Last October, Roche-Genentech and the US Food and Drug Administration (FDA) issued a" Dear Doctor" letter notifying rheumatologists about a case of progressive multifocal leukoencephalopathy (PML) in an arthritis patient treated with Rituxan (rituximab). This, the third PML case to emerge, is prompting concerns because the affected patient is the first to contract the condition on Rituxan without any prior treatment with another immune suppressant. Elsewhere, news that once again, cases of PML continue to be a concern for multiple sclerosis (MS) patients receiving Biogen Idec's Tysabri (natalizumab) is again prompting regulators to scrutinize current monitoring and control of this brain malady. As reports of PML cases mount, drug developers are understandably anxious that the potentially fatal brain infection could seriously compromise their most valuable antibody franchises.

When Cambridge, Massachusetts-based Biogen Idec launched Tysabri in late 2004, the monoclonal antibody (mAb) was one of biotech's brightest lights. It was the first IgG4 mAb directed against the a4 subunit of the integrin VLA-4 (very late antigen 4) adhesion complex expressed on activated lymphocytes, monocytes and other leukocytes. In addition, its safety profile appeared favorable and it was about twice as efficacious as existing treatments, such as interferon P and Copaxone (glatiramer acetate). In 2005, Biogen voluntarily withdrew the drug after PML, a rare, life-threatening brain disease, was diagnosed in two patients on Tysabri (Nat. Biotechnol. 23, 397-398, 2005). But the company was able to get the drug back on the market in 2006 after implementing a stringent PML patient monitoring program (Fig. 1; Nat. Biotechnol. 27, 986, 2009).