299 Oral difelikefalin improves itch and inflammatory biomarkers in atopic dermatitis subjects with moderate-to-severe pruritus

Abstract

Pruritus is the most frequent and burdensome atopic dermatitis (AD) symptom and can exacerbate disease via the itch-scratch cycle. Difelikefalin (DFK), a kappa-opioid receptor (KOR) agonist is approved for moderate-to-severe pruritus in adults with CKD undergoing hemodialysis. DFK blocks pruritic signaling through peripheral sensory neurons and may have anti-inflammatory activity. We tested the impact of DFK on pruritus-related and inflammatory transcriptomes of AD patients. In a phase 2 clinical study, subjects with AD and moderate-to-severe pruritus were randomized (1:1:1:1) to receive oral twice-daily DFK (3 doses) or placebo for 12 wk. A substudy (n=40) characterized effects of DFK on pruritus- and AD-related gene expression using baseline and wk 12 skin biopsies. Gene expression was measured using RNA-sequencing and TaqMan Low-Density Array qualitative polymerase chain reaction. Data from DFK groups were pooled. DFK altered expression of multiple individual pruritus- and AD-related genes. Gene set variation analysis confirmed downregulation of pruritus-related genes (eg, IL-31, TRPV2) and the Th2 pathway following 12 wk treatment with DFK, but not placebo. Changes in gene expression of pruritus- and immune-related genes significantly correlated with skin improvement for DFK-treated subjects. DFK downregulated expression of key genes implicated in pruritus and AD inflammation. Reports demonstrate an anti-pruritic effect of DFK in AD and other chronic itch conditions. DFK is a promising therapy for AD-related pruritus and may provide anti-inflammatory benefit by impacting the itch-scratch cycle.