Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis
Jennifer D Hamilton, Mayte Suárez-Fariñas, Nikhil Dhingra, Irma Cardinale, Xuan Li, Ana Kostic, Jeffrey E Ming, Allen R Radin, James G Krueger, Neil Graham, George D Yancopoulos, Gianluca Pirozzi, Emma Guttman-Yassky, Jennifer D Hamilton, Mayte Suárez-Fariñas, Nikhil Dhingra, Irma Cardinale, Xuan Li, Ana Kostic, Jeffrey E Ming, Allen R Radin, James G Krueger, Neil Graham, George D Yancopoulos, Gianluca Pirozzi, Emma Guttman-Yassky
Abstract
Background: Severe atopic dermatitis (AD) has a high unmet need for effective and safe therapeutics. In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor α, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized.
Objectives: We sought to evaluate dupilumab modulation of the AD molecular signature.
Methods: We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo.
Results: Exacerbation of the AD transcriptome was observed in placebo-treated patients. Dupilumab improved the AD signature in a dose-dependent manner. Expression of genes upregulated in AD lesions decreased in patients treated with dupilumab by 26% (95% CI, 21% to 32%) and 65% (95% CI, 60% to 71%) for treatment with 150 and 300 mg, respectively. Genes downregulated in AD lesions increased by 21% (95% CI, 16% to 27%) and 32% (95% CI, 26% to 37%) with dupilumab (150 and 300 mg, respectively). The molecular changes paralleled improvements in clinical scores. A dupilumab treatment signature of 821 probes (>2-fold change, P < .05) significantly modulated in the 300-mg dupilumab group at week 4 compared with baseline was identified in this sample set. Significant (P < .05) decreases in mRNA expression of genes related to hyperplasia (K16 and MKI67), T cells, and dendritic cells (CD1b and CD1c) and potent inhibition of TH2-associated chemokines (CCL17, CCL18, CCL22, and CCL26) were noted without significant modulation of TH1-associated genes (IFNG).
Conclusions: This is the first report showing rapid improvement of the AD molecular signature with targeted anti-IL-4 receptor α therapy. These data suggest that IL-4 and IL-13 drive a complex, TH2-centered inflammatory axis in patients with AD.
Trial registration: ClinicalTrials.gov NCT01259323 NCT01385657.
Keywords: Atopic dermatitis; IL-4 receptor α inhibition; T(H)2 axis; dupilumab; gene expression; skin; transcriptome.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed