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, TH2-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 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). 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, TH2-associated genes, and skin barrier–related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted.
Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis / Guttman-Yassky, E.; Facheris, P.; Da Rosa, J. C.; Rothenberg-Lausell, C.; del Duca, E.; David, E.; Estrada, Y.; Liu, Y.; Bose, S.; Chowdhury, M.; Munera, C.; Goncalves, J.; Nograles, K.; Kim, B. S.; Lebwohl, M.. - In: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. - ISSN 0091-6749. - 152:4(2023), pp. 916-926. [10.1016/j.jaci.2023.06.023]
Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis
del Duca E.;
2023
Abstract
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, TH2-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 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). 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, TH2-associated genes, and skin barrier–related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted.File | Dimensione | Formato | |
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