An anti-IL-13 antibody reverses epithelial-mesenchymal transition biomarkers in eosinophilic esophagitis: phase 2 trial results.

ABSTRACT Background Fibrostenosis, the most serious eosinophilic esophagitis (EoE) complication, is mediated by epithelial-mesenchymal transition (EMT). Transitioned cells contribute to pathogenesis by overproducing extracellular matrix. Objective To determine whether RPC4046 (anti‒IL-13 monoclonal antibody) modulates EMT biomarkers in biopsies from adults with active EoE in a substudy of a double-blind, placebo-controlled phase 2 trial. Methods Baseline and week-16 esophageal biopsies were taken from 69 patients randomized to weekly subcutaneous RPC4046 180 mg (n=19), 360 mg (n=26), or placebo (n=24). Duplex immunofluorescence slides stained for e-cadherin and vimentin were digitally analyzed by mapping each epithelial cell and recording fluorescence intensities. Endpoints included change from baseline to week 16 in percentage vimentin-positive epithelial cells (primary), total e-cadherin, and vimentin:e-cadherin ratio per cell (average of 47,000 cells/biopsy analyzed). Results Mean percentage vimentin-positive cells decreased 0.94%, 2.75%, and 4.24% in the placebo, low-dose, and high-dose groups (P = 0.032, high-dose vs placebo). Mean e-cadherin expression per cell increased 5.6-fold in both dose groups versus placebo (high-dose P = 0.047). Increases in e-cadherin per cell from baseline to week 16 were correlated with improvements in histology, eosinophil counts, endoscopic findings, and symptoms. Conclusion RPC4046 significantly reduced EMT markers in adults with active EoE, with greater effects at 360 mg. Together with results for eosinophil density and clinical endpoints from the main trial, these data support the hypothesis that pharmacologic IL-13 inhibition ameliorates both inflammatory and remodeling pathways, and could potentially reduce the risk of fibrostenotic complications.