Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.

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:

The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD.

• 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)
• 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

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)