Tysabri and PML: Several Recent Cases

Tysabri (natalizumab) is a monoclonal antibody, which is an effective treatment for relapsing forms of MS. However, it can cause progressive multifocal leukoencephalopathy (PML). Consequently, it is reserved for use in patients who have failed other medications. Due to the PML risk, this agent was withdrawn from the market in 2005, but re-introduced with additional restrictions, in 2006.

PML is a CNS viral infection which is quite disabling and typically fatal. It occurs in the setting of immune system compromise, and first came to wide recognition due to its incidence in persons with AIDS. Symptoms include weakness, ataxia, and speech and vision changes. As this is a disease of CNS neuronal white matter, symptoms may be quite similar to MS. Progression is generally rapid, measured in terms of weeks. This is a serious disorder.

Biogen-Idec and the FDA have been vigilant regarding PML cases in persons taking natalizumab. Recently, a tenth patient with PML was identified. Biogen-Idec reports that this case was identified on June 23, 2009. Three cases have been identified in June, and six (out of the total ten) have been found in 2009. It is not clear whether this apparent increase in the rate of case identification reflects an increased rate of agent usage, an increased incidence, or other factors.

The company notes that as of March 2009, some 40,000 persons worldwide were being treated with natalizumab. The reported cases are a small fraction of that, but it is quite likely that, like most adverse effects, it is underreported (despite the careful surveillance). The incidence of PML initially reported was 1/1,000. This was updated recently. A Biogen-Idec physician presented data at the recent American Academy of Neurology (AAN) meeting suggesting a much lower rate of 1.2/10,000. However, that rate is derived from a total of six PML patients which had been identified at the time of the presentation. Thus, this estimate is likely somewhat too low.

The initial PML cases, prior to the market withdrawal in 2005, were attributed to polytherapy. Many practitioners still hold this view. While concomitant use of other MS medications is not identified in the BIogen Idec materials, the FDA indication is for monotherapy, and use with another MS drug is strongly discouraged. As a result, it is likely that most, if not all, of the recent PML cases were in patients not taking other such medications. Biogen-Idec reports that all ten patients were on a regimen of natalizumab monotherapy. Therefore, polytherapy is likely not a primary cause of PML in these patients.

Natalizumab is somewhat more convenient, in some respects, than many other MS treatments, as the infusion is only required every four weeks. However, the PML risk is a very significant adverse effect and must be considered when contemplating initiation or continuation of natalizumab therapy. And, the rate of case identification seems to be increasing.

MS is a serious disease; so is PML. A treatment for psoriasis (another antibody) was recently withdrawn from the market because of PML. It is apparent that these immune system modifying agents have potent effects and adverse effects. I suspect that the end of this story has not yet been written.