Research: B Cell Depletion Inhibits MS

Kappos L, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011 Oct 31. [Epub]

BACKGROUND: B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis. 

METHODS: We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 μg) once a week. The randomisation list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an intention-to-treat basis. This trial is registered with, number NCT00676715. 

FINDINGS: 218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68-97; p<0·0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89-99; p<0·0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3·0-4·4) patients in the placebo group, one of 55 (2%; 1·3-2·3) in the 600 mg ocrelizumab group, three of 55 (5%; 4·6-6·3) in the 2000 mg group, and two of 54 (4%; 3·0-4·4) in the interferon beta-1a group. 

INTERPRETATION: The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials. 

FUNDING: F Hoffmann-La Roche Ltd, Biogen Idec Inc.

CoI: None

“You all have heard the story before as Rituximab (a chimeric human/mouse monoclonal anti-CD20) has been shown to similarly influence RR MS and Gadolium-enhancing PPMS. Rituximab is more likely to be destroyed folllowing injection as eventually the mouse aspects in the antibody will be recognised by the immune system. Therefore, ocrelizumab was developed, which is a more humanised antibody to avoid this and only the target-binding bits of the original mouse antibody are left. This new study shows that ocrelizumab inhibits the development of lesions just as has been shown already with rituximab. Although the level of inhibition of MRI lesions does not always reflect the level of efficacy at slowing relapses. Based on what we know of ritximab there is reason to be hopeful. Therefore bring on Phase III.”

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1 comment

  • Prof G,

    Thanks for all this info. Do the results presented look good? I can understand the results of trials which report a reduction in relapses, but more difficult for me to make a judgement when it's about a reduction in enhancing lesions (which I'm guessing is a good thing). Will B cell depleting treatments prove more effective than the injectibles? Than Tysabri?

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