Top 10 for '09: No. 7

No. 7: Pinning Down the Risk of PML With Tysabri

So do the benefits of Tysabri (natalizumab; Biogen Idec/Elan) in MS still outweigh the potentially deadly risk of progressive multifocal leukoencephalopathy (PML)?

Uh, probably. But as they say: Axe your doctor.

Head-to-head data with the standard treatment of interferon beta don't exist; but if we're using the common benchmark of placebo treatment,* the monoclonal antibody reduces the risk of clinical relapses by about 70% at 1 year. The interferon betas are about half as good.

At last count (October), there were 24 cases of PML linked to Tysabri since the drug's reintroduction into the marketplace in 2006, said the European Medicines Agency. But the risk of PML appears to depend on the length of therapy—an issue addressed in September by Shirley Wang of the WSJ.

According to Biogen Idec, the absolute risk of PML with Tysabri is 0.01%. However, the risk appears to increase with prolonged therapy (eg, >12 months)—which necessitates the use of an actuarial calculation, argued Wang and Cleveland Clinic neurologist Robert Fox in the WSJ. Wang calculated the actuarial risk of Tysabri-related PML at about 0.08%, and Fox reported a PML risk of more than 0.1%, when therapy extends beyond 30 months. The increased risk of PML with prolonged therapy has led some neurologists to advocate the use of so-called drug holidays; although data to support their use are lacking.

The risk of subclinical PML with Tysabri therapy appears to be substantially higher. In September, the NEJM published a study by Chen et al, who detected a significant rise in titers of JC virus, the cause of PML, among 19 MS patients after 1 year or longer of therapy. (The same NEJM issue also offered 2 case reports of attempted, and reasonably successful, therapy for PML.)

A quantitative risk-benefit analysis, published last year in Neurology, indicated that the "actual" risk of PML with Tysabri would have to increase more than 7 times to reduce the relative benefit of therapy below that of interferon beta. (The authors used an annual PML risk that was based on the published risk estimate of 1 per 1000 patients treated for an average of 17.9 months.)

The flagship organization for US neurologists, the American Academy of Neurology, provided its most recent recommendations for the use of Tysabri in MS last year. Because of the associated risk of PML, the AAN recommended that the drug be reserved for selected patients who are intolerant of other therapies (eg, interferon beta or glatiramer acetate [Copaxone; Teva]) or whose disease is unresponsive to other therapies. 

This month, the journal Multiple Sclerosis printed a company-sponsored supplement, defining "best practice recommendations" for the use of Tysabri. The 6-member panel, which was selected by Biogen Idec and led by neurologist Patricia Coyle, encouraged the "earlier and more rapid transition from first-line treatment to Tysabri." Editorial support for the supplement was provided by The Falk Group, LLC, a pharmaceutical marketing and advertising agency—a fact that doesn't necessarily negate the supplement's recommendations but makes their objectivity suspect.

In the meantime, the SEC is investigating Elan for its filing dated July 31, 2008, in which the company described 2 European patients with MS who developed PML after prolonged Tysabri monotherapy. The reason for the SEC's investigation of this particular filing remains unclear.

* Which is, admittedly, problematic.