Mixed Results for Tysabri in Crohn’s Disease Trial

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Results from the largest trial yet of the selective adhesion molecule inhibitor Tysabri (natalizumab) for Crohn’s Disease produced mixed results that raised more questions than they answered.

While the induction phase of the trial failed to demonstrate superiority to placebo, the maintenance phase demonstrated significant benefit over placebo—but only in patients who responded to the drug initially.

Furthermore, one patient treated with the drug died from a complication associated with it, progressive multifocal luekoencephalopathy, William J. Sandborn, Ph.DM.D.., of the Mayo Clinic here, and colleagues reported in the Nov. 3 issue of the New England Journal of Medicine.

Another death from this complication in a trial of the drug for multiple sclerosis led the manufacturer to withdraw the drug from the market in February of this year. Subsequently more deaths have been reported. The current study had finished in March of 2004.

Tysabri, a humanized IgG4 monoclonal antibody, blocks the adhesion and subsequent migration of leukocytes into the gut by binding to alpha-4 integrin. However, this immune suppressing power, which has the potential to mitigate autoimmune disease, may also allow the latent and ubiquitous JC virus to grow and spread, leading to progressive multifocal luekoencephalopathy.

In the induction phase of the current study, 905 patients with moderate to severe Crohni’s were randomly assigned to either 300 mg of the drug or placebo at weeks zero, four, and eight. In the maintenance phase, the 339 participants who responded to the drug were randomly assigned to continue with the drug or to placebo every four weeks through week 56.

In the induction phase, response rates were similar in the treatment group (56%) and the placebo group (49%; P=0.05). Remission rates were also not significantly different between the treatment group (37%) and placebo group (30%; P=0.12).

During the maintenance phase, there were higher rates of sustained response in the treatment group (61% vs. 28% for placebo; P<0.001). Remission rates were also significantly higher in the treatment group (44% vs. 26%; P=0.003).

Serious adverse events occurred at the same rate in both groups (7%) during the induction phase. During the maintenance phase, serious adverse events occurred in 10% of the treatment group and 8% of the placebo group.

The study authors concluded that “the clinical benefit of therapy with natalizumab will ultimately need to be weighed against the potential risk of rare but serious adverse events.”

While it might still be reasonable to use the drug with caution in patients with the severest need, i`in the meantime efforts should be focused not only on defining the true therapeutic efficacy of this and related agents but also on gaining a more precise understanding of the mechanisms of action and risk of treatment with antibody against alpha-4 integrins,i^ commented Daniel K. Podolsky, M.D., of the Massachusetts General Hospital in Boston, in an editorial.

“In time, pinpointing the cause of the major forms of inflammatory bowel disease should diminish our need to treat what appears to be a naturally occurring form of immunopathy with man-made forms of selective immunodeficiency,” Dr. Poldolsky said.

The study was supported by a grant from Biogen Idec. of Cambridge, Mass., and Elan Pharmaceuticals of San Diego, Calif., manufacturers and marketers of the drug.

Source: New England Journal of Medicine

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