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* = Presenting author

P592. A phase 1, double-blind placebo-controlled single-dose study to determine the immune response to systemic and mucosal antigenic challenge in the presence of vedolizumab

T. Wyant1, T. Leach1, S. Sankoh1, Y. Wang1, J. Paolino2, B. Feagan3, A. Parikh4, 1Millennium Pharmaceuticals, Inc., Cambridge, United States, 2University of Massachusetts Medical School, Worcester, United States, 3Robarts Research Institute, University of Western Ontario, London, Canada, 4Takeda Pharmaceuticals, Inc., Chicago, United States

Background

Vedolizumab (VDZ) is a humanised monoclonal immunoglobulin G antagonist of α4β7 integrin that mediates lymphocyte trafficking to the gastrointestinal tract. VDZ recently completed phase 3 trials in ulcerative colitis and Crohn's disease. To test the hypothesis that VDZ has gut-selective, anti-inflammatory activity without generalised immunosuppression, we assessed immune responses to oral and parenteral vaccines.

Methods

127 healthy subjects were randomised 1:1 to receive placebo (PLA) or VDZ 750 mg intravenously. Subjects with history or laboratory evidence of infection/vaccination to hepatitis B virus (HBV) or cholera were excluded. 4 days after receiving VDZ or PLA, subjects received intramuscular recombinant hepatitis vaccine (HBVAXPRO: days 4, 32, and 60) and inactivated oral cholera vaccine (DUKORAL: days 4 and 18). Vaccine responses were assessed through day 74 and safety through day 127. Primary and secondary endpoints were HBV and cholera seroconversion rates, respectively. Seroconversion was defined as anti-hepatitis B surface antibody (HBsAb) >10 IU/L and detectable anti-cholera toxin antibody (Ab). The noninferiority study had 81% and 71% power to detect a 15% decrease in HBV and cholera responses (respectively) using a 1-sided α of 0.05 and a 90% evaluability rate.

p592 

Results

In the intent-to-treat population, VDZ had no effect on HBV seroconversion rates or geometric mean serum concentrations of anti-HBsAb over time.

Although not crossing the noninferiority margin of 15%, VDZ was associated with numerically lower seroconversion rates to oral cholera vaccine and substantially decreased geometric mean concentrations of anti-cholera toxin Ab over time. Day 74 serum VDZ concentrations were 20.4 µg/mL; sufficient to saturate the target on peripheral blood lymphocytes. Adverse events (AEs) were reported by 50 (79%) of PLA and 41 (64%) of VDZ subjects. Individual AE rates were similar between treatment groups. 1 subject developed anti-VDZ Ab but did not manifest any hypersensitivity AEs.

Conclusion

These data support a gut-selective mechanism of VDZ in that it does not affect the ability of the immune system to mount a primary systemic immune response to a T-cell-dependent antigen, but may reduce response to mucosal challenge.