The return of the multiple sclerosis (MS) drug Tysabri (natalizumab) to the US market, sanctioned by the US Food and Drug Administration (FDA) on June 5, and its first-time approval in the EU, announced on June 29, was welcomed by investors. The move should also eventually lead to a clearer understanding of the association between the immunosuppressive monoclonal antibody and the risk of developing progressive multifocal leukoencephalopathy (PML). But, as officials from the drug's developers, Biogen Idec of Cambridge, Massachusetts, and Elan of Dublin, have warned, more cases of PML and more fatalities are expected before a proper risk-management plan can be developed to provide treating physicians with a fuller understanding of the danger involved in its use. The drug was initially approved by the FDA on November 23, 2004 as a first-line treatment for relapsing forms of MS, on the basis of one-year data from two phase 3 clinical trials. It was voluntarily withdrawn from the market on February 28, 2005, after the development of one confirmed and one suspected case of PML among patients who had received Tysabri along with Avonex (interferon β-1a) in a combination trial (Nat. Biotechnol. 23, 397–398 2005).

Tysabri has now gained US and EU approval as a second-line monotherapy for MS patients with actively remitting disease who have either an inadequate response to, or are unable to take, alternative therapies. Access to Tysabri will be strictly controlled in the US through a mandatory patient registration program, called Touch. Only authorized infusion centers will be permitted to administer the drug to qualifying patients under controlled conditions, designed to promote early detection of PML. In the EU, the core elements of the risk-management plan will be replicated, although, because of the absence of a centralized authority like the FDA, a pan-European patient registry will not be put in place.

I think it's really about quantifying what the risk is and identifying patterns in the future that might help minimize the risk. Eric Schmidt, SG Cowen in New York

Some 5,000 patients from the US and Europe will be enrolled in a five-year post-marketing safety study called TYGRIS (Tysabri Global Observation Program in Safety), which is expected to provide a firmer understanding of the association between Tysabri and PML. In its early stages, however, the risk-management framework that Biogen Idec and Elan have put in place is, inevitably, limited by a lack of data. “I think it's really about quantifying what the risk is and identifying patterns in the future that might help minimize the risk,” says Eric Schmidt, managing director and senior research analyst at investment bank SG Cowen in New York.

Despite the safety concerns, the drug still has blockbuster potential, because the MS market remains poorly served by existing therapies. Schmidt has forecast $1.1 billion in sales by 2010, whereas Cannacord Capital has forecast sales of $1.65 billion by 2011. “The current standard of care is not much better than placebo,” says Schmidt.