Do Over: New MS drug may be safe after all

An experimental drug for multiple sclerosis (MS) that was approved in 2004, then abruptly yanked off shelves last year because of safety concerns, may get a second chance.

Two studies show that the drug can curb MS symptoms and slow progression of the autoimmune disease over 2 years, the longest tests of this drug to date. A third investigation finds no further cases of the often-fatal complication that sidetracked the drug last year, beyond the three patients who fell ill at that time. All three papers appear in the March 2 New England Journal of Medicine.

The drug, natalizumab, was pulled 4 months after its approval by the Food and Drug Administration. Three patients in clinical trials had developed progressive multifocal leukoencephalopathy (PML), a rare nervous system disorder caused by a virus that attacks people with suppressed immunity. The withdrawal came after doctors had written roughly 7,000 prescriptions for natalizumab for MS, rheumatoid arthritis, and an intestinal ailment called Crohn’s disease. The drug was marketed as Tysabri by Biogen Idec of Cambridge, Mass., and Elan Corp. of Dublin, which both funded the new studies testing the drug’s effectiveness.

The drug combats MS by binding to a protein called alpha-4 integrin on the surface of white blood cells, interfering with their entry into the brain. This thwarts the brain inflammation and nerve damage that these immune system cells trigger, says neurologist Richard A. Rudick of the Cleveland Clinic.

Starting in 2001, Rudick’s U.S. team randomly assigned patients to get a monthly infusion of either natalizumab or a placebo. In 2002, researchers in the Netherlands began a similar trial. Together, these tests included 1,859 MS patients. In the U.S. study, all patients also received interferon-beta 1a, a current MS drug.

Over 2 years, the annual relapse rate in patients getting natalizumab was one-third or less in both studies, compared with more than three-fourths among patients getting a placebo.

Natalizumab’s relapse suppression “was more robust than that for currently available drugs,” says Chris H. Polman, a neurologist at Vrije University Medical Center in Amsterdam.

Magnetic resonance imaging showed that patients in the trials getting natalizumab were less likely to develop MS-type brain lesions than were those getting a placebo or a placebo plus interferon-beta 1a.

In the third study, researchers at the National Institute of Neurological Disorders and Stroke in Bethesda, Md., looked for signs of the virus that causes PML in 3,116 people who had taken natalizumab as part of the two new MS trials and several other trials.

No one aside from the three patients already identified had the disease, says virologist Eugene O. Major of the institute. The new findings indicate that the risk of developing PML while using natalizumab is roughly 1 in 1,000, he says.

All three patients who developed PML were taking natalizumab with other drugs and might have had overly suppressed immune systems, says Allan H. Ropper, a neurologist at Caritas St. Elizabeth’s Medical Center in Boston. Natalizumab alone “seems fairly safe, and it’s quite potent,” he says.

Some doubts persist, however. Neurologist Annette Langer-Gould of Stanford University says that even the 1-in-1,000 risk of PML “seems to outweigh the benefits” that natalizumab would provide many patients. Langer-Gould says that she would consider giving the drug only to MS patients “who are imminently at risk of developing severe disability … and have failed standard therapies.”

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