More Tysabri-Related PML Cases Prompt Search for Detecting Risk

Last Friday, the reported number of Tysabri-related PML cases jumped to 23, according to European regulators.* The news led to an abrupt drop in share prices for Tysabri drugmakers Elan and Biogen Idec.

Identifying treated patients who are at particular risk for PML, an often fatal, opportunistic infection due to JC virus, becomes increasingly urgent as the Tysabri-related risk (albeit still small) appears to climb. It is generally believed that latent infection with JC virus occurs in up to 90% of all individuals. But Matthew Herper at Forbes reports that latent infection may exist in only 50% of us, according to Tysabri's inventor, Ted Yednock.

Yednock (whose recent work has evidently not been publicly presented or peer reviewed) argues that current antibody tests for JC virus also detect antibodies to the genetically related BK virus (which is only potentially clinically important in immunocompromised renal-transplant patients). Yednock and others are working on a more specific antibody test for JC virus that may be used to anticipate the risk of PML in Tysabri recipients or to identify Tysabri candidates.

A recently published case series by Chen et al identified the subclinical reactivation of JC virus in 19 patients who received Tysabri monotherapy. The prevalence of virus** in urine increased significantly, from 19% to 63%, after 12 months of treatment. After 18 months, JC virus was found in 20% of plasma samples and in most samples (9/15) of peripheral mononuclear cells. Measures of BK virus, used as a control, remained stable in urine and were not detected in blood samples. Increased shedding of JC virus was associated with a significant drop in the virus-specific cellular response. Whether the reactivation of JC virus in Tysabri-treated patients is associated with a limited antibody response (and I don't know if it is) may have repercussions for the utility of Yednock's antibody assay during therapy.

PML = progressive multifocal leukoencephalopathy; Tysabri = natalizumab.

* From 11 in September. 

** Detected by using quantitative polymerase chain-reaction assays.

10/30/09 update: Bloomberg reports the Tysabri-related PML case load at 24, with 4 deaths, according to the European Medicines Agency.