Elan Corp, plc (DUBLIN, Ireland) and Biogen Idec (CAMBRIDGE, Massachusetts) announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency, has adopted a negative opinion on the marketing authorization for natalizumab (Tysabri®) as a treatment for moderate-to-severe, active Crohn's disease (CD) in patients who had an inadequate response to or could not take conventional treatments and who have evidence of active inflammation. Natalizumab was proposed to be used alone or in combination with other medicines for CD. The decision is on the appeal the companies filed following a previous negative opinion adopted by CHMP in July 2007. The current negative opinion has now been referred to the European Commission (EC), which grants marketing authorizations in the EU. Final EC decision, which customarily follow the CHMP's recommendation, is expected during the first quarter of 2008.

The effects of natalizumab were tested in two main studies involving a total of 905 patients with moderate-to-severe CD. The first study compared the effects of natalizumab with placebo. The main measure of effectiveness was the proportion of patients whose symptoms improved after 10 weeks. The 354 patients who responded to treatment with natalizumab went on to enter the second study. The main measure of effectiveness was the proportion of patients maintaining a response over an additional 9 months of treatment.

In July 2007, CHMP was concerned that the effectiveness of natalizumab was modest in study patients; there was also insufficient evidence of maintenance of the medicine's effects. CHMP also was concerned over the safety of natalizumab in patients with CD, because of a risk of serious infections, including progressive multifocal leucoencephalopathy (PML). In November 2007, following the reexamination, CHMP removed their concern regarding the effectiveness of the medicine in patients starting treatment. However, all other concerns remain, and CHMP decided that the benefits of natalizumab in the treatment of CD did not outweigh its risks. Hence, the committee recommended that the drug be refused marketing authorization.

Tysabri is a monoclonal antibody treatment approved for relapsing forms of multiple sclerosis (MS) in the US and relapsing-remitting MS in the EU. According to published data, after 2 years, drug treatment led to a 68% relative reduction (P <.001) in the annualized relapse rate compared with placebo and reduced the relative risk of disability progression by 42% to 54% (P <.001).

The drug appears to increase the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Other serious adverse events that have occurred in Tysabri-treated patients include hypersensitivity reactions (eg, anaphylaxis) and infections. Serious opportunistic and other atypical infections have been observed in Tysabri-treated patients, some of whom were receiving concurrent immunosuppressants. The drug binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s). The receptors for the α4 family of integrins include vascular cell adhesion molecule-1, which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue.

In addition to the US and EU, Tysabri is approved for MS in Switzerland, Canada, Australia, New Zealand, and Israel. Tysabri was discovered by Elan and is codeveloped with Biogen.