Dupilumab progressively improves systemic and cutaneous abnormalities in atopic dermatitis patients

Publication date: Available online 5 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Emma Guttman-Yassky, Robert Bissonnette, Benjamin Ungar, Mayte Suárez-Fariñas, Marius Ardeleanu, Hitokazu Esaki, Maria Suprun, Yeriel Estrada, Hui Xu, Xiangyu Peng, Jonathan I. Silverberg, Alan Menter, James G. Krueger, Rick Zhang, Usman Chaudhry, Brian Swanson, Neil M.H. Graham, Gianluca Pirozzi, George D. Yancopoulos, Jennifer D.D. Hamilton

ABSTRACT

Background

Dupilumab is an IL-4Rα monoclonal antibody inhibiting signaling of IL-4/IL-13, key drivers of Type 2-driven inflammation, as demonstrated by its efficacy in atopic/allergic diseases.

Objective

This placebo-controlled, double-blind trial (NCT01979016) evaluated efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic Type 2 biomarkers of moderate-to-severe atopic dermatitis (AD) patients.

Methods

Skin biopsies and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous 200 mg dupilumab or placebo for 16 weeks.

Results

Dupilumab (versus placebo) significantly improved AD clinical signs and symptoms, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P<0.001). Dupilumab significantly reduced expression of genes involved in Type 2 inflammation (IL-13/IL-31/CCL17/CCL18/CCL26), epidermal hyperplasia (K16/MKi67), T-cells, dendritic cells (ICOS/CD11c/CTLA4), and Th17/Th22 activity (IL-17A/IL-22/S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid-metabolism genes (FLG/LOR/claudins/ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P=0.001; week 16, P=0.0002). Improvements in clinical and histological measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed Type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs.

Conclusion

Dupilumab-mediated inhibition of IL-4/IL-13 signaling via IL-4Rα blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of Type 2 inflammation, and reversed AD-associated epidermal abnormalities.

https://ift.tt/2PIpu34