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DOP058. Pharmacokinetic and pharmacodynamic relationship and immunogenicity of vedolizumab in adults with inflammatory bowel disease: Additional results from the GEMINI 1 and 2 studies

M. Rosario1, T. Wyant2, C. Milch3, A. Parikh4, B. Feagan5, W.J. Sandborn6, H. Yang7, I. Fox1, 1Takeda Pharmaceuticals International Company, Clinical Pharmacology, Cambridge, United States, 2Takeda Pharmaceuticals International Company, Translational Medicine, Cambridge, United States, 3Takeda Pharmaceuticals International Company, Clinical Research, Cambridge, United States, 4Takeda Pharmaceuticals International, Inc., General Medicine, Deerfield, United States, 5University of Western Ontario, Department of Epidemiology and Biostatistics, London, Canada, 6University of California, San Diego, Division of Gastroenterology, La Jolla, United States, 7Takeda Pharmaceuticals International Company, Statistics, Cambridge, United States

Background

Vedolizumab (VDZ) is a humanised monoclonal antibody in development for treating ulcerative colitis (UC) and Crohn's disease (CD). Efficacy and pharmacokinetic (PK) profiles of VDZ in patients with UC and CD have been previously reported (GEMINI 1 [NCT00783718] and 2 [NCT00783692]). Here the PK/pharmacodynamic (PD) relationship and immunogenicity of VDZ are described.

Methods

Both GEMINI studies had a 6-week induction phase, wherein patients received 2 intravenous infusions of placebo or VDZ 300 mg (weeks 0, 2) and were assessed at week 6. VDZ-treated patients who had a clinical response at week 6 (intention-to-treat [ITT] population) were randomised to receive placebo or VDZ 300 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) during the 46-week maintenance phase. VDZ induction nonresponders (non-ITT population) received open-label VDZ 300 mg Q4W; patients who received placebo during induction continued on placebo. At prespecified times, blood samples were collected for determination of VDZ levels, PD assessment (alpha4beta7 [receptor] saturation via MAdCAM-1-Fc binding interference assay), and anti-VDZ antibody (AVA) assessment. Study data were examined separately for each disease and also pooled for VDZ PK/PD and AVA analyses. Receptor saturation plots were generated for each dose group.

Results

VDZ Q4W or Q8W led to median serum VDZ levels ≥10 mcg/mL in both ITT and non-ITT UC and CD patients at steady state during maintenance. Complete receptor saturation was observed by week 6 and maintained until week 52 in both VDZ dose groups. Among pooled UC and CD patients, 4% (56/1434) tested positive for AVAs at any time during continuous VDZ therapy and 10% (32/320) tested positive off drug (5 VDZ half-lives after last dose). In patients with an investigator-defined infusion-related reaction, 5% (3/61) tested persistently (≥2 consecutive visits) AVA positive; these persistently AVA-positive patients generally had lower serum VDZ trough levels than did the general study population. In the combined ITT and non-ITT VDZ group, the percentage of AVA-positive patients was similar between those with (3% [5/161]) and without (4% [51/1273]) concomitant immunomodulator use. In patients randomised to placebo, however, the impact was greater where AVA positive rates were 3% (1/32) and 18% (44/247) in those with and without concomitant immunomodulator use, respectively.

Conclusion

Median VDZ serum levels ≥10 mcg/mL were maintained when VDZ 300 mg was administered (Q8W or Q4W) to patients with UC or CD, resulting in complete receptor saturation. The PK profile and immunogenicity during continuous treatment with VDZ were similar in patients with UC and CD.