Similar drugs may all pose a risk of infections, experts say.

The future of a promising treatment for multiple sclerosis (MS) is in question after two patients takinag the drug were diagnosed with a rare neurological disorder.

Scientists are scrambling to determine the exact relationship between the drug, Tysabri, and progressive multifocal leukoencephalopathy (PML). If the drug is deemed to pose a significant risk, it could be a serious setback for the entire class of drugs, which work by blocking passage of immune cells into the brain.

“Other cell-migration inhibitors in development will have to be carefully tested,” says Howard Weiner, director of the Partners MS Center at Brigham and Women's Hospital.

Other cell-migration inhibitors in development will have to be carefully tested. , . Howard Weiner, Brigham and Women's Hospital

Several companies are developing drugs that use the same rationale to treat Crohn disease, rheumatoid arthritis and asthma. But according to Lawrence Steinman, an MS specialist at Stanford University, all of these drugs are likely to carry a similar risk for infections.

The US Food and Drug Administration (FDA) has halted a phase 2 trial of a GlaxoSmithKline drug that targets the same protein, alpha-4 integrin, as Tysabri. Australian biotech Antisense Therapeutics stopped phase 2 trials in March for a similar MS drug, which the company had also planned to develop as an asthma treatment. Switzerland-based Roche also has a similar compound in early clinical trials, but declined to comment on its plans for the trial.

Steinman has warned for more than a decade that such drugs might carry nasty side effects. In 1992, he was one of the first to develop this new approach—to block the homing molecules that allow immune cells to access the brain. But he says he soon realized that targeting these molecules also blocks immune cells from entering infected tissue outside the brain, leaving patients susceptible to infections. This might have led to the cases of PML, a disorder most often seen in people with compromised immune systems, such as those with AIDS, Steinman says.

The FDA in November 2004 granted Tysabri fast-track approval, after initial phase 3 results showed the drug reduces the frequency of MS attacks by as much as 66%.

Tysabri was expected to be a major blockbuster for its manufacturer Biogen Idec, with predicted sales of $3 billion annually. But the company suspended sales of Tysabri in February, after learning of the two PML cases, one of which was fatal. The company also halted trials of the drug for rheumatoid arthritis and Crohn disease.

There has never previously been a documented case of PML in MS patients, even though these patients have been treated with many types of immunosuppressants. Both patients diagnosed with PML had taken Tysabri with Avonex, another MS drug, for two years in clinical trials. Biogen is testing all patients who took Tysabri for signs of PML.