Natalizumab ( Tysabri ), a humanized monoclonal antibody against 4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue.

Two controlled trials have evaluated Natalizumab as induction and maintenance therapy in patients with active Crohn's disease.

In the first trial, 905 patients were randomly assigned to receive 300 mg of Natalizumab or placebo at weeks 0, 4, and 8.
The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index ( CDAI ) score of at least 70 points, at week 10.

In the second trial, 339 patients who had a response to Natalizumab in the first trial were randomly reassigned to receive 300 mg of Natalizumab or placebo every four weeks through week 56.
The primary outcome was a sustained response through week 36.

In the first trial, the Natalizumab and placebo groups had similar rates of response ( 56 percent and 49 percent, respectively; p=0.05 ) and remission ( 37 percent and 30 percent, respectively; p=0.12 ) at 10 weeks.

Continuing Natalizumab in the second trial resulted in higher rates of sustained response ( 61 percent vs. 28 percent, p<0.001 ) and remission ( 44 percent vs. 26 percent, p=0.003 ) through week 36 than did switching to placebo.

Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the Natalizumab group in the second trial.

In an open-label extension study, a patient treated with Natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus.

“ Induction therapy with Natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if Natalizumab was continued every four weeks. The benefit of Natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy,” the authors conclude.

On February 28, 2005, Elan Corporation, and Biogen Idec announced that they voluntarily suspended TYSABRI from the U.S. market and all ongoing clinical trials. This decision was based on reports of progressive multifocal leukoencephalopathy ( PML ), a rare and potentially fatal, demyelinating disease of the central nervous system.

Source: The New England Journal of Medicine, 2005


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