A new study found that in patients treated with natalizumab, PML incidence was about 11 cases per 1000 patients with 25 to 48 months of treatment, prior immunosuppressant use, and anti–JC virus antibody–positive status. The incidence was estimated to be 0.09 cases or fewer per 1000 antibody-negative patients.
Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is approved for the treatment of relapsing-remitting multiple sclerosis in more than 50 countries and also for the treatment of moderate-to-severe Crohn’s disease in the United States. As of February 2012, approximately 100,000 patients were treated worldwide.
• What effect does natalizumab have on progression and relapse in relapsing-remitting multiple sclerosis?
In the pivotal Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis trial (published in the Journal in 2006), natalizumab monotherapy decreased the risk of sustained progression of disability (defined as progression over a period of 12 to 24 weeks) by 42 to 54% and reduced the annualized rate of relapse by 68%.
• What is the association between natalizumab and progressive multifocal leukoencephalopathy (PML)?
Natalizumab treatment is associated with the risk of PML, an opportunistic brain infection that is caused by the JC virus. PML appears to occur after a complex interaction between host and viral factors, leading to the development of a pathogenic form of JC virus that can infect and destroy oligodendrocytes in the central nervous system. As of February 29, 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients).
Morning Report Questions
Q: What factors confer an increased risk of developing PML in a patient taking natalizumab?
A: Positive status with respect to anti-JC virus antibodies, increased duration of natalizumab treatment, and prior use of immunosuppressants, alone or in combination, were associated with discrete levels of PML risk in patients with multiple sclerosis. The risk of PML increased with increasing duration of treatment, with the greatest increase in risk occurring after 2 years of therapy (25 to 48 months in this study). A total of 35% of natalizumab-treated patients with PML, as compared with 20.3% of all natalizumab-treated patients in the Tysabri Global Observational Program in Safety study (TYGRIS), had received one or more immunosuppressants before the initiation of natalizumab therapy; the immunosuppressants used most frequently among natalizumab-treated patients with PML and among natalizumab-treated patients in the TYGRIS study included mitoxantrone, methotrexate, cyclophosphamide, azathioprine, and mycophenolate.
Q: How do JC virus antibodies differ between the general population with multiple sclerosis and those who go on to develop PML?
A: In this study, there was a 100% prevalence of positive status for anti-JC virus antibodies before the diagnosis of PML among natalizumab-treated patients with multiple sclerosis in whom PML subsequently developed. This differed significantly from the estimated 54.9% prevalence of positive status for anti-JC virus antibodies in the general population with multiple sclerosis.