Rising PML Rate Raises Questions About Long-Term Natalizumab

Allison Gandey

January 25, 2011

January 25, 2011 — Biogen Idec has disclosed 6 new cases of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with natalizumab (Tysabri). This brings the total number of patients to 85. The company also reports an additional death for a total of 16.

The overall incidence of PML is 1.06 per 1000 patients treated, but the risk doubles for those receiving treatment for more than 2 years. The incidence with long-term therapy is now estimated at 2.13 per 1000.

"The risk of PML is highest for people who have been taking the drug for more than 2 years," Kate Weiss, a company spokesperson, told Medscape Medical News. "This is telling us what we already know and described in our label."

Biogen, which produces the drug with Elan, temporarily withdrew natalizumab from the market in 2005 after it was first associated with the viral disease. It was brought back in 2006 with stronger safety warnings.

The company and international regulators have already warned that long-term therapy increases risk, as does prior immunosuppressant use. These new numbers confirm this.

Next Steps

Mathias Buttmann, MD, from the Department of Neurology and MS Research Group at Julius Maximilian University in Würzburg, Germany, says this new information suggests that patients who are doing well with interferon beta or glatiramer acetate should not be switched to natalizumab even though some people consider the newer option more effective.

"For patients already on natalizumab, who had only moderate clinical disease activity at treatment initiation, I would consider switching them back to a baseline therapy after 2 years — preferably to an agent they had not previously tried," he said. This can be tricky, however, because the change presents a risk for rebound disease activity. "Disease activity at natalizumab initiation seems to correlate with activity after cessation," Dr. Buttmann pointed out.

Some physicians may be inclined to try fingolimod after 2 years of natalizumab. "But this may present unknown and possibly multiple safety risks in contrast to other better-evaluated strategies," Dr. Buttmann said. "Some may opt instead to continue natalizumab beyond 2 years and carefully monitor for symptoms of PML."

When considering natalizumab for more than 2 years, prior therapy plays an important role in risk stratification, he emphasized. "Patients with previous immunosuppressive treatment have a 2- to 3-fold higher PML risk than the overall population currently receiving natalizumab."

US Food and Drug Administration to Weigh In

Jack Burks, MD, chief medical officer for the Multiple Sclerosis Association of America, says he agrees that cases of PML will continue to rise as natalizumab is given longer term.

"Personally, I doubt the [US Food and Drug Administration] will stop drug distribution if the PML risk is 2 in 1000," he said. "Natalizumab has helped many of my patients with MS. I have not had a patient with PML."

It is a decision regulators will have to determine in the days to come. What is the new acceptable risk? "What this shows," Dr. Burks said, "is the MS treatment decision is becoming more complex."

Large-scale, prospective clinical studies are currently under way to determine whether a new JC virus assay will help physicians predict which patients are most at risk for PML.

Dr. Buttmann and Dr. Burks have disclosed no relevant financial relationships.

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