Treatment of ulcerative colitis and Crohn’s disease: efficacy of Vedolizumab
Vedolizumab ( Entyvio ) is a humanized version of Act-1, a murine antibody originally developed in the 1980s with activity against the alpha4beta7-integrin heterodimer. During leukocyte extravasation into tissues, the alpha4beta7-integrin heterodimer, found on the surface of T cells, binds to its ligand MAdCAM-1, which is expressed on the endothelial surface of venules within the gastrointestinal ( GI ) tract as well as associated lymphoid tissue. By blocking the interaction of the alpha4beta7-integrin with MAdCAM-1, Vedolizumab prevents leukocyte binding to the endothelial surface and, as a result, extravasation into affected tissue.
Unlike Natalizumab, which binds the alpha4-chain directly and inhibits the activities of both alpha4beta7 and alpha4beta1, Vedolizumab binds to the beta7-chain only when it is heterodimerized with alpha4. This results in selective inhibition of alpha4beta7/MAdCAM-1 without affecting the ability of alpha4beta1/VCAM-1 to function.
Vedolizumab is undergoing evaluation for the treatment of Crohn’disease and ulcerative colitis. To date, Phase I and Phase II trials are completed with several Phase III trials nearing completion. Phase III trials underway are designed to evaluate the effect of Vedolizumab on patients with moderately-to-severely active Crohn’disease or ulcerative colitis as well as its safety profile.
A Phase II trial conducted by Feagan et al. demonstrated the efficacy of Vedolizumab for the induction of clinical and endoscopic remission in 181 patients with active ulcerative colitis. Participants received 0.5 mg/kg of Vedolizumab, 2.0 mg/kg of Vedolizumab, or placebo intravenously. Infusions were performed on days 1 and 29 and patients were followed for up to 6 weeks with sigmoidoscopy performed at weeks 4 and 6.
The primary end point was clinical remission at week 6, which was achieved by 33% of patients in the 0.5 mg/kg group, 32% of patients in the 2.0 mg/kg group, and 14% of patients in the placebo group ( p = 0.03 overall; p = 0.02 for 0.5 mg/kg group vs placebo as well as 2.0 mg/kg group vs placebo ).
At week 6, 28% of patients who received 0.5 mg/kg and 12% of patients who received 2.0 mg/kg were in endoscopic remission compared with 8% of patients who had received placebo ( p = 0.007 for Vedolizumab groups vs placebo ).
The rate of adverse events was similar in all three treatment groups with exacerbation of ulcerative colitis, nausea and vomiting being the most common.
There were no differences in lymphocyte counts between patients treated with Vedolizumab and those who received placebo.
A second Phase II trial conducted by Feagan et al. examined the efficacy of Vedolizumab for the induction of clinical response and remission in 185 patients with active Crohn’disease. In this study, patients were treated with 0.5 mg/kg of Vedolizumab, 2.0 mg/kg of Vedolizumab, or placebo intravenously. Infusions were performed on days 1 and 29.
At day 57, 37 and 30% of patients treated with 2.0 mg/kg and 0.5 mg/kg, respectively, of Vedolizumab achieved clinical remission compared with 21% of patients receiving placebo ( p = 0.04 for 2.0 mg/kg vs placebo ). There was no significant difference in the proportion of patients achieving clinical response at day 57 among the three treatment groups.
Rates for clinical response, defined as a decrement of greater than or equal to 70 points in the Crohn’s Disease Activity Index, were 53, 49 and 41% in the 2.0 mg/kg, 0.5 mg/kg and placebo groups, respectively.
Rates for the secondary end point of enhanced clinical response, defined as a decrement of greater than or equal to 100 points in the Crohn’s Disease Activity Index, were 47, 43 and 31% in the 2.0 mg/kg, 0.5 mg/kg and placebo groups, respectively ( p less than 0.05 for 2.0 mg/kg vs placebo ).
The rate of adverse events was similar in all three treatment groups. There was no difference in lymphocyte counts between patients treated with Vedolizumab and those treated with placebo.
The safety and efficacy of Vedolizumab are being investigated further in Phase III trials ( GEMINI I, II, III and LTS ). GEMINI I and II are randomized, blinded, placebo-controlled, multicenter trials examining the efficacy of Vedolizumab for induction and maintenance in moderate-to-severe ulcerative colitis and Crohn’disease, respectively.
GEMINI I trial evaluated 374 patients with moderately-toseverely active ulcerative colitis who had failed at least one prior therapy ( corticosteroids, purine antimetabolites and/or TNF-alpha inhibitors ). Vedolizumab was found to be more effective than placebo for achieving clinical response, clinical remission and mucosal healing.
The maintenance phase of this trial was treated as an independent study with results unavailable at the time of this review. Patients were randomized to 300 mg intravenous Vedolizumab or placebo, given on days 1 and 15. The primary outcome was clinical response at 6 weeks. Secondary outcomes were clinical remission and mucosal healing at 6 weeks. A total of 225 patients received Vedolizumab and 149 received placebo. A significantly greater proportion of Vedolizumab-treated patients achieved clinical response ( 47.1 vs 25.5%; p less than 0.0001 ), as well as clinical remission ( 16.9 vs 5.4%; p = 0.001 ), and mucosal healing ( 40.9 vs 24.8%; p = 0.0013 ), when compared with those receiving placebo. Of the 374 patients studied, 39% had been previously exposed to TNF-alpha therapy. Within this population, both clinical response ( 39.0 vs 20.6% ) and clinical remission ( 9.8 vs 3.2% ) were higher in Vedolizumab-treated patients than in those who received placebo.
The development of adverse events was evaluated and found no significant difference in the rate of adverse events or serious infections between patients treated with Vedolizumab and those receiving placebo. ( Xagena )
McLean LP et al, Immunotherapy 2012; 4: 883–898
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