The most promising treatment for CD patients refractory to anti-TNFα therapy, are inhibitors of T-cell trafficking to the GI tract. The first of these, natalizumab, was approved by the FDA in 2008 and is indicated for CD and multiple sclerosis. Natalizumab binds to the α4 integrins (α4β1 and α4β7), disrupting interaction with its ligands VCAM-1 and MAdCAM-1 and impeding leukocyte adhesion and trafficking to the CNS and GI tract respectively. The ENACT study demonstrated a 6% improvement in clinical response in patients receiving natalizumab compared to placebo (56% vs 49%, p = 0.05) in 905 patients with moderate to severe Crohn's disease defined as a CDAI score of between 220-450. While the overall therapeutic efficacy was modest, in a subgroup analysis of patients refractory to anti-TNFα therapy 55% of patients in the treatment arm responded compared to 35% in the placebo arm (P < 0.05). One negative feature of natalizumab is that general blockade of α4 integrins inhibits T-cell trafficking to the CNS in addition to the intestine and has been shown to increase the risk of progressive multifocal leukoencephalopathy (PML), a fatal infection caused by the JC Virus (JCV).