ORLANDO — Increasing experience with the α4β7 integrin antibody vedolizumab (Entyvio) continues to support the observation that this agent represents a new chapter in the treatment of inflammatory bowel disease beyond the tumor necrosis factor (TNF) inhibitors, a researcher reported here.
“It’s important to recognize that we are approaching a quarter century of TNF inhibitor use, and that those are yesterday’s drugs,” said Brian G. Feagan, MD, of Western University in London, Ontario, at the annual Advances in Inflammatory Bowel Diseases meeting.
The TNF inhibitors have been “far from perfect” with regard to efficacy in inflammatory bowel disease. “We’re not seeing 70, 80, 90% response rates — it’s more like 30-40%,” Feagan said.
Moreover, “we’ve come to understand that these drugs have a significant Achilles’ heel, which is the risk of serious infection,” he added. The most common serious infections with the TNF inhibitors today are pneumococcal pneumonia, influenza, and pelvic abscesses, and immunizations can help overcome these, but “those drugs are systemic immunosuppressives, and infection is a limitation.”
Vedolizumab inhibits the tracking of lymphocytes specifically in the gut, and has been approved for use in ulcerative colitis and Crohn’s disease based on the GEMINI studies.
GEMINI 1 evaluated vedolizumab for the induction and maintenance treatment of ulcerative colitis in almost 900 patients, and found a “very strong” maintenance effect, said Feagan, who was the lead investigator for the trial. By week 52, a total of 41.8% of patients receiving the drug every 8 weeks and 44.8% receiving it every 4 weeks were in remission, compared with 15.9% given placebo.
But in GEMINI 2, which included more than 1,100 patients with Crohn’s disease, a statistically significant difference in remission responses versus placebo was seen for the induction phase at week 6 (14.5% vs 6.8%), but the clinical differences were less clear, with no significant difference seen between the active treatment and placebo in the numbers having a 100-point decrease in the Crohn’s disease activity index.
The lack of clinically significant improvements during the induction phase seemed to be a negative finding, “and people began to question the drug’s value, which curtailed the advance of the drug into the marketplace,” Feagan said.
However, a subsequent study demonstrated that an induction phase of 10 weeks was more effective, with a clinically meaningful effect versus placebo for remission response, not only in patients who were anti-TNF naïve but also for those for whom treatment with a TNF inhibitor had failed.
“So a very important clinical takeaway is that this is not a 6-week induction drug. One needs to look at a 10- to 12-week induction period,” Feagan said.
Another common misconception about vedolizumab is that because it’s a gut-selective drug, it might not help with extraintestinal manifestations of disease, the most common of which is arthralgia/arthritis. “For many patients, this is debilitating,” he noted.
It turns out that if the colonic disease can be controlled, the extraintestinal manifestations also improve, particularly the arthritis, according to observational studies.
Other findings from recent observational studies have suggested that response rates, if anything, have been even higher than what was seen in the randomized clinical trials, including endoscopic response rates, he said.
Vedolizumab also has had an “unprecedented safety record,” Feagan stated. Combination rates for any infection, lower respiratory tract infection, and upper respiratory tract infection actually had lower point estimates when adjusted for exposure time for vedolizumab versus placebo (63.5/100 patient-years vs 82.9/100 patient-years).
“You might say that’s impossible, but remember that placebo-treated patients also have high disease activity and are exposed to steroids, which are risk factors for infection,” he pointed out.
The GEMINI trials were sponsored by Millennium Pharmaceuticals.
Feagan reported financial ties to Millennium and multiple other companies.