Elan Corporation, plc (DUBLIN, Ireland) and Biogen Idec (headquartered in CAMBRIDGE, Massachusetts) announced that they have been informed by the European Medicines Agency that the Committee for Medicinal Products for Human Use has adopted a negative opinion on the marketing application for the use of Tysabri^R (natalizumab), a recombinant humanized IgG4K monoclonal antibody manufactured by Biogen Idec and distributed by Elan, in patients with Crohn's disease. The companies plan to apply for a reexamination of the negative opinion through the appeal procedure; a decision on the appeal is expected by the first quarter of 2008. An application for approval of Tysabri for treatment of moderate-to-severe Crohn's disease was filed in December 2006 with the US FDA, which will discuss the application on July 31, 2007.

Tysabri is approved as a monotherapy for relapsing forms of multiple sclerosis (MS) in the US and for highly active relapsing-remitting MS in the EU. Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability, and is prescribed for  patients who have not responded adequately to, or cannot tolerate, other MS treatments.

Tysabri was initially approved by the FDA in November 2004, but was withdrawn by Biogen Idec in February 2005 after three patients in the drug's clinical trials developed PML: two cases occurred in 1869 patients with MS who were treated for a mean of 120 weeks with Tysabri plus interferon β-1a; the third case occurred in 1043 patients with Crohn's disease who were evaluated for PML. In February 2005, the FDA put on hold clinical trials of the drug, allowing them to resume a year later after confirming no additional PML cases. In March 2006, the FDA consulted its advisory committee on drugs for peripheral and central nervous systems about the possibility of making Tysabri available to appropriate MS patients. The advisory committee recommended a risk-minimization program with mandatory patient registration and periodic follow-up. In response Biogen Idec submitted to the FDA the TOUCH™ Prescribing Program to ensure safe use of Tysabri. TOUCH is a distribution program of Tysabri, which is limited to registered and authorized infusion centers, whereby patients must discuss with their doctor the risks and benefits of the agent and understand and agree to all of the instructions in the TOUCH Prescribing Program.

As of mid-April 2007 approximately 12,500 patients have been prescribed Tysabri worldwide, and Elan and Biogen Idec estimate that there are currently over 10,000 patients on the therapy worldwide. In the EU, approximately 2500 patients have received Tysabri infusions commercially, mostly in Germany and the Nordic countries.

According to safety data gathered from TOUCH as well as ongoing clinical trials and registries, there have been no new reports of confirmed cases of PML or other serious opportunistic infections.

The specific mechanism(s) by which Tysabri exerts its effects in MS have not been fully defined. Tysabri 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 counterreceptor(s). The receptors for the α4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MadCAM-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 vitro, anti-α4-integrin antibodies also block α4-mediated cell binding to ligands, such as osteopontin, and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, Tysabri may further act to inhibit the interaction of α4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells.

—A.Techman