Cendakimab (Anti-IL-13) administration improves esophageal gene expression in eosinophilic esophagitis.

Abstract

BACKGROUND IL-13 has been implicated as a key contributor to the pathogenesis of eosinophilic esophagitis (EoE) based in part on the finding that cendakimab (a humanized monoclonal anti-IL-13 antibody) significantly improved esophageal eosinophils, endoscopic severity, histology grade and stage, and clinician's assessment of severity in the HEROES phase 2 trial. OBJECTIVE We aimed to determine how cendakimab administration impacted esophageal gene expression in the HEROES phase 2 trial (NCT02098473). METHODS EoE-related transcripts were quantified in biopsies collected at baseline (week 0) and after 16 weekly injections (week 16) of cendakimab (180 mg or 360 mg) or placebo. Genes exhibiting differential expression after cendakimab treatment were identified. Esophageal gene expression pre- and post-treatment in histologic and endoscopic responders and non-responders was compared. Additionally, we assessed whether esophageal gene expression correlated with histologic and endoscopic parameters. RESULTS Compared with placebo, cendakimab (at both doses) reversed the gene expression profiles of cardinal genes and molecular pathways involved in EoE pathogenesis. These changes included genes involved in IL-13 signaling (eg, CCL26), mastocytosis (eg, CPA3, TPSB2/TPSAB1), epithelial differentiation (eg, DSG1), and remodeling (eg, POSTN). Transcript changes correlated with histologic and endoscopic observations. Patients who did not achieve histologic remission still demonstrated improved post-treatment transcript expression, although patients who achieved histologic remission exhibited greater improvement in post-treatment expression in a subset of genes than did patients who did not achieve histologic remission. Both endoscopic responders and non-responders exhibited improvement in post-treatment expression. CONCLUSION Cendakimab treatment normalizes the aberrant esophageal gene expression seen in patients with EoE, and the changes in transcripts correlate with histologic and endoscopic improvements. The finding that cendakimab corrects esophageal transcript expression even in endoscopic non-responders suggests that the IL-13 pathway is driving EoE pathogenesis in most patients. These collective findings, derived from a multisite, double-blinded, placebo-controlled trial, add molecular evidence that IL-13 drives EoE pathogenesis.