March 9, 2005
No MS Drug Safety Issues Noted
The FDA found that Tysabri appeared more effective than existing drugs but reviewers were unsure of its long-term effects.
By Ricardo Alonso-Zaldivar and Denise Gellene, Times Staff Writers
WASHINGTON — The Food and Drug Administration raised no red flags about safety in its review of multiple sclerosis drug Tysabri, according to documents released Tuesday.
The intravenous medicine was pulled from the market last week by co-developers Biogen Idec Inc. and Elan Corp. after one patient died from a rare brain disease and a second patient developed the illness.
A team of FDA reviewers, according to agency documents, concluded the drug offered significant benefit to patients and deserved accelerated approval based on less than two years' worth of data, the amount typically required for an MS drug.
MS, which affects as many as 400,000 Americans, is a chronic nervous system disease that leaves about half its victims permanently disabled. The disease is marked by periods of flare-ups, or relapse, and good health, or remissions. Patients undergo long-term treatment with a range of medications.
In hundreds of pages of documents that offered the first detailed look at the FDA's handling of the drug, reviewers noted that Tysabri appeared more effective than existing drugs, reducing relapses in patients by 66%, based on one year's data. The reviewers said it was "reasonably likely" that the drug would provide long-term benefits.
Nonetheless, the agency's drug reviewers acknowledged they were unsure about Tysabri's long-term effects.
"The clinical meaningfulness of a decrease in the incidence of relapses at one year is uncertain," the reviewers wrote.
FDA reviewers found that Tysabri had an acceptable safety profile, though they noted that health risks "beyond one year are not known."
Infections, including urinary and respiratory, were seen with Tysabri, but they were "generally routine and did not have a complicated course," the reviewers said.
Stanford University professor Dr. Lawrence Steinman, an MS specialist, had warned there was a clear risk of infection for patients taking such drugs, because they tend to suppress the body's immune system.
Steinman had helped discover the active agents in the drug, but later became concerned about potential side effects, and is working on a competing drug. He noted that the infection rate of Tysabri patients in one trial was 2.1%, compared with 1.3% in the placebo group.
"There were hints of an increase in the infection rate," said Steinman. "The FDA should have dug deeper."
But FDA officials have stressed that, before the drug's approval, no patients had developed the rare viral infection that prompted the drug's withdrawal.
Known as PML, or progressive multifocal leukoencephalopathy, the central nervous system disease usually strikes AIDS patients and others with severely compromised immune systems. Two cases of PML have been detected among an estimated 8,000 patients who have taken Tysabri.
Both patients were taking part in a long-term clinical study that involved taking Tysabri with another MS drug, Avonex. Some academics suspect it was the combination of drugs that left patients vulnerable to PML.
The FDA, in the documents, asked Biogen and Elan for follow-up studies, but none asked for a closer look at how Tysabri and Avonex, Biogen's brand name for interferon, affected patients' immune systems.
"Not one of these issues talks about a combination effect immunologically with interferon," said Norman J. Kachuck, associate professor of neurology at the USC School of Medicine, who administered Tysabri to patients as part of the clinical trials. "If the FDA missed anything," he said, it should have asked for more "studies looking at the interaction of these two medicines."
At the same time, Kachuck said, there was no evidence in the data that patients' immune systems were being severely compromised. "We did not see activation of tuberculosis or herpes, two major chronic infections that you look for."
After one patient died, Biogen Idec and Elan voluntarily withdrew their drug. Tysabri had been available a scant three months in the United States, since its Nov. 23 approval by the FDA. In Europe, regulators decided to wait for more data.
The companies are trying to determine what went wrong to see whether Tysabri can safely be returned to market.
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