A Trial of Upadacitinib for Non-responsive Eosinophilic esophagitis (ATUNE)

About This Grant

A Trial of Upadacitinib for Non-responsive Eosinophilic esophagitis (ATUNE) ABSTRACT Eosinophilic esophagitis (EoE) is an immune-mediated chronic disease defined by abnormal infiltration of eosinophils into the esophageal mucosa, leading to dysphagia, progressive esophageal stenosis, and food impaction. The incidence and prevalence are rising dramatically, and EoE is now a major cause of upper gastrointestinal morbidity. EoE has a complex pathogenesis due to multi-faceted immune profiles, perturbation of structural cell function, and infiltration with other inflammatory cells. Optimal therapeutic options must address this underlying immune complexity, but few therapies target EoE pathogenesis, and treatment non- response and disease relapse are frequently encountered. Uncontrolled and treatment-resistant EoE leads to progressive fibrostenosis due to activated fibroblasts which generate a unique pathogenic extracellular matrix. Fibroblasts isolated from esophageal biopsies of patients with difficult to treat active EoE have predicted enrichment of interferon response which rely on JAK/STAT signals. Accordingly, treatment of EoE esophageal fibroblasts with the JAK1/2 inhibitor ruxolitinib decreases production of the eosinophil chemotactic cytokine CCL26/eotaxin-3. Our preliminary work with in vivo spatial transcriptomics demonstrates that esophageal biopsies have abundant transcripts for JAK1, STATs, and regulators of JAK1 activation. Upadacitinib, a specific JAK1 inhibitor, was superior to IL-4Rα blockade with dupilumab in atopic dermatitis, a disease with significant pathogenic overlap with EoE. These data provide the framework and feasibility for our central hypothesis that JAK1 inhibition with upadacitinib will treat steroid-resistant EoE and improve architectural and immune cell dysfunction in EoE. To test this hypothesis, we will perform a proof of concept randomized, placebo-controlled clinical trial of upadacitinib in topical steroid-resistant EoE subjects and assess disease response with validated clinical outcome metrics. We will also generate novel mechanistic data by investigating in vivo effects of upadacitinib on tissue structural cell transcriptomes and functions, spatial localization, and tissue cell neighborhoods comprised of fibroblasts and immune cells. The specific aims are to 1) evaluate the efficacy of upadacitinib versus placebo for improving clinically important disease activity outcomes in patients with EoE; and 2) understand the effects of JAK inhibition on tissue inflammation and remodeling. This proposal will have a major clinical impact for the large number of refractory EoE patients without current treatment options, provide data for planning a pivotal trial, and elucidate the role of the JAK/STAT pathway in EoE. Given the strong scientific premise, our expert multidisciplinary team with a proven track-record in EoE, clinical trials, and translational research conduct, is uniquely situated to successfully complete this study.