Novel treatment options for inflammatory bowel disease: targeting alpha 4 integrin

The aetiology of inflammatory bowel disease (IBD) is complex and many aspects still remain unclear. However, significant progress has been made in understanding the pathogenesis of chronic inflammation in the intestine, and new insights have been gained recently. A better understanding of the immunopathology of IBD has led to the development of novel biological agents to target crucial molecules and processes in the inflammatory cascade. The development of novel therapies in the management of IBD has moved from empirical to scientific rational translation from bench to bedside. Lymphocyte infiltration into the intestinal tract in Crohn's disease (CD) is mediated by interaction between alpha4 integrin expressed on lymphocytes and its specific ligand mucosal vascular addressin cell adhesion molecule-1, expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against alpha4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, a recombinant humanised monoclonal antibody against alpha4 integrin, was effective in CD in a phase II randomised controlled trial. The highest response rate and remission rate were 71% and 44%, respectively, at 6 weeks after two infusions of natalizumab 3mg administered 4 weeks apart. Natalizumab was well tolerated in this trial. The phase III trial results are encouraging, although the primary efficacy endpoint of response at week 10 was not achieved. The maintenance of response and remission trial, ENACT (Evaluation of Natalizumab as Continuous Therapy)-2, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT-1) trial. This was associated with an improvement in quality-of-life parameters. A second humanised monoclonal antibody, MLN-02 (LDP-02), developed against alpha4beta7 has also shown evidence of efficacy in ulcerative colitis and CD. Although the clinical trials showed that inhibition of alpha4 integrin was well tolerated, use of natalizumab in multiple sclerosis and CD has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML) in a small number of patients, and the drug has been withdrawn from the market pending further safety evaluation. PML is caused by polyoma JC virus infection, is progressive and generally fatal, and is recognised to occur in patients with severe immunosuppression. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with CD receiving open-label natalizumab treatment.