In data presented at UEG, investigators find post-dupilumab transcriptome closely resembles the transcriptome of a healthy control group.
Jennifer D. Hamilton, PhD
Dupilumab (Dupixent) could be a treatment option for patients suffering from eosinophilic esophagitis (EoE).
A team, led by Jennifer D. Hamilton, PhD, Senior Director of Precision Medicine, Regeneron Pharmaceuticals, presented data during the United European Gastroenterology (UEG) Virtual 2020 conference on the effect of dupilumab on the expression of type 2 inflammatory genes in patients suffering from EoE.
Eosinophilic esophagitis is a chronic type 2 inflammatory disease that causes eosinophilic inflammation of the esophagus, remodeling, and barrier dysfunction. These patients often have an altered esophageal transcriptome when compared to healthy individuals, including changes in genes associated with type 2 inflammation, eosinophils, and mast cells.
Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin (IL)-4 and IL-13, both of which are central drivers of type 2 inflammation in multiple diseases.
In the double-blind, placebo-controlled, phase 2 study, the investigators examined 41 adult patients with active EoE. Each participant received either 12 weeks of subcutaneous dupilumab 300 mg weekly or placebo.
The investigators collected pinch biopsies from proximal, mid, and distal esophagus at baseline and week 12 and extracted RNA for transcriptome sequencing. The mean gene expression of the 3 esophageal regions for each patient was also examined at baseline and week 12.
The team then compared these results across patients with the published EoE and healthy transcriptomes. A relative change from baseline of ≥ 2-fold, q < 0.05 was considered significant, reflecting appropriate adjustment for multiple testing.
The investigators found dupilumab significantly improved dysphagia and histological and endoscopic measures of the disease.
The study drug modulated 1302 genes, with very similar transcriptomes in all 3 analyzed esophageal regions. Dupilumab also significantly normalized the expression of genes associated with type 2 inflammation, including genes associated with type 2 inflammatory cell responses, proinflammatory cytokine production, and mucins.
Dupilumab also significantly normalized genes associated with eosinophils and mast cells by downregulating genes linked to eosinophil recruitment and genes encoding eosinophil and mast cell surface proteins, which are all dysregulated in the EoE transcriptome.
The post-dupilumab transcriptome more closely resembled that of healthy controls than the published EoE transcriptome and no changes in gene expression in the placebo group met significance thresholds.
“In this phase 2 study, dupilumab reversed the EoE disease transcriptional signature, and normalized multiple genes associated with type 2 inflammation, eosinophils, and mast cells,” the authors wrote. “This confirms the congruence of the mechanism of action of dupilumab and the mechanism of disease, highlighting the IL-4/IL-13 pathway as a central mediator of EoE pathogenesis.”
In September, the US Food and Drug Administration (FDA) granted a Breakthrough Therapy Designation for dupilumab to treat EoE.
The designation will expedite the development and review of the drug developed by Regeneron Pharmaceuticals and Sanofi for the treatment of patients at least 12 years old.
Currently, there are no FDA-approved treatments for eosinophilic esophagitis.
The study, “Dupilumab Normalizes Expression of Genes Associated with Type 2 Inflammation in Patients with Eosinophilic Esophagitis,” was published online by UEG Week Virtual 2020.