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ORLANDO -- The real promise of vedolizumab (Entyvio) as a first-line therapy in inflammatory bowel disease is its safety, a researcher stated here.
Unlike tumor necrosis factor (TNF) inhibitors, which have systemic immunosuppressive effects and therefore carry a burden of infection, vedolizumab is an antibody to α4β7 integrin that is gut-selective, according to , of Robarts Clinical Trials and the University of Western Ontario in Canada.
"In clinical practice we all recognize the limitations of TNF antagonists. They're good drugs but we're not having 90% success rates, and we need to do better and get patients off steroids to a greater degree," he said at the Advances in Inflammatory Bowel Diseases meeting.
"If you look at the product monograph and the adverse events for any of the TNF antagonists, regardless of the indication, one trademark item stands out -- upper respiratory tract infection always has a difference compared with placebo," he said.
"So who cares if a patient gets a common cold? Well, that's actually the canary in the coal mine -- for lobar pneumonia, which is the most common cause of mortality among patients receiving TNF antagonists," said Feagan, who headed the clinical trials that led to the drug's approval.
Vedolizumab initially was tested in a primate model, and then went on to be evaluated in a called GEMINI that included almost 900 patients with ulcerative colitis, showing efficacy for both induction and maintenance. For example, at week 6 the response rates were 47.1% for the vedolizumab group compared with 25.5% for placebo, which was a difference of 21.7% after adjustment for stratification factors (95% CI 11.6-31.7, P<0.001). The study included 40% of patients who had failed on a TNF antagonist. "This was a really striking effect," he said.
And with maintenance therapy, there was a "very strong steroid-sparing effect, which is the real signature of the whole class of anti-integrin drugs," he said.
Then vedolizumab also was tested in 1,100 patients with , and at week 6, the difference between the active treatment group and the placebo group was not significant on the primary endpoint of the Crohn's Disease Activity Index (CDAI, 31.4% vs 25.7%, P=0.23). However, by week 52, among patients receiving vedolizumab every 8 weeks, 39% were CDAI responders as were 36.4% of those on an every 4 week schedule, compared with 21.6% of those given placebo (P<0.001 and P=0.004, respectively).
"The takeaway message was don't give up on the drug. Give corticosteroids to get them through induction, because subsequently there's a highly effective steroid-sparing effect. It's well tolerated over the long term and is a very safe therapy," he said.
More recently, he and other researchers undertook an for both ulcerative colitis and Crohn's disease. "The advantage of placebo-controlled trials is that you have a contemporaneous comparator, while the disadvantage is that placebo patients tend to drop out, so you have to adjust for follow-up time," he explained.
"We had fully expected based on the mechanism of action that vedolizumab would have approximately the same rate of respiratory tract infections as placebo, but we found that the point estimates for vedolizumab were in fact lower than for placebo," he said.
For instance, in GEMINI 1, the exposure-adjusted incidence rates of upper respiratory tract infections were 8.6 per 100 patient-years (95% CI 7.2-10) in the vedolizumab group compared with 30.7/100 (95% CI 17.7-43.7) in the placebo group. And when all six of the original clinical trials were included, the adjusted incidence rates were 7.7/100 (95% CI 6.8-8.5) versus 11.6/100 (95% CI 6.9-16.3).
"How can that be? Think of your last patient that got infected on a TNF antagonist -- malnourished, on steroids, with active disease. You can imagine that if you give patients an effective therapy and get more of them into remission, infection rates might be lower," he said.
"So this is very powerful evidence of why vedolizumab is really a transformational drug," he concluded.