Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis
Emma Guttman‐Yassky, Paola Facheris, Joel Corrêa da Rosa, Camille Rothenberg‐Lausell, Ester Del Duca, Eden David, Yeriel Estrada, Ying Liu, Swaroop Bose, Mashkura Chowdhury, Catherine Munera, Joana Gonçalves, Kristine Nograles, Brian Kim, Mark Lebwohl
Abstract
BackgroundPruritus 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.ObjectiveWe 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.MethodsA 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, TH2-associated genes, and skin barrier–related genes.ResultsIn 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 TH2 pathways. DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism–associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1).ConclusionsDFK 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, TH2-associated genes, and skin barrier–related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted. 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. 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. 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, TH2-associated genes, and skin barrier–related genes. 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 TH2 pathways. DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism–associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1). 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, TH2-associated genes, and skin barrier–related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted.