Vedolizumab for the treatment of ulcerative colitis and Crohn's disease

Abstract

Crohn's disease and ulcerative colitis are chronic, relapsing inflammatory disorders of the GI tract. In both Crohn's disease and ulcerative colitis, leukocytic infiltration of the mucosa is associated with epithelial damage. Recently, monoclonal antibodies directed against cell adhesion molecules (CAMs) involved in leukocyte extravasation have been developed. Natalizumab, the first drug brought to market targeting CAMs, is clinically effective but is associated with serious adverse effects including the uncommon, but often fatal, neurological disease progressive multifocal leukoencephalopathy. Vedolizumab targets a subset of the CAMs blocked by natalizumab and is currently in Phase III trials to study its efficacy and safety in patients with inflammatory bowel disease. Here, we discuss the current treatment options available for patients with Crohn's disease or ulcerative colitis, the history of CAM inhibitors, the current state of development of vedolizumab and its future role in inflammatory bowel disease, if approved by regulatory agencies.

Figure 1. Blockade of α-integrins inhibits leukocyte migration into gut mucosa

(A) Tethering/rolling, activation, adhesion and extravasation/migration of leukocytes into gut mucosa occurs through interactions between leukocytes and endothelial cells. (B) Natalizumab prevents leukocyte migration by targeting both the α₄β₁ and α₄β₇ integrins whereas (C) vedolizumab targets only the α₄β₇ integrin, minimizing potential off-target effects such as progressive multifocal leukoencephalopathy, while continuing to inhibit leukocyte migration into gut mucosa. PSGL: P-selectin glycoprotein ligand. Reproduced with permission from [64].