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 JC, Rothenberg-Lausell C, Del Duca E, David E, Estrada Y, Liu Y, Bose S, Chowdhury M, Munera C, Goncalves J, Nograles K, Kim BS, Lebwohl M

The Journal of allergy and clinical immunology13 Jul 2023Cited by 19 (Europe PMC)

PMID37453614DOI10.1016/j.jaci.2023.06.023PepBankPUB-37453614

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Summary

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, T_H2-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 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).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, T_H2-associated genes, and skin barrier-related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study12

12 results from studies that gave the peptide. 10 results from people.

01HumanNon-randomized trialEfficacy outcome
In subjects with AD-related pruritus, difelikefalin 0.25 mg reduced itch versus placebo without statistical significance at week 12.
In plain wordsIn subjects with dermatitis, difelikefalin 0.25 mg reduced itch versus placebo without statistical significance at week 12.
Peptide
Difelikefalin
Outcome
No significant changeItch intensity at week 12
Study
n = 401
Comparator
Placebo
Outcome group
Skin and hair · Skin and wound
Studied dose
0.25 mg · oral · 12 weeksAs given in this study (human).
Source sentences
Summary
In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361401
02HumanNon-randomized trialEfficacy outcome
In subjects with AD-related pruritus, difelikefalin 0.5 mg reduced itch versus placebo without statistical significance at week 12.
In plain wordsIn subjects with dermatitis, difelikefalin 0.5 mg reduced itch versus placebo without statistical significance at week 12.
Peptide
Difelikefalin
Outcome
No significant changeItch intensity at week 12
Study
n = 401
Comparator
Placebo
Outcome group
Skin and hair · Skin and wound
Studied dose
0.5 mg · oral · 12 weeksAs given in this study (human).
Source sentences
Summary
In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361402
03HumanNon-randomized trialEfficacy outcome
In subjects with AD-related pruritus, difelikefalin 1.0 mg reduced itch versus placebo without statistical significance at week 12.
In plain wordsIn subjects with dermatitis, difelikefalin 1.0 mg reduced itch versus placebo without statistical significance at week 12.
Peptide
Difelikefalin
Outcome
No significant changeItch intensity at week 12
Study
n = 401
Comparator
Placebo
Outcome group
Skin and hair · Skin and wound
Studied dose
1.0 mg · oral · 12 weeksAs given in this study (human).
Source sentences
Summary
In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361403
04HumanNon-randomized trialEfficacy outcome
In the itch-dominant AD subgroup, difelikefalin reduced itch at week 12 versus placebo.
In plain wordsIn subjects with itch-dominant dermatitis, difelikefalin reduced itch at week 12 versus placebo.
Peptide
Difelikefalin
Outcome
DecreaseItch in itch-dominant phenotype
Study
n: not reported in source
Comparator
Placebo
Outcome group
Skin and hair · Skin and wound
Studied dose
Dose not stated · oral · 12 weeksAs given in this study (human).
Source sentences
Summary
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.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361404
05HumanNon-randomized trialMechanism
In the AD biomarker substudy, difelikefalin reduced expression of the pruritus-related gene IL-31.
In plain wordsIn subjects with dermatitis, difelikefalin reduced expression of the itch-related gene IL-31.
Peptide
Difelikefalin
Outcome
DecreaseIL-31 expression
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Skin and wound
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (eg, IL-31 and TRPV1) and the AD phenotype (eg, CCL17).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361405
06HumanNon-randomized trialMechanism
In the AD biomarker substudy, difelikefalin reduced expression of the pruritus-related gene TRPV1.
In plain wordsIn subjects with dermatitis, difelikefalin reduced expression of the itch-related gene TRPV1.
Peptide
Difelikefalin
Outcome
DecreaseTRPV1 expression
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Skin and wound
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (eg, IL-31 and TRPV1) and the AD phenotype (eg, CCL17).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361406
07HumanNon-randomized trialMechanism
In the AD biomarker substudy, difelikefalin reduced expression of the AD phenotype-associated gene CCL17.
In plain wordsIn subjects with dermatitis, difelikefalin reduced expression of the dermatitis-associated gene CCL17.
Peptide
Difelikefalin
Outcome
DecreaseCCL17 expression
Study
n: not reported in source
Outcome group
Inflammation markers · Skin and wound
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (eg, IL-31 and TRPV1) and the AD phenotype (eg, CCL17).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361407
08HumanNon-randomized trialMechanism
In the AD biomarker substudy, difelikefalin improved skin barrier integrity markers.
In plain wordsIn subjects with dermatitis, difelikefalin improved markers of skin barrier integrity.
Peptide
Difelikefalin
Outcome
Direction not reportedSkin barrier integrity markers
Study
n: not reported in source
Outcome group
Skin and hair · Skin and wound
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism-associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361410
09HumanNon-randomized trialMechanism
In the AD biomarker substudy, difelikefalin increased claudin expression.
In plain wordsIn subjects with dermatitis, difelikefalin increased claudin expression.
Peptide
Difelikefalin
Outcome
IncreaseClaudin expression
Study
n: not reported in source
Outcome group
Skin and hair · Skin and wound
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism-associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361411
10HumanNon-randomized trialMechanism
In the AD biomarker substudy, difelikefalin increased lipid metabolism-associated gene expression, including SEC14L6, ELOVL3, CYP1A2, and AKR1D1.
In plain wordsIn subjects with dermatitis, difelikefalin increased expression of genes associated with lipid metabolism.
Peptide
Difelikefalin
Outcome
IncreaseLipid metabolism-associated gene expression
Study
n: not reported in source
Outcome group
Skin and hair · Skin and wound
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism-associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361412
11Computer modelIn silicoMechanism
In the AD biomarker substudy, gene set analysis showed that difelikefalin, but not placebo, reduced pruritus-related gene expression.
In plain wordsIn subjects with dermatitis, difelikefalin reduced itch-related gene expression, whereas placebo did not.
Peptide
Difelikefalin
Outcome
DecreasePruritus-related gene set
Study
n: not reported in source
Gene set variation analysis
Comparator
Placebo
Outcome group
Receptor activity and mechanism · Skin and wound
Studied dose
Dose not stated
Source sentences
Summary
Gene set variation analysis confirmed that DFK, but not placebo, downregulated pruritus-related genes and T_H2 pathways.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361408
12Computer modelIn silicoMechanism
In the AD biomarker substudy, gene set analysis showed that difelikefalin, but not placebo, downregulated TH2 pathways.
In plain wordsIn subjects with dermatitis, difelikefalin reduced TH2 pathway activity, whereas placebo did not.
Peptide
Difelikefalin
Outcome
DecreaseTH2 pathways
Study
n: not reported in source
Gene set variation analysis
Comparator
Placebo
Outcome group
Immune response · Skin and wound
Studied dose
Dose not stated
Source sentences
Summary
Gene set variation analysis confirmed that DFK, but not placebo, downregulated pruritus-related genes and T_H2 pathways.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T_H2-associated genes, and skin barrier-related genes.
Show in the study text Report a problemFND-3745361409

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
28 Oct 2026, 02:03 UTC
Study results updated
Version 1
27 Oct 2026, 16:35 UTC
First added · source update from Europe PMC

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