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J Allergy Clin Immunol. 2019 Jul 26. pii: S0091-6749(19)30961-3. doi: 10.1016/j.jaci.2019.07.013. [Epub ahead of print]

Oral JAK/SYK-inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in atopic dermatitis.

Author information

1
Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
3
Asana Biosciences, Princeton, New Jersey, USA.
4
Innovaderm Research, Montreal, Canada.
5
Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 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 JAK/SYK signaling pathways, targeting several cytokine axes (Th2/Th22/Th17/Th1) and epidermal differentiation.

OBJECTIVE:

To evaluate the effect of ASN002 on 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:

36 patients with moderate-to-severe AD were randomized to dose escalation of ASN002 20mg, 40mg, 80mg, and placebo groups. Skin biopsies were performed at baseline, day15, and day29. Gene expression studies were conducted using microarray and qRT-PCR, and cellular infiltrates and protein expression were studied by immunohistochemistry.

RESULTS:

ASN002 reversed the lesional skin transcriptome towards a non-lesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including Th2 (IL4R, IL-13, CCL13/MCP-4, CCL17/TARC, CCL18/PARC, CCL22/MDC, CCL26/Eotaxin-3), Th17/Th22 (LCN, PI3/elafin, CCL20, S100A7/S100A8/S100A9, IL36G/IL36RN), Th1 (IFN-γ, CXCL9/ CXCL11, MX1) axes and barrier-related measures (FLG, CLDN23). Significant improvements in AD gene-signatures were observed predominantly in the 40mg and 80mg groups. Smaller and largely non-significant molecular changes were seen in the 20mg group or placebo.

CONCLUSION:

The JAK/SYK inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 may be an effective novel therapeutic agent for moderate-to-severe AD.

KEYWORDS:

ASN002; Atopic dermatitis; JAK; JAK inhibitors; SYK; SYK inhibitors; Th17; Th2; Th22; barrier; tyrosine kinase

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

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