Development of Tocilizumab for the Treatment of Rheumatoid Arthritis

Though the cause of rheumatoid arthritis (RA) has not been elucidated, current treatments target the inflammatory process. Available biologic agents act by inhibiting tumor necrosis factor (ie, etanercept, adalimumab, and infliximab), interleukin-1 (IL-1) (ie, anakinra), B-cell activation (ie, rituximab), or T-cell activation (ie, abatacept). A new biologic agent, tocilizumab, is under review by the US Food and Drug Administration (FDA) for the treatment of adult patients with moderately to severely active RA.¹

Tocilizumab is a humanized monoclonal antibody that binds to both soluble and membrane-bound interleukin-6 (IL-6) receptors.² IL-6 is believed to be involved in numerous immunologic processes that contribute to the pathogenesis of RA, including T-cell activation and the induction of osteoclast differentiation.³ Data from two recent clinical trials support the efficacy of tocilizumab as a treatment for RA. In a randomized, double-blind, placebo-controlled, phase 3 trial, tocilizumab (4 mg/kg or 8 mg/kg IV at baseline and every 4 weeks thereafter) was associated with significantly greater rates than placebo of symptom reduction at week 24, as assessed by a 20% improvement in signs and symptoms of RA according to American College of Rheumatology criteria (ACR20 response).² Additionally, compared to placebo recipients, patients receiving tocilizumab also demonstrated significantly greater rates of ACR50 and ACR70 responses at week 24 (Figure 2).² Similar results were observed in another placebo-controlled trial in which patients were maintained on their conventional disease-modifying antirheumatic drugs while treated with tocilizumab (8 mg/kg) or placebo.³ In both trials, infections occurred more frequently in the active treatment groups than in the placebo group.^2,3 There were no cases of tuberculosis in tocilizumab-treated patients in either study, though one patient was diagnosed with asymptomatic Mycobacterium avium-intracellulare.^2,3

The Biologics License Application for tocilizumab was submitted in November 2007, and in July 2008 the Arthritis Advisory Committee of the FDA voted to recommend approval of the agent. In December 2008 the FDA delayed a decision on tocilizumab pending nonclinical animal model data to confirm that tocilizumab does not affect perinatal and postnatal development and fertility. The manufacturer anticipates providing the requested data in the third quarter of 2009.¹

Practice Points

• Randomized, double-blind, placebo-controlled trials demonstrate the efficacy of tocilizumab, an anti–IL-6 receptor antibody, in improving symptoms in patients with moderate to severe rheumatoid arthritis
• An FDA decision regarding approval of tocilizumab has been delayed pending new animal data

Figure 2. Response rates as assessed by American College of Rheumatology (ACR) criteria in a double-blind, placebo-controlled, clinical trial of tocilizumab.²

*P<0.0001 vs placebo

References

1. Roche. Roche and FDA agree on pathway towards US approval of Actemra (tocilizumab). Basel, Switzerland. December 4, 2008.
2. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987-997.
3. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58:2968-2980.