Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis

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 TH 2-associated chemokines ( CCL17 , CCL18 , CCL22 , and CCL26 ) were noted without significant modulation of TH 1-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, TH 2-centered inflammatory axis in patients with AD.