A small clinical trial using rituximab, a drug used to treat non-Hodgkin’s lymphoma and rheumatoid arthritis, has shown promising results in treating the most common type of multiple sclerosis (MS) and opened a new window on the disease, said researchers.
The multi-center study is published in the February 14th issue of the New England Journal of Medicine, and was carried out by lead investigator Dr Stephen L Hauser, professor and chair of the Department of Neurology at the University of California, San Francisco (UCSF), and colleagues. Hauser said their findings:
“Shift the perspective on the cause of MS and open up a new frontier for investigation.”
More conventional treatments for MS rely on targeting the T-cells of the immune system. However, in this new study, the researchers used a drug that targets the immune system’s B-cells, and opened a new window on the disease.
Using rituximab led to a dramatic reduction in the number of inflammatory nerve fibre lesions in patients’ brains. These symptoms are the characteristic hallmark of MS, and lead to intermittent, temporary disruption of brain processes, as seen in temporary loss of mobility in a limb or vision in one eye.
Hauser said that:
“The magnitude and rapidity of the drug’s effect suggest that therapies targeting B-cells may provide an important treatment strategy if proven effective and safe in larger and longer-term clinical trials.”
Scientists believe MS to be an autoimmune disease, where immune system cells of different types attack the body itself. In the case of MS, the target is myelin, the protective insulating tissue that surrounds nerve fibres. This results in scars and plaques in the brain and spinal cord, which disrupt electrical nerve impulses that control neurological processes.
All currently available therapies for MS, some of them quite successful, target the T-cells. This is because since the 1970s scientists have believed T-cells to be the main culprit in the destruction of the myelin sheath in the progress of MS. However, in recent years, work at UCSF and other research centres has suggested that B-cells may also be implicated, particularly those that carry the CD20 protein on the cell surface.
Rituximab is a genetically engineered chimeric monoclonal antibody that depletes CD20 positive B-cells.
The double blind study was carried out as a 48 week phase II trial at 32 medical centres in Canada and the US and involved 104 participants with 69 receiving rituximab by infusion and 35 receiving a placebo. Double blind means neither the doctor nor the patient know if they are using the active drug or the placebo.
Rituximab is marketed by Genentech Inc. and Biogen Idec as Rituxan, and the two drug companies were involved in study design and data analysis, as well as sponsoring the trial.
The participants in the trial had the most common type of MS, the relapsing-remitting form that is characterised by acute flare ups where the myelin sheath becomes inflamed, which is then accompanied by loss or malfunction in some neurological processes. When the flare up subsides (in days or weeks), most, if not all, of normal function returns. But there can be residual damage (some scars can be permanent, as can myelin loss, causing neuron and axon injury), which accrues with each flare up. The cumulative damage results in a gradual decline of neurological function and increasing disability.
The participants were given an intravenous course of rituximab on days 1 and 15 of the trial and underwent regular MRI brain scans and clinical exams. The primary end point was the total number of lesions, as detected by MRI, at weeks 12, 16, 20, and 24.
At week 24 of the trial, those who had the active drug had a 91 per cent reduction in inflammatory lesions and 58 per cent reduction in relapse episodes, compared to participants who were on the placebo.
At week 48, at the end of the trial, the results were broadly similar. Adverse events were also largely the same in both groups and included mild to moderate infusion-associated reactions, with four patients having more severe, grade 3 reactions that included headache, back pain, depression, pain, pruritis and rash. No opportunistic infections were reported.
Hauser said that discovering that B-cell depletion has such a large impact on MS is “a beautiful proof of principal”:
“It signals a paradigm shift in our understanding of how MS develops,” he added.
The researchers did not look into how exactly the depletion of the B-cells led to the reduction in symptoms, that would require further investigation.
Writing about the study in Journal Watch, Dr Samia J Khoury, Professor of Neurology, Harvard Medical School, and Co-Director of the Partners MS Center, Brigham and Women’s Hospital, Boston, commented that:
“If these encouraging results are confirmed in a phase III trial, they will establish B cells as a novel cellular target for MS therapy. As the authors note, issues of long-term safety of rituximab must still be addressed, given reports to the FDA of progressive multifocal leukoencephalopathy in patients with lupus who were treated with rituximab.”
“B-Cell Depletion with Rituximab in Relapsing-Remitting Multiple Sclerosis.”
Hauser, Stephen L., Waubant, Emmanuelle, Arnold, Douglas L., Vollmer, Timothy, Antel, Jack, Fox, Robert J., Bar-Or, Amit, Panzara, Michael, Sarkar, Neena, Agarwal, Sunil, Langer-Gould, Annette, Smith, Craig H., the HERMES Trial Group.
N Engl J Med 2008 358: 676-688.
Volume 358:676-688, February 14, 2008, Number 7.
Sources: NEJM article, UCSF press release, Journal Watch.
Written by: Catharine Paddock, PhD