The May 5, 2008 article (Med Lett Drugs Ther 2008; 50:34) on the approval of natalizumab (Tysabri) for treatment of Crohn's disease in the "Adverse Effects" section on page 35 included the statement: "post-marketing hepatotoxicity, sometimes fatal or requiring liver transplantation, has occurred." Actually, no fatal hepatotoxicity or liver transplantation has been reported to date. The FDA warning about post-marketing hepatotoxicity with Tysabri that was the basis for our statement said: "The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to [emphasis added] death or the need for a liver transplant in some patients." Also, in the last sentence of the Conclusion, we should have said: "Because of the risk of serious hepatic toxicity and the rare but even more serious risk of developing progressive multifocal leukoencephalopathy, it should be used only in patients who have not responded to other drugs, including a TNF inhibitor." The italicized words should be substituted for "it is FDA-approved for use."

Download: U.S. English

Natalizumab (Tysabri - Elan and Biogen) is a monoclonal antibody approved for induction and maintenance treatment of moderate to severe Crohn's disease (CD) refractory to conventional therapies and inhibitors of tumor necrosis factor (TNF). Initially approved in 2004 for the treatment of multiple sclerosis (MS), natalizumab was temporarily withdrawn from the market after 3 patients developed progressive multifocal leukoencephalopathy (PML). It is now available for treatment of both MS and CD through a restricted distribution program.

Soon after The Medical Letter first reviewed use of natalizumab (Tysabri – Biogen Idec and Elan) for treatment of relapsing forms of multiple sclerosis (MS) (Med Lett Drugs Ther 2005; 47:13), the drug was withdrawn from the market. The unpublished clinical trials that led to its approval by the FDA have since been published, and now the drug has been returned to the market with prescribing restrictions.

Natalizumab decreases the number of relapses and new brain lesions in patients with MS. It was withdrawn because progressive multifocal leukoencephalopathy (PML) occurred in 3 (of about 3000) patients being treated with the drug; two were taking the drug in combination with interferon beta for MS, and one was taking it with azathioprine for Crohn’s disease. PML is an opportunistic infection of the brain, caused by reactivation of the JC virus in immunosuppressed patients, that often causes death or severe neurological disability. There is no treatment for PML.

The publication of the natalizumab clinical trials in MS provided information on the drug’s effect on the progression of disability, which was not available when it was first reviewed here. In one study, combination therapy with natalizumab and interferon beta-1a for 2 years led to an estimated cumulative probability of progression of 23%, compared to 29% with interferon beta-1a alone (RA Rudick et al. N Engl J Med 2006; 354:911). In the second study, the estimated cumulative probability of progression over 2 years was 17% with natalizumab alone and 29% with placebo (CH Polman et al. N Engl J Med 2006; 354:899).

Download U.S. English