The inhibition of leukocyte trafficking to the gut mucosa has been a second important target for the development of drugs for inflammatory bowel disease (IBD). Blocking antibodies inhibit the interaction between leukocytes and the intestinal vasculature, thus decreasing the influx of inflammatory cells into affected gastrointestinal tissues. Natalizumab is one such antibody that targets the α4 subunit of the α4β7 and α4β1 integrins that control leukocyte adhesion to the vascular endothelium. However, its large-scale use was limited by the potential for reactivation of JC virus which can lead to progressive multifocal leukoencephalopathy (PML). In the New England Journal of Medicine, researchers report the results of two phase 3, placebo-controlled studies of vedolizumab, a monoclonal antibody that blocks the entire α4β7 heterodimer. Both reports are among the largest clinical studies in patients with IBD.
One of the studies was conducted in adults with active Crohn’s disease of at least 3 months duration, with a score of 220 to 450 on the Crohn’s Disease Activity Index (CDAI, on which scores range from 0 to ~600, with higher scores indicating greater disease activity), and who had one of the following: CRP>2.87 mg/L, colonoscopic findings showing ≥3 large ulcers or ≥10 aphthous ulcers, or faecal calprotectin concentrations of >250 μg per gram of stool plus evidence of ulcers on CT or magnetic resonance enterography. Eligible patients had had no response to or had had unacceptable side effects from one or more of the following: glucocorticoids, immunosuppressive agents (i.e., azathioprine, mercaptopurine, or methotrexate), or TNF antagonists. Stable doses of oral prednisone (≤30 mg per day) or budesonide (≤9 mg per day), immunosuppressive agents, mesalamine, and antibiotics were permitted.
The study consisted of separate induction and maintenance trials, assessing intravenous vedolizumab (300 mg). In the induction trial, 368 patients were randomised to vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomised to placebo or vedolizumab every 8 or 4 weeks until week 52. The two primary end points in the trial of induction therapy were clinical remission (CDAI score of ≤150 points) and CDAI-100 response (≥100-point decrease in the CDAI score) at week 6. In the trial of maintenance therapy, the primary end point was clinical remission at week 52.
The following findings were reported:
• At week six, 14.5% of patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (p =0.02), i.e. CDAI ≤150; a total of 31.4% and 25.7% of patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) [P = 0.23].
• Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% on vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, vs. 21.6% on placebo (p<0.001 and p=0.004 for the two vedolizumab groups, respectively, vs. placebo).
• Antibodies against vedolizumab developed in 4.0% of patients.
• Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients on placebo.
• Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).
• Cancer was reported in 4 patients treated with vedolizumab; 5 deaths occurred during the study period four among patients receiving vedolizumab; no cases of PML were identified.
The researchers conclude that among patients with moderately to severely active Crohn’s disease in whom conventional therapy has failed, those on vedolizumab induction therapy were more likely than those on placebo to have a remission at week 6; however, they were not more likely to have a CDAI-100 response. In an analysis of patients who had a response to induction therapy with vedolizumab, the rates of clinical remission and CDAI-100 response at week 52 were higher among patients receiving vedolizumab every 8 weeks or every 4 weeks than among patients who were switched to placebo. They note that the modest effect of vedolizumab on the induction of clinical remission and its non-significant effect on the CDAI-100 response at week 6 may be either attributable primarily to modest efficacy or to potential confounders. They suggest disease severity as a possible confounder, which may have precluded a robust inductive effect. About 50% of patients had had treatment failure with ≥1 TNF antagonists; half of these patients did not have an initial response, and approximately 30% of patients had had treatment failure with ≥2 TNF antagonists- a population with such refractory disease has not been evaluated in previous trials of TNF antagonists. In addition, they suggest anti-integrin therapy could be relatively slower acting in Crohn’s disease, given the transmural nature of the disease, with the predominant benefit seen during the maintenance phase.
The researchers acknowledge that long-term epidemiological studies are needed to fully characterise the safety of vedolizumab and that the study leaves some questions unanswered, including which specific patients with Crohn’s disease may derive the most benefit from vedolizumab.
An editorial considers why vedolizumab was less efficacious at inducing a clinical response in patients with Crohn's disease than in ulcerative colitis. One hypothesis is that Crohn's disease may represent a more systemic disorder, as it affects any portion of the GI system from mouth to anus and is characterised by transmural inflammation, fistulas, and multiorgan involvement; whereas ulcerative colitis is considered a more localised disease that is limited to the superficial mucosal layers of the large bowel. An alternative hypothesis is that inhibition of leukocyte trafficking in patients with Crohn's disease requires a longer time to produce a measurable clinical response than in patients with ulcerative colitis. The editorial concludes that given the results of the two phase 3 studies, vedolizumab will likely “become part of the growing armamentarium of new drugs available to the practicing gastroenterologist for the treatment of IBD, particularly in patients who did not have a response to a TNF inhibitor.”
In March 2013, vedolizumab was filed for approval in the EU for the treatment of adults with moderately to severely active ulcerative colitis and Crohn’s disease. A NICE clinical guideline on Crohn’s disease was published in 2012..