Transatlantic PML

The European Medicine Agency and US Food and Drug Administration (FDA) published in September the proceedings of a joint workshop held to address questions related to progressive multifocal leukoencephalopathy (PML), a rare and sometimes fatal brain disease that can occur as an adverse drug reaction to some therapeutics that affect immunological functions. The meeting attended by 170 regulators, academic scientists, funding bodies and clinical researchers, called for work on animal models, predictive biomarkers and long-term studies. “No one company is going to answer all the questions; they’re going to be answered by research consortia,” says co-convener and European Medicines Agency (EMA) pharmacovigilance head Peter Arlett. Five companies—Cambridge, Massachusetts–based Biogen Idec, New York–based Bristol-Myers Squibb, Elan of Dublin, Pfizer of New York and Roche of Basel—already fund basic research into drug-related PML through a nonprofit consortium. Concerns over drug-related PML were prompted by patients receiving Biogen’s multiple sclerosis therapy Tysabri (natalizumab) and other biologics such as Roche-Genentech’s antibody Rituxan (rituximab) (Nat. Biotechnol. 28, 105–106, 2010). By weakening patients’ immune system, these treatments allow the reactivation of John Cunningham (JC) virus, which is normally latent, to infect the central nervous system and cause the disease. According to risk calculations that took into account duration of treatment, published by the FDA in April 2011, in an average sample of 3,333 people taking Tysabri, up to 5 could develop PML and of those one would die. In June 2011, the EMA released a more complete risk stratification algorithm, which also accounts for the presence of anti-JC virus antibodies and prior exposure to immunosuppresants. However, there is no treatment for JC virus or PML and even diagnosis is difficult. In addition to the consortium-funded research, Biogen is at work on two potential JC virus therapies that might help protect its large investment in Tysabri: one is a small molecule targeting the large T antigen on the JC virus and one is a neutralizing antibody against the JC virus. But the biggest result in the last year, says Biogen Idec senior vice president and global head of drug safety and risk management Carmen Bozic, is the improved quantification of risk factors for PML now available in the EMA label. As Nature Biotechnology went to press, Biogen was awaiting a decision from the FDA for a new label for Tysabri that would include anti-JC virus antibody status to help clinicians stratify the risk of PML.

First published by Nature Biotechnology: [html] [pdf].