Lessons for clinical trials from natalizumab in multiple sclerosis

On 28 February 2005 Biogen Idec and Elan voluntarily suspended marketing natalizumab (Tysabri or Antegren) for clinical use because two patients with multiple sclerosis developed progressive multifocal leucoencephalopathy (PML) while being treated. Clinicians were advised to suspend all ongoing trials, and commercial distribution of the drug was halted. Three months earlier the US Food and Drug Administration gave natalizumab accelerated approval to treat relapsing multiple sclerosis. Approval was given on the basis of short term (one year) data from two multicentre, randomised double blind placebo controlled phase 3 trials. Neither trial was published in a peer reviewed journal and the FDA granted approval before final trial and cumulative safety data were available. PML has been confirmed in three patients taking natalizumab.1^–3

The unpublished multiple sclerosis trials

Natalizumab is a humanised monoclonal antibody to α4 integrin, which plays a key role in the adhesion and migration of immunocompetent T cells through its interaction with endothelial selective adhesion molecule.4 Approximately 3000 patients, mostly with multiple sclerosis and Crohn's disease, were treated with natalizumab in clinical trials, and nearly 5000 patients have been treated in the United States since it became commercially available in 2004. In the United Kingdom, natalizumab was due for appraisal by the National Institute for Health and Clinical Excellence in 2006 for use in multiple sclerosis.

T cell attacking a cluster of foreign red blood cells: natalizumab prevents the migration of immunocompetent T cells across biological barriers and suppresses T cell mediated immune responses

Credit: BSIP PIR/SPL

In the two studies that formed the basis of its approval by the FDA, natalizumab was given intravenously every four weeks to patients with multiple …