MTX, receiving biologics plus MTX, and 10–15% of patients who receive a biologic after TNF blockade has failed.

With several biologics targeting different cells or cytokines now available, the question of what might be the best option for patients with RA is increasingly important, but it is not yet possible to predict who will respond best to which agent. Although response rates to the various biologics overall seem similar, it is not clear if good responses occur in 'global' good responders or in mostly non-overlapping populations of patients. The lack of reliable biomarkers for differential prediction of response is therefore another unmet need. This can only be resolved by trials addressing the question of individualized therapy through appropriate trial design and molecular technology.