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02.10.2008
Photomicrograph of a demyelinating MS-Lesion
A drug therapy currently used to treat non-Hodgkin's lymphoma and rheumatoid arthritis had a significant effect in treating the most common form of multiple sclerosis in a small, short-term clinical trial.
The multi-center study was led by Stephen L. Hauser, MD, professor and chair of the Department of Neurology. "These findings shift the perspective on the cause of MS and open up a new frontier for investigation," Hauser said.
Because the drug targets the immune system's B-cells, rather than the immune system's traditionally targeted T-cells -- long considered the primary culprit -- the finding provides a new insight into the cause of the disease.
The study was reported in the Feb. 14, 2008 issue of the "New England Journal of Medicine," and received wide media coverage.
It showed that the drug, rituximab, dramatically reduced the number of inflammatory lesions that form along nerve fibers in patients' brains -- the hallmark of the disease. It also significantly decreased the clinical symptom of the disease: sporadic, temporary disruptions in certain neurological functions, such as mobility in a limb or vision in an eye. The study of the drug, which is administered by infusion, was a 48 week, phase II trial.
"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," said Hauser.
MS is thought to be an autoimmune disease, a condition in which one or more types of cells of the immune system turn against a tissue of the body. MS, specifically, occurs when the immune system attacks myelin, the protective insulating sheath that surrounds nerve fibers in the central nervous system, leaving scars of hardened sclerotic patches called plaques in multiple places within the brain and spinal cord. Nerve fibers allow the transmission of electrical impulses between the nerve cells and damage to the myelin disrupts this transmission, affecting neurological function.
Since the early 1970s, scientists have focused on the role of T-cells in MS, and all currently available therapies target these cells, some quite successfully. Rituximab targets B-cells, specifically, those with a protein on their surface known as CD20.
Hauser and his team, including Emmanuelle Waubant MD, PhD, associate professor of neurology, proposed the clinical trial based on accumulating evidence found by UCSF scientists and a handful of other teams during the last decade that CD20+ B-cells and related pathways played a central role in damaging the myelin sheath.
| The discovery that B-cell depletion has such an impact on MS is "a beautiful proof of principle," says Hauser. "It signals a paradigm shift in our understanding of how MS develops." |
Genentech Inc. and Biogen Idec, which market rituximab (Rituxan), sponsored the trial, co-designing the study and analyzing the data. The trial was conducted at 32 medical centers in the U.S. and Canada, and involved 104 patients, 69 of whom received the drug and 35 of whom received a placebo. It was a "double blind" study, meaning that neither the physicians nor patients knew who received rituximab and who received placebo.
The trial focused on patients with relapsing-remitting MS, the most common form of the disease. UCSF is also involved in an ongoing Phase II/III trial to evaluate the safety and efficacy of rituximab in primary-progressive MS (PPMS), a severe form of the disease with significant unmet medical need. Data from that trial are expected in the first half of 2008.
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