Blocking adhesion molecules with natalizumab in multiple sclerosis

Natalizumab is a humanized, monoclonal antibody, that inhibits adhesion molecules (alpha(4)-integrins) on the surface of immune cells. These adhesion molecules are important for binding of lymphocytes to endothelial cells of blood vessels and infiltration of inflammatory cells into tissues. Natalizumab is currently being tested in large clinical trials for the treatment of multiple sclerosis (MS) and other autoimmune diseases (inflammatory bowel diseases, rheumatoid arthritis). After demonstrating the safety and potential effectiveness of natalizumab in MS therapy during shorter treatment periods (</=6 months) in clinical phase I and II studies, two ongoing large, double-blinded, placebo-controlled phase III trials (named AFFIRM and SENTINEL) are evaluating its efficacy for patients with relapsing-remitting MS in respect to primary clinical endpoints (relapse rate, disease progression). Based a 1-year interim analysis of these studies, natalizumab was recently authorized by the U.S. Food and Drug Administration for treatment in reducing the frequency of clinical surges in multiple sclerosis, and an application was also made for its use in Europe. After more than 2 years of combined natalizumab (Tysabri) and interferon beta-1a (Avonex) therapy in the so-called Sentinel Study, there was one unexpected death and one appearance of progressive multifocal leukoencephalopathy. As a result, in February 2005 the manufacturers (Biogen/Elan) stopped all running studies of natalizumab and removed the drug from the market. New studies are underway to gain more understanding and especially to determine the risk to patients treated in the Sentinel Study. This article summarizes and updates the results of previous and ongoing natalizumab trials in the context of MS

Severe relapses after the first infusion of natalizumab in active relapsing-remitting multiple sclerosis

Abstract We describe three patients suffering from a very active form of relapsing-remitting multiple sclerosis (MS), who experienced severe disease worsening, associated with a marked increase in brain inflammation, a few days after the first administration of natalizumab. In line with preclinical studies, our observations suggest that natalizumab, when administered during active disease phases, may worsen disease evolution possibly by modifying the regulatory network in the brain. We suggest that relapsing-remitting MS patients having had a recent relapse should be treated with natalizumab only after achieving complete clinical and radiological remission