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J Allergy Clin Immunol. 2019 Oct;144(4):1011-1024. doi: 10.1016/j.jaci.2019.07.013. Epub 2019 Jul 26.

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

Author information

1
Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY.
2
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
3
Asana Biosciences, Princeton, NJ.
4
Innovaderm Research, Montreal, Quebec, Canada.
5
Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: emma.guttman@mountsinai.org.

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.

KEYWORDS:

ASN002; Atopic dermatitis; Janus kinase; Janus kinase inhibitors; T(H)17; T(H)2; T(H)22; barrier; spleen tyrosine kinase; spleen tyrosine kinase inhibitors; tyrosine kinase

PMID:
31356921
DOI:
10.1016/j.jaci.2019.07.013

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