Anti-inflammatory Drug's Potentially Deadly Side Effect Found To Be Rare

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 disorder.

"Our analysis suggests about one in every1,000 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, M.D., the Melba and Forest Seay Professor of Clinical Neuropharmacology in Neurology 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 MS treatment, are published in this week's issue of The New England Journal of Medicine.

The brand name of natalizumab, which was jointly developed by Biogen and Elan Pharmaceuticals, is Tysabri. The drug 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 MS patients treated with the natalizumab, which has to be injected on a monthly basis.

Clifford predicts that his group's report and the other studies of natalizumab will be important elements in "lively" discussions to be held by the Food and Drug Administration regarding the future of this therapy.

"Patients with MS are eager to access more effective therapy," he says. "But regulators, physicians and patients alike will first have to weigh the risks of a potentially fatal brain infection against the benefits that this drug may afford."

A number of factors can affect the survival of patients with PML, 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 PML 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 PML onset are still unclear, but based on their prior dealings with the disorder, PML experts like Clifford strongly suspect an immune system connection.

"As many as half of all adults are infected with the virus that causes PML, 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 PML, 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."

MS 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 MS 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.

To help insure their independence in the review of patients who took natalizumab, Clifford and his colleagues formed an independent adjudication committee with its own charter. The committee's other members were Tarek Yousry, M.D., chief of radiology at the Institute of Neurology in Queen's Square, London; and Eugene Major, M.D., acting director of research at the National Institute of Neurological

Disorders and Stroke. It could convene meetings with or without a representative from the drug's makers. With Biogen and Elan Pharmaceuticals' assistance, researchers were able to conduct follow-up evaluations of 92 percent of the patients who had taken natalizumab in trials that were halted last year after reports of PML. These studies involved patients at 485 sites around the world. Clinical data, magnetic resonance imaging brain scans and cerebrospinal fluid were collected for analysis.

Organizers sent guides for evaluation to local neurologists, who evaluated patients and either sent the results to a central database if they suggested little chance of PML or, if indications of potential PML were detected, to the three committee members.

Based on data from these tests and evaluations, researchers identified 44 "cases of concern" that were referred to the three senior organizers, who were able to clear all but one of the cases. That case involved a patient who declined the repeated testing needed to finalize or dismiss a diagnosis of PML. Because of the ambiguity, this case was not included among the total PML cases cited by the study's final results.

Clifford says the concerns researchers are confronting now in natalizumab will likely have to be considered again as other drugs are developed using the same customized targeting techniques.

"This drug is a good example of the potential of developing drugs with very specific biological targets in mind," Clifford says. "But this experience also reminds us that there are a lot of hidden icebergs in the ocean we're navigating, and we're going to bump up against those icebergs and have to work out ways to navigate around them."

Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E, Barkhof F, Radue E-W, Jäger HR, Clifford DB. Evaluation for progressive multifocal leukoencephalopathy in patients treated with natalizumab. New England Journal of Medicine, March 3, 2006.

Funding from Biogen and Elan Pharmaceuticals supported this research.