WEDNESDAY, Nov. 2, 2005 (HealthDay News) -- The potential side effects of a once-promising drug for multiple sclerosis and Crohn's disease are of serious concern and may outweigh any potential benefit, researchers report.
A new study of the drug, natalizumab (Tysabri), found that while there was some positive response, one patient died from progressive multifocal leukoencephalopathy (PML), a brain infection. This is not the first time PML has surfaced in relation to Tysabri.
"Response rates weren't overwhelming but they were certainly exciting, particularly for people who had failed other therapies," said Dr. John F. Thompson, professor of pediatrics and director of the Division of Pediatric Gastroenterology and Nutrition at the University of Miami's Miller School of Medicine. "It probably would have become another important medication to consider for people with problematic Crohn's disease but the opportunistic infection is going to be problematic. I certainly would be uncomfortable using it in my patients."
Thompson was not involved with the current study, which appears in the November 3 issue of the New England Journal of Medicine.
Tysabri has had a short and complicated history. First approved in November 2004 for the treatment of relapsing forms of multiple sclerosis (MS), it was voluntarily removed from the market by Elan Corp. and Biogen Idec Inc. after reports that three patients taking it had developed PML.
At this stage, at least three patients taking Tysabri have developed PML, two of whom died, an accompanying editorial reports. One of the deaths occurred in a patient with MS, while the other -- also noted in this current paper -- occurred in a patient with Crohn's disease.
Thompson said it did not seem likely that the drug would go back on the market, given these latest results.
However, a representative from Elan was more optimistic. "Both companies are extremely positive about its prospects for coming back onto the market," said Davia Temin, an Elan spokeswoman. "Obviously, we want to come up with an appropriate risk analysis and patient safety comes first, but there is a huge unmet patient need."
"There has been a very stringent and comprehensive risk analysis safety evaluation that's been done and that has been extremely favorable," Temin added. "For PML, there were no new cases found in any population. It's the exact same three people."
The FDA is currently reviewing data on Tysabri and should be done within six months, Temin said.
Tysabri is a monoclonal antibody which works by attaching itself to white blood cells called lymphocytes, preventing them from entering the intestine. In people with Crohn's disease, large numbers of killer lymphocytes enter the intestine to cause inflammation.
"This is a relatively novel approach to the treatment of Crohn's disease," Thompson explained.
The current paper really comprised two trials and was supported by Elan, Biogen and the National Institutes of Health.
The first was a 12-week trial in which 905 patients with moderate-to-severe Crohn's disease were randomized to receive 300 milligrams of Tysabri or a placebo at weeks 0, 4 and 8.
The drug and placebo groups had similar response rates (56 percent and 49 percent respectively) and remission rates (37 and 30 percent respectively) at 10 weeks. Response rates were gauged according to the Crohn's Disease Activity Index (CDAI).
A subanalysis revealed that people who had elevation of C-reactive protein or CRP, a marker of how active the Crohn's disease is, had a better response. In other words, it's possible that many of the original group of participants did not have active Crohn's as measured on the CDAI, which can be subjective.
The 339 patients who demonstrated a response to Tysabri during this initial phase were then randomly assigned again to receive either 300 milligrams of that drug or a placebo every four weeks through week 56.
Those who continued the drug in the second trial had higher rates of sustained response (61 percent versus 28 percent) and of remission (44 percent versus 26 percent) through week 36 than those who had switched to a placebo.
While these results are "encouraging," side effects pose a considerable problem. One person who continued to take Tysabri in an open-label extension of the study died from PML.
"The big concern is that this medication seemed pretty clearly to unravel this JC virus which causes PML," Thompson said. "That's a major concern because up to 80 percent of people have this as a latent virus."
Unless more specific versions of the medication can be found, or ways to screen patients, the drug may not be of much use, Thompson said.
"It looks seriously concerning. There's a risk-benefit ratio," he said. "There are still a number of other, newer approaches for the treatment of Crohn's disease that hopefully will not involve opportunistic infection."
More information
For more on Crohn's disease, visit the National Institutes of Health.
