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P478 Immunogenicity is not the driving force of treatment failure in vedolizumab-treated inflammatory bowel disease patients

N. Van den Berghe*1, B. Verstockt2,3, S. Tops1, M. Ferrante2,3, S. Vermeire2,3, A. Gils1

1KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium, 2University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium, 3KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium

Background

The pivotal GEMINI trials reported low immunogenicity (4%) of vedolizumab during treatment. However, 16 weeks after treatment discontinuation, 10% of patients were anti-vedolizumab antibody (AVA) positive using a drug-sensitive assay. AVA are frequently underestimated since most assays are not drug-tolerant and unable to detect anti-drug antibodies while there is drug in the circulation. This study aimed to explore which anti-drug antibody assay is best suited to detect AVA and investigated immunogenicity of vedolizumab in inflammatory bowel disease (IBD) patients discontinuing vedolizumab therapy.

Methods

A drug-tolerant assay was developed for the measurement of AVA in the presence of vedolizumab and compared with the previously established drug-sensitive (lower limit of quantification (LLOQ) = 5 ng/ml) and drug-resistant (LLOQ = 3800 ng/ml) assay by application on samples of IBD patients with proven AVA levels (Bian et al., IBD 2017). After selection of the most suitable assay, vedolizumab and AVA were measured at Week 6, at the last infusion and 12–20 weeks after treatment discontinuation in a cohort of 40 vedolizumab-treated IBD patients who stopped treatment due to primary non-response (n = 23), loss of response (n = 8), adverse events (n = 7), or a combination (n = 2).

Results

The drug-tolerant assay had an LLOQ of 350 ng/ml and could detect AVA in 20 samples compared with 1 and 10 samples with the drug-sensitive and drug-resistant assay, respectively. Using the drug-tolerant assay, three (8%) out of 40 vedolizumab-treated IBD patients who discontinued therapy were AVA positive at Week 6. All three patients also had AVA at least at one other time point. These three patients, as well as the other 37 did not have AVA at the time of the last infusion nor after treatment discontinuation. The median Week 6 vedolizumab concentration of 40 patients who discontinued therapy was 23.2 μg/ml (IQR 14.7–31.9 μg/ml). Primary non-responders had numerically lower median vedolizumab concentrations at Week 6 compared with patients with loss of response (20.3 vs. 30.7 μg/ml, respectively, p = 0.0570). Vedolizumab Week 6 concentrations of patients who stopped therapy due to adverse events were comparable to those of patients with loss of response.

Conclusion

Immunogenicity of vedolizumab is not the driving force of treatment failure and AVA do not increase upon treatment discontinuation in vedolizumab-treated IBD patients. We hypothesise that clinicians can stop and restart vedolizumab without the risk of adverse events or a diminished clinical response due to anti-drug antibodies. Additionally, our data suggest that underexposure during induction might partially be responsible for primary non-response.