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Alpha4beta7 antagonists: Vedolizumab better for ulcerative colitis than Crohn's disease in trials


Vedolizumab ( Entyvio ) is a humanized monoclonal antibody that inhibits adhesion and migration of leukocytes into the gastrointestinal tract by preventing the alpha4beta7 integrin subunit from binding to mucosal addressin cell adhesion molecule-1 ( MAdCAM-1 ). It was developed as a treatment for patients with moderate to severe ulcerative colitis or Crohn's disease who have failed at least one conventional therapy, including tumor necrosis factor ( TNF ) antagonists.

A theoretical concern about Vedolizumab is the risk of progressive multifocal leukoencephalopathy ( PML ), a potentially fatal brain infection associated with Vedolizumab's parent molecule, Natalizumab ( Tysabri ), which is approved for use in both multiple sclerosis and Crohn’s disease.

JC polyomavirus, the causative factor in progressive multifocal leukoencephalopathy, is present in about 70% of the population, but is harmful only in immunosuppressed patients or those undergoing therapy with biologic agents such as Natalizumab.

According to Edward V. Loftus Jr., at Mayo Clinic in Minnesota, Natalizumab affects adhesion molecules at the level of the blood-brain barrier system as well as in the gut.
The goal has always been to develop more gut-specific targets. Vedolizumab claims to meet that goal.

Because MAdCAM-1 is preferentially expressed on blood vessels in the intestinal tract, Vedolizumab is theoretically more gut-specific and therefore a more targeted form of immunosuppression. The overall rate of progressive multifocal leukoencephalopathy cases among patients treated with Natalizumab is about 1.16 per 1,000 patients. Nearly 3,000 patients have been treated with Vedolizumab in phase III clinical trials with no reported cases of PML.

The results of the trials [ GEMINI I, a placebo-controlled induction and maintenance study in patients with ulceratve colitis, and GEMINI II, a similar study in Cronhn’s disease patients ] were published in The New England Journal of Medicine ( NEJM ).

Findings from GEMINI I have shown that Vedolizumab met primary endpoints for improvements in clinical response at six weeks and clinical remission at 52 weeks. A statistically significant number of ulcerative colitis patients also showed mucosal healing ( Mayo endoscopic subscore of 0 or 1 ) compared with placebo.

In GEMINI II, Vedolizumab-treated patients with active Crohn's disease were more likely to achieve remission but not a Crohn's Disease Activity Index-100 response at week six and more likely to be in remission at week 52 compared with patients receiving placebo. Adverse events, including nasopharyngitis, were more common than in placebo or ulcerative colitis patients.

The data raise several issues, including how and for whom the drugs will be used and possible side effects. Vedolizumab met its primary endpoint for Crohn's disease but not all secondary endpoints were met. The induction data are not as robust as the maintenance data, which is also true for Natalizumab. So it's possible these drugs, the lymphocyte trafficking blockers, have a slower onset of action in Crohn's. The efficacy-to-safety ratio may also not be as good for Crohn's as for ulcerative colitis.

The presumed gut selectivity of Vedolizumab may also make patients more susceptible to gastrointestinal ( GI ) infections. There is a small signal that there may be increased risk of Clostridium difficile infection in these patients. ( Xagena )

Source: Mayo Clinic, 2013

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