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Vedolizumab Scores on Safety, Efficacy for Ulcerative Colitis

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'Impressive Results'

Vedolizumab is a biological therapy that blocks alpha-4/beta-7 integrins. This mechanism is novel within our arm­­­­a­­men­tarium of available therapies for ulcerative colitis, and vedo­lizumab is also the first non-sys­temically acting biologic therapy. The induction and maintenance results of this phase III trial of vedolizumab in moderate to severe ulcerative colitis are very encouraging and represent a major advance in our field. It appears that the impressive safety profile (infection rate was similar to placebo) seen in this trial is likely due to its gut-specific activity.

Furthermore, it is of interest that despite inhibition of lymphocyte trafficking in the gut, there does not appear to be an increased risk of GI infections. If these impressive results pan out in clinical practice, vedolizumab undoubtedly will become a significant option for the management of our ulcerative colitis patients, and will have a prominent place in our treatment algorithms. We eagerly await FDA review and further studies, including the Crohn’s disease trial results.

David T. Rubin, M.D., AGAF, is Professor of Medicine, Associate Section Chief for Education, and Co-Director, Inflammatory Bowel Disease Center, University of Chicago.


 

FROM THE ANNUAL DIGESTIVE DISEASE WEEK

SAN DIEGO – Vedolizumab, a novel drug that selectively blocks lymphocyte trafficking to the gut, was safe and highly effective for inducing and maintaining clinical remission in patients with moderate to severe ulcerative colitis in a pivotal phase III trial.

"If the findings hold up with more detailed analysis, it looks like we’ll have the efficacy of a biologic agent without some of the toxicity issues that we’ve seen with anti-TNF [tumor necrosis factor] drugs," said Dr. William J. Sandborn, professor of medicine and chief of gastroenterology at the University of California, San Diego.

Dr. William J. Sandborn

"This potentially could be a first-line drug," for treating moderate to severe ulcerative colitis, said Dr. Sandborn, a coinvestigator in the study.

"Vedolizumab was more effective than placebo for induction and maintenance treatment, including both anti-TNF–exposed and naive patients," Dr. Brian G. Feagan, the study’s lead investigator, said at the annual Digestive Disease Week. In addition, there was little difference between the vedolizumab and placebo groups in terms of adverse events, serious adverse events, and serious infections, said Dr. Feagan, professor of medicine at Western University in London, Ont.

At the end of a year of maintenance treatment, patients kept on the more frequent vedolizumab dosage tested, 300 mg delivered intravenously once every 4 weeks, showed a potent efficacy effect, surpassing the placebo group in corticosteroid-free clinical remissions by 31 percentage points (45% vs. 14%). "Nothing else is that good," Dr. Sandborn said in an interview. "Steroid-free remission with a delta over placebo of 30% is very impressive, especially when you factor in that many of the patients had failed anti-TNF treatment.

"We thought that vedolizumab would be safer than systemic immunosuppression, and I think the data are consistent with that. This will be a first-line treatment," Dr. Feagan said.

Dr. Brian G. Feagan

Equally important, total worldwide experience with vedolizumab, which now includes about 2,500 patients, has not yet resulted in a single case of progressive multifocal leukoencephalopathy (PML), an adverse effect produced by vedolizumab’s cousin drug, natalizumab (Tysarbi), ’approved for U.S. marketing to treat multiple sclerosis and Crohns disease.

Vedolizumab is a humanized monoclonal antibody that specifically binds to the alpha-4 beta-7 integrin protein that helps move leukocytes into the gut. Natalizumab is a less specific integrin antagonist that affects the protein’s actions and immune-cell trafficking to a variety of body sites, including the brain. Natalizumab "essentially blocks immune surveillance in the brain, and that allows for the JC virus [carried by about 50% of people] to cause PML," explained Dr. Sandborn. In contrast, vedolizumab does not cause "a systemic blockade of lymphocytes trafficking; it only affects a small fraction of lymphocytes, and leaves the brain completely unaffected."

Patients most at risk for PML are those who previously received immunosuppressive treatment with a drug such as azathioprine, methotrexate, or an anti-TNF drug. Patients with that history who received natalizumab for 1-2 years have about a 1 in 500-600 risk for PML, and those who got natalizumab for more than 2 years have a 1% risk.

By comparison, vedolizomab’s clean record based on 2,500 recipients "looks like it might have a very nice safety profile. If people can get comfortable with vedolizumab being different from natalizumab, then it has the potential to be first-line therapy for patients who have the worst prognosis," those who don’t respond to treatment with mesalamine.

The GEMINI I trial enrolled patients at 105 international sites with ulcerative colitis who had a Mayo score of at least 6 and an endoscopic subscore of at least 2 (indicating moderate disease) despite standard treatments. Patients were an average age of 40 years, their average duration of disease was 7 years, and their average Mayo score at entry was 8.5. Roughly 40% had previously received an anti-TNF treatment, about a third had failed on an anti-TNF drug, and just over half of the patients entered the study on a corticosteroid.

The trial included an induction phase that randomized 225 patients to a 6-week regimen with vedolizumab infusions and 149 patients to placebo. The researchers started another 521 ulcerative colitis patients on an open-label induction regimen, and then randomized 373 patients who responded after 6 weeks to maintenance infusion with vedolizumab every 4 weeks, a vedolizumab infusion every 8 weeks, or placebo.

The primary end point of the induction phase was clinical response, defined as a drop in the Mayo score of at least 3 points and at least 30%, plus a drop in the rectal bleeding score of at least 1 point or an absolute rectal bleeding subscore of 1 point or less. Achievement of this end point occurred in 47% of patients on vedolizumab and in 26% of those on placebo, a statistically significant difference. Among patients previously treated with an anti-TNF drug, 39% had a clinical response after 6 weeks on vedolizumab compared with 21% in the placebo arm, a significant difference. Among anti-TNF–naive patients, the rates were 53% and 26%.

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