Natalizumab: new drug. Multiple sclerosis: risky market approval.

(1) In relapsing-remitting multiple sclerosis, the standard therapy (other than symptomatic treatment) is interferon beta. It prevents about one exacerbation every 2.5 years but has no demonstrated effect on the progression of disability. However, interferon beta can cause serious adverse effects. (2) Natalizumab, an immunosuppressant, has been approved for first-line treatment of patients with "aggressive" multiple sclerosis (with frequent exacerbations) and for second-line treatment after failure of interferon beta. (3) In first-line treatment, natalizumab has not been compared with interferon beta. In a double-blind placebo-controlled trial involving 942 patients who were treated for 2 years, natalizumab prevented about 1 exacerbation every 2 years (0.24 versus 0.73 exacerbations per year). A retrospective subgroup analysis suggested that efficacy was better in patients with aggressive disease. As this was a post-hoc subgroup analysis, this exploratory hypothesis requires further testing. Natalizumab appeared to slow the progression of disability, but this result is undermined by the small percentage of patients who had an exacerbation (18% versus 27%). (4) In second-line treatment, a combination of natalizumab and interferon beta (rather than natalizumab monotherapy) was compared with interferon beta in 1171 patients in whom interferon beta had failed. The combination prevented about one exacerbation every 2.5 years. It is not known whether a combination of natalizumab and interferon is more effective than natalizumab alone. (5) Three cases of progressive multifocal leukoencephalopathy occurred during clinical trials, two of which were fatal. The risk of this viral infection, which is usually symptomatic only in severely immunosuppressed patients, was estimated at about 1 case per 1000 patients on natalizumab. (6) Little is known of the risks of long-term treatment with natalizumab, especially the risks of infections and cancer. (7) During two years of treatment, 6% of patients developed persistent anti-natalizumab antibodies, leading to reduced efficacy and a higher incidence of reactions during the infusion, as well as hypersensitivity reactions. (8) In practice, given the poorly assessed and potentially fatal risks of long-term treatment with natalizumab, the limited improvement in efficacy does not justify the use of natalizumab other than in comparative trials.