The comeback kid: TYSABRI now FDA approved for Crohn disease.

The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 3 March 2008 825 The comeback kid: TYSABRI now FDA approved for Crohn disease The US FDA recently approved the monoclonal antibody TYSABRI (natalizumab) for use in the treatment of adults with moderately to severely active Crohn disease (CD) who do not respond to, or do not tolerate, conventional therapies for CD and inhibitors of TNF-α. This represents a comeback for a drug that was temporarily pulled from the market in February 2005. TYSABRI is a monoclonal antibody specific for the α4 integrin that pairs with either the β1 integrin or β7 integrin to form α4β1 (also known as VLA4) and α4β7, respectively. These integrin heterodimers are expressed by distinct subsets of T cells, and binding of α4β1 and α4β7 to their respective ligands is important for directing T cell migration to different tissues. Interactions between α4β7 and MAdCAM-1 direct T cells to the intestine, both under steady-state conditions and during inflammation, whereas interactions between α4β7 and VCAM-1 are important for directing T cells to the inflamed CNS. Given its specificity for the α4 integrin, TYSABRI blocks T cell homing to the intestine and the inflamed CNS. Two randomized, placebo-controlled phase III clinical trials indicated that TYSABRI markedly reduced the number of relapses in individuals with MS (1). The results were so promising that the FDA approved TYSABRI for the treatment of individuals with relapsing forms of MS in November 2004, only halfway through the phase III clinical trials. However, Elan Corp. and Biogen Idec, the manufacturers of TYSABRI, pulled the drug from the market and halted all ongoing clinical trials only 3 months later, after two patients developed progressive multifocal leukoencephalopathy (PML) — a demyelinating brain disorder caused by a polyomavirus known as the JC virus. Although one patient was successfully treated for the disorder (2), the other died. An additional fatal case of PML was uncovered when the data from one of the halted clinical trials, which had been assessing the efficacy of TYSABRI as a treatment for CD, was retrospectively reviewed (3). A review of the data from all clinical trials (i.e., the completed and halted trials assessing the efficacy of TYSABRI in patients with MS as well as the halted trials assessing the efficacy of the drug in patients with CD) revealed no more cases of PML. The FDA therefore reapproved the use of TYSABRI to treat individuals with relapsing forms of MS in June 2005 (4). However, because the two affected patients with MS