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Selective adhesion blockade for treatment of Crohn’s disease

▸ Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the α4β7 integrin. Clin Gastroenterol Hepatol 2008;6:1370–7.

Leucocytes respond to inflammatory stimuli by adhering to and migrating through the vascular endothelium. This involves a complex interaction between leucocyte cell surface proteins called integrins and adhesion molecules on the vascular wall that act as receptors. This process has emerged as a promising target for anti-inflammatory therapy. Natalizumab is a monoclonal antibody to integrin heterodimers that contain the α4 subunit. While effective for inducing and maintaining remission of Crohn’s disease, natalizumab has been associated with rare cases of progressive multifocal leucoencephalopathy. MLN0002 is a humanised monoclonal antibody that specifically targets the α4β7 integrin heterodimer, which is expressed preferentially in the gut. This increased specificity is suggested to improve safety while retaining efficacy. Feagan et al randomised 185 patients with active Crohn’s disease to receive MLN0002 0.5 mg/kg, MLN0002 2.0 mg/kg or placebo at days 1 and 29 in a phase 2 trial. The primary endpoint of clinical response (70 point drop in the Crohn’s Disease Activity Index (CDAI)) on day 57 was achieved in 53, 49 and 41% of subjects, respectively. While these differences were not significantly different, a more stringent definition of improvement (100 point drop in the CDAI) was achieved by 47% on MLN0002 2.0 mg/kg vs 31% on placebo (p = 0.05), …

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