Background: Pruritus is the most common and burdensome symptom of atopic dermatitis (AD). Pruritus-targeted treatments in AD are lacking, particularly for patients with milder skin disease.

Objective: We sought to evaluate the impact of the selective κ-opioid receptor agonist difelikefalin (DFK) on pruritus intensity and pruritus- and immune-related biomarkers in subjects with moderate to severe AD-related pruritus.

Methods: A phase 2 clinical trial investigated the efficacy and safety of oral DFK 0.25, 0.5, and 1.0 mg in subjects with moderate to severe AD-related pruritus. A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.

Results: In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12. In a subgroup of subjects in the trial with mild to moderate skin inflammation and moderate to severe itch (itch-dominant AD phenotype), DFK reduced itch at week 12 versus placebo. In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (eg, IL-31 and TRPV1) and the AD phenotype (eg, CCL17). Gene set variation analysis confirmed that DFK, but not placebo, downregulated pruritus-related genes and T_H2 pathways. DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism-associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1).

Conclusions: DFK treatment reduced itch in subjects with moderate to severe AD-related pruritus, particularly those with an "itch-dominant" AD phenotype, and had an impact on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted.