Abstract | BACKGROUND: Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/ spleen tyrosine kinase signaling pathways, targeting several cytokine axes (TH2/TH22/TH17/TH1) and epidermal differentiation. OBJECTIVE: We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus. METHODS: Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry. RESULTS:
ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including TH2 ( IL4 receptor [IL4R], IL13, CCL13/ monocyte chemoattractant protein 4, CCL17/ thymus and activation-regulated chemokine, CCL18/ pulmonary and activation-regulated chemokine, CCL22/ macrophage-derived chemokine, and CCL26/ eotaxin-3), TH17/TH22 ( lipocalins, PI3/ elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and TH1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrier-related measures ( filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. CONCLUSION:
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Authors | Ana B Pavel, Teresa Song, Hyun-Je Kim, Ester Del Duca, James G Krueger, Celina Dubin, Xiangyu Peng, Hui Xu, Ning Zhang, Yeriel D Estrada, Louis Denis, Niranjan Rao, Sandeep Gupta, David J Zammit, Robert Bissonnette, Emma Guttman-Yassky |
Journal | The Journal of allergy and clinical immunology
(J Allergy Clin Immunol)
Vol. 144
Issue 4
Pg. 1011-1024
(10 2019)
ISSN: 1097-6825 [Electronic] United States |
PMID | 31356921
(Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved. |
Chemical References |
- Acetonitriles
- Anti-Inflammatory Agents
- Biomarkers
- Enzyme Inhibitors
- FLG protein, human
- Filaggrin Proteins
- Piperidines
- Pyridazines
- gusacitinib
- Janus Kinases
- SYK protein, human
- Syk Kinase
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Topics |
- Acetonitriles
(therapeutic use)
- Adult
- Anti-Inflammatory Agents
(therapeutic use)
- Biomarkers
(metabolism)
- Dermatitis, Atopic
(drug therapy, pathology)
- Double-Blind Method
- Enzyme Inhibitors
(therapeutic use)
- Epidermis
(drug effects, pathology)
- Female
- Filaggrin Proteins
- Humans
- Inflammation
(drug therapy, pathology)
- Janus Kinases
(antagonists & inhibitors)
- Male
- Middle Aged
- Piperidines
(therapeutic use)
- Pyridazines
(therapeutic use)
- Syk Kinase
(antagonists & inhibitors)
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