Delgocitinib Reduces Inflammation and Restores Skin Barrier in CHE as a Topical Pan-JAK Inhibitor

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As a topical pan-JAK inhibitor, delgocitinib blocks JAK-mediated signaling of inflammatory cytokines that play a key role in the pathogenesis of chronic hand eczema (CHE). CHE is characterized by various clinical subtypes and an association with innate immune and T helper (Th)1/Th2/Th17/Th22 inflammation.¹

A recent poster presented at the 2024 European Academy of Dermatology and Venereology Congress in Amsterdam, the Netherlands, September 25 to 28, detailed the results from an analysis of a phase 2a study (NCT02664805) of topical delgocitinib’s efficacy and safety. Worm et al evaluated the molecular endotype underlying various CHE severities and whether the topical application of delgocitinib ointment for 8 weeks could reduce local inflammation and improve skin barrier function.

“Delgocitinib is a pan-JAK inhibitor because it strongly inhibits JAK1, JAK2, JAK3, and TYK2 and can effectively treat multiple subtypes of CHE. Importantly, it does so safely because it has been shown to have negligible systemic absorption,” said Christopher Bunick, MD, PhD, associate professor of dermatology and translational biomedicine at Yale School of Medicine in New Haven, Connecticut, and Dermatology Times’ 2024 winter editor in chief.

The study was a randomized, double-blind, vehicle-controlled trial involving adults with various CHE severities. Investigators randomly assigned patients 2:1 to receive either delgocitinib ointment (30 mg/g) or a vehicle ointment applied twice daily for 8 weeks.

Forty-one patients provided skin biopsy samples, with 31 (delgocitinib ointment, n=20; ointment vehicle, n=11) having paired samples collected at baseline and the end of treatment. A pairwise comparison focused on the 141 most significantly differentially expressed genes between severe and mild CHE. Notably, the study results showed that the greatest differences in gene expression were seen between severe and mild cases, with inflammatory markers such as S100A9 being upregulated in severe cases, whereas genes associated with skin barrier integrity, such as LORICRIN (LOR) and FLG2, were downregulated.

“In more extreme CHE, S100A9, which is a calcium-binding protein associated with inflammation, was increased, while LORICRIN and FLG2, associated with skin barrier homeostasis, were actually downregulated. This highlights the connection between the skin barrier dysfunction, which enables irritants to penetrate the skin more readily, as well as other insults too, thereby triggering more inflammation, which in turn triggers more barrier dysfunction. It’s very important to understand that patients with chronic hand eczema suffer this trigger cycle of barrier dysfunction and inflammation,” said Bunick.

The results demonstrated that delgocitinib treatment effectively reversed the expression of key mediators associated with baseline disease severity. Specifically, treatment with delgocitinib led to a significant decrease in the expression of inflammatory markers that were elevated in severe cases compared with mild cases at baseline. Delgocitinib ointment increased the expression of genes related to skin barrier function and tissue integrity that was previously downregulated in severe cases. This reversal profile was identified in 55 significantly differentially expressed genes, with a fold change greater than 1.5, a P-value of less than .05, and a false discovery rate of less than 0.3.

Importantly, investigators observed no similar changes in the vehicle-treated group, underscoring the specific efficacy of delgocitinib in modulating the molecular signature of CHE. The findings suggest that delgocitinib not only alleviates inflammation but also enhances skin barrier integrity, addressing 2 critical aspects of CHE’s pathogenesis.

According to Worm et al, by targeting JAK-mediated signaling pathways, delgocitinib demonstrates the potential to reverse inflammatory processes and restore skin barrier function.

Reference

1. Worm M, Jiang L, Litman T, Atkinson S, Thyseen J, Molin S. Topical pan-JAK inhibition with delgocitinib restores the molecular signature of lesional skin in patients with chronic hand eczema: insights from a phase 2a study. Poster presented at: European Academy of Dermatology and Venereology Congress; September 25-28, 2024; Amsterdam, Netherlands.