May 06, 2014
By David Douglas
NEW YORK - The experimental drug vedolizumab (Entyvio, Takeda) significantly reduces the humoral response to enterically administered oral cholera vaccine, but not to parenterally administered antigens, indicating a gut-selective mechanism of action, researchers say.
The data show that vedolizumab "reduces the immune response in the gastrointestinal tract without affecting a patient's general immune response or other tissues," Dr. Tim Wyant told Reuters Health by email. "This is positive news as we seek to understand how best to administer oral or intramuscular vaccines to patients who are candidates for this type of treatment."
Dr. Wyant is with Takeda Pharmaceuticals, Cambridge, Massachusetts. Takeda is developing vedolizumab, a humanized monoclonal IgG1 antagonist of the alpha4beta7 integrin, for the treatment of ulcerative colitis and Crohn's disease. The drug selectively downregulates gut inflammation by inhibiting intestinal T-lymphocyte trafficking.
In an April 24th online paper in Gut, he and his colleagues say the drug's action are thought to be limited to the gastrointestinal tract. This could be advantageous, as conventional treatments for these conditions, such as corticosteroids and TNF-alpha antagonists, act systemically and are associated with an increased risk of serious infection. Moreover, natalizumab, a systemically active anti-alpha4 integrin agent, has been linked to serious central nervous system viral infection.
However, safety data from phase III studies of vedolizumab demonstrated that the overall rates of serious infections were similar in active treatment and placebo patients.
To gain further information on possible effects on immune responses, the researchers randomized 127 healthy participants to a single IV dose of vedolizumab 750 mg or placebo. After four days, participants began a three-dose course of intramuscular hepatitis B vaccine (HBV) and a two-dose course of oral cholera vaccine (OCV).
At 74 days, 88.5% of the vedolizumab participants and 90.3% of the placebo group responded to HBV. Geometric mean anti-hepatitis B titers were also similar.
At the same point, 82.5% of the vedolizumab group and 96.8% of the placebo arm responded to OCV. Geometric mean anti-cholera toxin IgG levels were higher for placebo than for vedolizumab, but were similar for anti-cholera toxin IgA.
These clinical findings, say the investigators "may reflect the fact that the gut immune response, as demonstrated in this study, is attenuated -- rather than entirely abrogated -- by vedolizumab."
"We speculate," they go on to say, "that this level of immune modulation may be adequate to exert therapeutic effects without compromising host immune defenses."
In December 2013, the US Food and Drug Administration's Gastrointestinal Drugs and Drug Safety and Risk Management Advisory Committee voted in favor of approval for vedolizumab, but the FDA has yet to act on this recommendation.
Likewise, in March 2014, the Committee for Medicinal Products for Human Use of the European Medicines Agency issued a positive opinion on use of vedolizumab for ulcerative colitis and Crohn's disease, but no action has yet been taken.
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