Although Crohn’s disease and ulcerative colitis are the two most common forms of inflammatory bowel disease, treatment options remain less than ideal
Although Crohn’s disease and ulcerative colitis are the two most common forms of inflammatory bowel disease, treatment options remain less than ideal. Typically, drug therapies include anti-inflammatories such as mesalazine and its prodrugs sulfasalazine and basalazide, steroids, or tumour necrosis factor alpha (TNF-alpha) antagonising antibodies. Surgical removal of the worst affected sections of the small intestine or colon is also common.
Symptoms range from unpleasant to debilitating. Any part of the digestive tract can be affected in Crohn’s patients, whose symptoms include diarrhoea, abdominal pain, weight loss, bleeding from the rectum and even fever. Ulcerative colitis affects the colon and rectum only, with patients experiencing abdominal discomfort, and diarrhoea containing pus or blood.
An alternative is being developed by Takeda. Vedolizumab is a humanised monoclonal antibody designed to antagonise alpha-4 beta-7 integrin, which is expressed on some circulating white blood cells and is thought to be involved in mediating the inflammatory process in these two diseases.1 This effect inhibits the integrin’s ability to bind to the intestinal mucosal addressin cell adhesion molecule 1 (or MAdCAM-1), which is expressed on lymph nodes and blood vessels in the gastrointestinal tract.
Several long-term clinical trials have shown its effectiveness in IBD patients. In one, 72 patients with ulcerative colitis or Crohn’s disease were given 2, 6 or 10mg/kg doses of the antibody on days 1, 15 and 43, followed by a maintenance dose every eight weeks.2 Of these, 38 were following on from a previous placebo-controlled study in ulcerative colitis; these were treated for up to 630 days, compared with a maximum 547 days for the 34 naïve patients. Overall, 28 patients achieved a clinical response, and 42 achieved clinical remission, with response rates higher in those patients with colitis.
Further trials looking at its effectiveness as an induction and maintenance therapy have also been carried out, in colitis patients and in those with Crohn’s. Two integrated randomised, double blind, placebo-controlled trials were carried out in patients with active ulcerative colitis.3 First, its effectiveness as an induction therapy was assessed, with 374 patients receiving intravenous 300mg doses or placebo at weeks 0 and 2, and a further 521 patients open label vedolizumab. Their disease was evaluated at week six, and any patients who had a response were randomly assigned to continue receiving the antibody every four or eight weeks, or placebo.
At week six, the response rate was 47% for the treated group, compared with 26% for placebo. After 52 weeks, 42% of the eight-weekly dosed patients and 45% of those given the antibody every four weeks were in clinical remission, compared with 16% of those switched over to placebo. Adverse event profiles were similar across all patients.
A similar trial took place in patients with Crohn’s disease. This time, with a similar dosing schedule, 368 patients were given vedolizumab or placebo, and a further 747 open-label drug.4 A total of 461 patients who achieved a response continued into the maintenance trial. This time, 14% of those given vedolizumab and 7% of placebo treated patients were in clinical remission; in the maintenance phase, 39% of those dosed every eight weeks and 36% of the four-weekly dosed patients were in clinical remission after a year, compared with 22% for the placebo-dosed group. In the light of these results, the company has filed for approval, and has been granted priority review status by FDA.
1. D. Soler et al. J. Pharmacol. Exp. Therap. 2009, 330, 864
2. A. Parikh et al. Inflamm. Bowel Dis. 2013, 19, 1691
3. B.G. Feagan et al. N. Eng. J. Med. 2013, 369, 699
4. W.J. Sandborn et al. N. Eng. J. Med. 2013, 369, 711