Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis Jennifer D. Hamilton, PhD, Mayte Suárez-Fariñas,

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Presentation transcript:

Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis Jennifer D. Hamilton, PhD, Mayte Suárez-Fariñas, PhD, Nikhil Dhingra, BS, Irma Cardinale, MSc, Xuan Li, PhD, Ana Kostic, PhD, Jeffrey E. Ming, MD, PhD, Allen R. Radin, MD, James G. Krueger, MD, Neil Graham, MD, George D. Yancopoulos, MD, PhD, Gianluca Pirozzi, MD, PhD, Emma Guttman-Yassky, MD, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 6, Pages 1293-1300 (December 2014) DOI: 10.1016/j.jaci.2014.10.013 Copyright © 2014 The Authors Terms and Conditions

Fig 1 Clinical and molecular changes with dupilumab. A, Clinical responses (percentage change in EASI score) in the substudy were similar to parent trials. Bar plots represent means ± SEMs. B, Dose-dependent changes in the AD transcriptome with dupilumab (150/300 mg) versus placebo. Bar plots represent means ± SEMs. C, Transcriptomic differences between lesional and nonlesional skin showed dose-dependent decreases with dupilumab. Red indicates upregulated and blue indicates downregulated genes in the AD transcriptome (lesional vs nonlesional). Week 4 NLs were not available for the placebo group. Bar plots represent means ± SDs. P values of changes from baseline or between groups are listed. Journal of Allergy and Clinical Immunology 2014 134, 1293-1300DOI: (10.1016/j.jaci.2014.10.013) Copyright © 2014 The Authors Terms and Conditions

Fig 2 Pretreatment versus posttreatment gene expression profiles. A, Differentially expressed genes (DEG) with all treatments. B, Heat map of an immune gene subset. Upregulation of inflammatory genes characterizes lesional skin at baseline. Whereas inflammatory genes were strongly downregulated with 300 mg of dupilumab (red to blue transition in pretreatment vs posttreatment lesional samples), no changes were seen with placebo. Red indicates gene upregulation and blue indicates gene downregulation with treatment. Journal of Allergy and Clinical Immunology 2014 134, 1293-1300DOI: (10.1016/j.jaci.2014.10.013) Copyright © 2014 The Authors Terms and Conditions

Fig 3 A summary heat map of all quantitative RT-PCR mRNA expression changes with treatments. Dose-dependent inhibition of epidermal proliferation and inflammatory markers were observed in biopsy specimens from patients treated with 150 or 300 mg of dupilumab for 4 weeks compared with exacerbations with placebo. Values represent the mean fold change (FCH) ± SEM. *P < .1, **P < .05, and ***P < .01. Journal of Allergy and Clinical Immunology 2014 134, 1293-1300DOI: (10.1016/j.jaci.2014.10.013) Copyright © 2014 The Authors Terms and Conditions

Fig 4 Dupilumab (DPL)– and placebo-induced lesional skin changes in inflammatory and epidermal markers, as quantified by using qRT-PCR. Panels A through S show posttreatment versus pretreatment mRNA expression differences (fold change) of selected genes, as grouped by inflammatory pathway, in lesional skin at week 4 of treatment. Values represent means ± SEMs with posttreatment versus pretreatment P values compared with baseline. FCH, Fold change. Journal of Allergy and Clinical Immunology 2014 134, 1293-1300DOI: (10.1016/j.jaci.2014.10.013) Copyright © 2014 The Authors Terms and Conditions

Fig 5 Dose-dependent genomic changes were observed by using microarrays in previously defined immune pathways and epidermal gene subsets with dupilumab. Transcriptomic improvement refers to transition toward a noninflammatory molecular phenotype. Values represent means ± 95% CIs. Numbers in the bottom row represent the number of probes representing AD genes in each pathway. Detailed gene lists are provided in Table E5. Journal of Allergy and Clinical Immunology 2014 134, 1293-1300DOI: (10.1016/j.jaci.2014.10.013) Copyright © 2014 The Authors Terms and Conditions