Much excitement surrounded Tysabri's launch, but the drug's trajectory has been a turbulent one. It is almost a decade since the first cases of Tysabri-associated progressive multifocal leukoencephalopathy (PML) shocked patients and physicians and underlined the perils of adopting long-term, systemic immunosuppression as a strategy for treating chronic autoimmune disease (Nat. Biotechnol. 23, 397–398, 2005). Originally approved as a first-line multiple sclerosis (MS) therapy in November 2004, and then withdrawn the following February, Tysabri returned to the market in June 2006 as a second-line MS therapy, available only under a strict safety-monitoring program. It has since attained blockbuster status on the strength of its strong efficacy. It gained FDA approval in Crohn's disease in January 2008, although the European Medicines Agency rejected the drug in that indication on safety grounds. But in the US, its use in Crohn's disease has been minimal, even in patients with minimal risk. “It just has not got over the stigma of PML,” says Brian Feagan, professor of medicine at the University of Western Ontario, in London, Ontario.
PML is an often fatal, demyelinating condition triggered by activation of John Cunningham virus, a common but normally dormant brain infection. Virus reactivation is thought to be due to a loss of immunosurveillance in the central nervous system (CNS). Tysabri-associated PML cases reached 430 by January 6, 2014, and the incidence of PML now stands at 3.45 cases per 1,000 patients, according to Cambridge, Massachusetts–based Biogen Idec, which markets the drug. Entyvio therapy has not been linked with any PML cases so far, although that in itself is insufficient evidence to rule out a potential link. “It's impossible to prove a negative, but I think the risks are really low, given the biology of the target of vedolizumab,” says Ulrich von Andrian, professor of microbiology and immunology at Harvard Medical School, in Boston, who has worked as a consultant to Takeda. “If the risk was anywhere similar to natalizumab, there should have seen several cases.”
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