Researchers have completed an extensive study of more than 3,000 patients who received a Natalizumab ( Tysabri ), that was linked to three cases of a serious brain infection in large clinical trials halted in early 2005.

The new study found no new cases of progressive multifocal leukoencephalopathy ( PML ) and confirmed the three previously identified cases of PML associated with use of the drug. One fatal and one nonfatal case of PML occurred in a trial using Natalizumab as a multiple sclerosis treatment; a second fatality happened in a trial that used the drug to treat patients with Crohn's disease, an inflammatory bowel disease ( IBD ).

" Our analysis suggests about one in every 1,000 people who took Natalizumab contracted this disease; however, there weren't enough patients exposed to the drug to allow us to precisely estimate the risk, which could be as low as one in 5,000 or as high as one in 300," says senior author David Clifford, at Washington University School of Medicine in St. Louis.

The results of the study, along with two separate studies of Natalizumab's effectiveness as an multiple sclerosis treatment, are published in The New England Journal of Medicine ( NEJM ).

. Natalizumab is a monoclonal antibody that binds to inflammatory immune T cells and prevents them from crossing membranes that protect the brain and the central nervous system.
Prior to the studies that were halted last year, earlier studies showed a 66 percent reduction in the rate of relapses in multiple sclerosis patients treated with the Natalizumab, which has to be injected on a monthly basis.

A number of factors can affect the survival of patients with multifocal leukoencephalopathy, but for now Clifford believes that developing a method to diagnose PML early in its development may be the best approach to averting future fatalities linked to Natalizumab.

" It takes two months or more for the drug's effects to stop, but if multifocal leukoencephalopathy is discovered early and has started in a less-than-critical region of the brain, that may give us time to stop therapy and prevent serious brain injury or death," he explains. " We may also want to look at whether there are ways to end Natalizumab's effects on a patient more quickly."

The links between Natalizumab and multifocal leukoencephalopathy onset are still unclear, but based on their prior dealings with the disorder, experts strongly suspect an immune system connection.

" As many as half of all adults are infected with the virus that causes multifocal leukoencephalopathy, which normally doesn't bother us," he says. " It only becomes a problem in those with suppressed immune systems, where it can enter the brain and cause PML. That includes AIDS patients, organ transplant patients and patients with blood-related malignancies such as leukemia. And even in those patients it's still rare. We've seen about 50 cases over the last decade at Washington University School of Medicine."

In patients with multifocal leukoencephalopathy, the virus ( named the JC virus for the first patient it was identified in ) destroys the cells that make protective sheaths surrounding brain cells.
Symptoms include vision loss, mental deterioration, speech disturbances, loss of coordination and, in advanced phases, paralysis and coma.

" It leaves the brain short-circuited," Clifford says. " It's a very bad disease that normally progresses to death within a few months unless we can reverse the immune suppression."

Multiple sclerosis is an autoimmune disease believed to result from misguided immune system attacks on nervous system tissues. It comes in various forms and affects an estimated 400,000 Americans, with 200 new diagnoses of multiple sclerosis every week.
Researchers have tried with limited success to treat MS with immune suppression drugs before, Clifford notes, without ever previously unleashing the JC virus on the brain.

" There has to be something very specific about the way the body controls the JC virus that is being affected by the action of Natalizumab," he says.

Source: Washington University School of Medicine, 2006


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