Dupilumab reverses gene dysregulation in EoE

Treatment with dupilumab helps normalize the expression of genes dysregulated in children with active eosinophilic esophagitis (EoE), according to a study.

“Gene expression dysregulation in EoE includes genes related to eosinophils and type 2 (T2) inflammation, epithelial proliferation, barrier function, remodelling, and fibrosis,” Dr Evan Dellon of the University of North Carolina School of Medicine in Chapel Hill, North Carolina, US, said in a presentation at AAAAI 2024.

Unique gene expression patterns in EoE have been studied by analysing esophageal biopsies from patients compared with those from healthy individuals, leading to the development of a 94-gene set known as the EoE Diagnostic Panel. This panel, according to Dellon, is notable for its consistency across age groups, despite some variation in EoE presentation between children and adults.

Another gene signature, one that is specific to T2 inflammation in EoE, was derived from a combination of existing scientific knowledge, preclinical experiments, studies on dupilumab response signatures from atopic dermatitis, and a phase II study of EoE (R668-EE-1324).

T2-specific signature

In the cohort of children between 1 and <12 years of age from the phase III EoE KIDS study, treatment with once-weekly dupilumab 300 mg (higher exposure) led to a normalization of T2 inflammation gene expression compared with placebo. [AAAAI 2024, abstract 458]

T2 inflammation transcriptome heatmaps showed that the pattern seen in the reference set of active EoE patients was similar to the pattern seen at baseline both in the placebo group and the dupilumab group, Dellon noted.

“After 16 weeks of treatment, there were really no visual changes in the heatmap for the placebo group. But for the dupilumab group, the heatmap showed a normalization of the pattern that was very similar to [the pattern seen in] the reference set of healthy individuals,” he said.

Importantly, the normalization continued for up to 52 weeks of treatment with dupilumab, Dellon added. On the other hand, the placebo group started seeing normalization from week 16 through week 52, after switching to dupilumab.

Higher-exposure dupilumab significantly suppressed the T2 inflammation signature, with a median Normalized Enrichment Scores (NES) of –1.895 versus 0.340 with placebo at week 16 (median difference, –2.22, 95 percent confidence interval [CI], –2.44 to –1.95; p<0.0001).

“These NES are a way to compress all of the data from the heatmap into one value that summarizes the gene expression changes. So the way this works is that a negative NES score indicates a reversal of the disease signature, [while] a positive score indicates a more active disease or worsening,” Dellon explained.

EoE Diagnostic Panel

Dupilumab also targeted the broader EoE Diagnostic Panel genes. The changes in the heatmap data for the EoE Diagnostic Panel were consistent with those seen in the heatmap data for T2 inflammation signature.

Dellon noted that the heatmap pattern for the active EoE reference was seen at baseline for the placebo and dupilumab groups, with the pattern remaining unchanged for most of the patients in the placebo group after 16 weeks of treatment.

In contrast, the heatmap pattern at week 16 for the dupilumab group showed a normalization that was similar to how the pattern for the healthy control reference was. This was again maintained for up to 52 weeks, according to Dellon. The placebo group achieved the same response at week 52, following a switch to dupilumab at week 16.

The EDP signature was significantly suppressed with dupilumab versus placebo, with a median NES of −2.630 versus 0.180 at week 16 (median difference, –2.84, 95 percent CI, –3.35 to –1.96; p<0.0001).

Correlation data

“The gene expression changes observed in children were highly similar to those seen in adolescents and adults [from the LIBERTY EoE TREET study],” Dellon stated.

There was a near-perfect correlation in the gene expression changes regardless of age, which Dellon described as remarkable.

“This molecular evidence supports the efficacy of dupilumab to improve histologic, symptomatic, and endoscopic outcomes [in EoE],” he said.