The role of natalizumab in the treatment of multiple sclerosis: benefits and risks

Natalizumab is an alpha(4)-integrin antagonist, the first in its class for the treatment of multiple sclerosis (MS). Although multiple mechanisms have been proposed for the efficacy of natalizumab in MS, the most likely explanation is that it interferes with the migration of immune cells into the central nervous system. It does this by binding to the alpha(4) subunit of alpha(4)beta(1)-integrin and preventing leukocyte adhesion to endothelial vascular cell adhesion molecule-1. The efficacy of natalizumab in relapsing-remitting MS has been demonstrated in several double-blind, placebo-controlled trials. Natalizumab has been shown to slow the progression of disability in relapsing-remitting MS significantly better than placebo, and to reduce the number of new and enlarging T2 hyperintense and gadolinium-enhanced magnetic resonance imaging lesions. In a post hoc analysis, the proportion of patients with relapsing-remitting MS free of disease activity was significantly greater with natalizumab compared with placebo. Due to the rare risk of progressive multifocal leukoencephalopathy as a complication, natalizumab is primarily recommended in patients who fail, or cannot tolerate, treatment with interferon (IFN) beta or glatiramer acetate (GA). Stratification of those patients most likely to benefit from natalizumab treatment--such as those with highly active disease, severe disease, or extensive functional loss, or those who have failed or cannot tolerate IFN beta or GA therapy--would help define natalizumab's appropriate place in therapy.