Vedolizumab better for UC than Crohn's disease in trials

Vedolizumab (proposed trade name 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 (UC) or Crohn's disease (CD) who have failed at least one conventional therapy, including tumor necrosis factor (TNF) antagonists.

In December 2013, two Food and Drug Administration (FDA) advisory committees voted in favor of recommending vedolizumab for treatment of both types of inflammatory bowel disease. The final decision regarding its use in patients with UC is expected in late May, and the decision for Crohn's disease is expected in June.

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 CD.

JC polyomavirus, the causative factor in PML, is present in about 70 percent of the population, but is harmful only in immunosuppressed patients or those undergoing therapy with biologic agents such as natalizumab.

Edward V. Loftus Jr., M.D., a gastroenterologist at Mayo Clinic in Minnesota, points out that 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," he says.

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 PML 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. It is not yet clear if the FDA will require a risk management program if vedolizumab is approved.

Clinical trials

The results of the trials — GEMINI I, a placebo-controlled induction and maintenance study in patients with UC, and GEMINI II, a similar study in CD patients — appeared in the Aug. 22, 2013, issue of The New England Journal of Medicine.

Findings from GEMINI I showed that vedolizumab met primary endpoints for improvements in clinical response at six weeks and clinical remission at 52 weeks. A statistically significant number of UC 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 UC patients.

Vedolizumab's future

Dr. Loftus says 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," he notes. "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 UC."

He adds, "When you look at the data, it raises the question: 'If you have a Crohn's disease patient who is steroid-dependent and has failed anti-TNFs and you're ready to pull the trigger on a biologic, would this be the first choice?' In the end, there is an unmet need for agents with a different mechanism of action for desperate patients."

But the drug's presumed gut selectivity may also make patients more susceptible to gastrointestinal (GI) infections. "There is a small signal that there may be increased risk of C. difficile infection in these patients," Dr. Loftus says, "but the magnitude of this won't become fully apparent until the drug is used in clinical practice."

Ultimately, he says, "I suspect approval of vedolizumab for UC will be a slam-dunk, and we may see a somewhat watered-down indication for Crohn's. The key advantages are the new mechanism of action and potential gut selectivity. The issue of GI infections remains to be sorted out."

For more information

Feagan BG, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. The New England Journal of Medicine. 2013;369:699.

Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. The New England Journal of Medicine. 2013;369:711.