Rituximab (Rituxan)

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Rituximab (brand name: Rituxan; manufacturer: Genentech and Biogen Idec) is a chimeric monoclonal antibody therapy that targets the protein CD20 on the surface of B-cells (a type of lymphocyte that plays a key role in immune response) and causes select mature B-cells to self-destruct. CD20 plays an important role in helping B-cells function in the immune response, so inhibiting CD20 depletes B-cells and limits their proinflammatory function.

 

How far along is rituximab in the development process?

Rituxan was approved by the FDA for the treatment of non-Hodgkins lymphoma in 1997 and approved by the European Union (branded as MabThera) in 1998. It is also approved by the FDA for the treatment of rheumatoid arthritis and chronic lymphocytic leukemia. Rituxan is used to treat a number of other conditions in which inhibition of B-cell function is important. Although results from a Phase 2 study with rituximab in people with relapsing forms of MS were impressive, no Phase 3 study is ongoing.
 

What evidence do we have that rituximab works in MS?

The effectiveness of rituximab in people with MS was tested in Phase 2 and 2/3 studies.

A 48-week, randomized, placebo-controlled Phase 2 study included 104 people with relapsing-remitting MS (RRMS) who were randomly assigned to receive intravenous rituximab 1000 mg (given as 2 infusions separated by 2 weeks) (n=69) or placebo (n=35). Rituximab resulted in a 91% reduction in gadolinium (Gd)-enhancing lesions compared with placebo. Additionally, a significantly lower percentage of people who received rituximab (20%) had relapses compared with those who received placebo (40%).

Rituximab vs placebo: key efficacy outcomes

Outcome

Rituximab (n=69)

Placebo (n=35)

Statistical significance

Number Gd-enhancing lesions (mean)

0.5 5.5 P<0.001

Relapses at 24 weeks

14.5% 34.3% P=0.02

Relapses at 48 weeks

20.3% 40% P=0.04
Adapted from Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358:676-88.

 

A 96-week, Phase 2/3 randomized, placebo-controlled study of rituximab in people with primary-progressive MS (PPMS) was also conducted as the OLYMPUS trial. This study included 439 participants who were randomly assigned to receive intravenous rituximab 1000 mg (2 infusions given 2 weeks apart every 24 weeks through week 74) (n=292) or placebo (n=147). The primary efficacy endpoint (the key measure used to determine the effectiveness of the medication) for the study was time to confirmed disease progression defined by sustained increase in disability as measured by the Expanded Disability Status Scale (EDSS). While rituximab did not result in a significant improvement in time to progression compared with placebo in the overall study population, it did result in significant improvement in this measure among people under the age of 51 years and among people with Gd-enhancing lesions at the start of the study. Additionally, rituximab resulted in a significantly lower volume of T2 brain lesions on magnetic resonance imaging (MRI) compared with placebo in the study population as a whole.

OLYMPUS Study: rituximab vs placebo, key efficacy outcomes

Outcome

Rituximab (n=292)

Placebo (n=147)

Statistical significance

Confirmed progression of disability at week 96

30.2% 38.5% NS

T2 lesion volume change from baseline to 96 weeks (mean)

1,507 2,205 P<0.001
Adapted from Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009;66:460-71.

 

What are the most common adverse effects with rituximab?

In the Phase 2 and Phase 2/3 studies, infusion-related adverse effects, which were of mild-to-moderate severity, were more common with rituximab than with placebo. The frequency of serious adverse effects, including infections, was similar between rituximab and placebo, although urinary tract infections and sinusitis were somewhat more frequent with rituximab. While cases of progressive multifocal leukoencephalopathy (PML) have been reported with rituximab in people with rheumatoid arthritis and lymphoma, no cases occurred in either MS study.

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