P035 ETROLIZUMAB TREATMENT MODULATES SOLUBLE MADCAM-1 LEVELS IN SERUM IN PATIENTS WITH CROHN’S DISEASE (2019)

Etrolizumab, a monoclonal antibody to the β7 integrin, inhibits both α4β7:mucosal addressin cell adhesion molecule 1 (MAdCAM-1)–mediated lymphocyte trafficking to the gut mucosa and αEβ7:E-cadherin–mediated lymphocyte retention. In patients with ulcerative colitis (UC) from the Phase 2 EUCALYPTUS trial (NCT01336465), treatment with etrolizumab resulted in a reduction in serum levels of soluble (s) MAdCAM-1 compared with placebo; this reduction in sMAdCAM-1 paralleled a reduction in free β7 receptors in the peripheral blood, with complete receptor occupancy (RO) observed at day 5 after the first dose in both dose cohorts (100 mg and 300 mg).1,2 Pharmacodynamic (PD) activity in patients with Crohn’s disease has yet to be evaluated. The effect of etrolizumab treatment on serum levels of sMAdCAM-1 (PD biomarker) and β7 RO in patients with moderate to severe Crohn’s disease was evaluated in a substudy of cohort 1 of the Phase 3 BERGAMOT trial (NCT02394028). Patients were randomly assigned (2:2:1) to receive subcutaneously administered etrolizumab 105 mg once every 4 weeks, etrolizumab 210 mg at weeks 0, 2, 4, 8, and 12 or placebo during a 14-week induction period. Biomarker and pharmacokinetic (PK)/PD analysis was conducted using serum and whole blood samples obtained at baseline and weeks 1 (days 3, 4, or 5), 2, 4, 10, and 14 from patients who enrolled in the PK/PD substudy. Measurements of serum sMAdCAM-1 were performed using a validated assay on the Gyrolab xP immunoassay platform. Whole blood samples were evaluated by flow cytometry within 24-48 hours of collection to assess β7 occupancy and enumeration of peripheral blood lymphocyte subsets. This preliminary analysis included 64 patients with Crohn’s disease (etrolizumab 105 mg, n = 29; etrolizumab 210 mg, n = 24; placebo, n = 11). Patients treated with etrolizumab showed a decline in sMAdCAM-1 from baseline (week 1: group median decline of ~ 40%, weeks 4 through 14: group median decline of ~ 80%) with minimal (< 10%) changes from baseline observed in the placebo arm (Figure 1). β7 integrin receptors on “β7high intestinal homing” CD3+ T cells were rapidly and completely occupied in etrolizumab-treated patients as indicated by a near 100% decrease in CD3+ T cells with “available” β7 receptors (Figure 2). Similar RO results were observed with CD4+ T, CD8+ T, and CD19+ B lymphocytes. There were no dose-related differences observed in sMAdCAM-1 reduction and RO. In this preliminary analysis, sMAdCAM-1 was reduced following etrolizumab treatment in patients with Crohn’s disease. Full β7 RO was achieved with both doses of etrolizumab. Overall, results were similar to those reported in UC1 and confirm the expected pharmacologic profile of etrolizumab. 1Fuh F et al. Presented at UEGW 2016. P0843. 2Vermeire S et al. Lancet. 2014;384(9940):309-318. Figure 1. Serum levels of sMAdCAM-1 (median/MAD) were greatly reduced following etrolizumab dosing. BL, baseline; MAD, median absolute deviation; sMAdCAM-1, soluble mucosal addressin cell adhesion molecule 1. Figure 2. Full β7 receptor occupancy (median/MAD) on intestinal homing CD3+ T cells was observed following etrolizumab dosing. BL, baseline; MAD, median absolute deviation.