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 (T H 2/T H 22/T H 17/T H 1) 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 T H 2 (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), T H 17/T H 22 (lipocalins, PI3/ elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and T H 1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrierrelated 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.

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…Additionally, IL31 expression was reduced more efficiently by the dual inhibition approach than that seen in dupilumab treatment. Although recent approaches using pan-JAK inhibition in psoriasis were without a major patient health improvement, this multitarget approach might be worth testing, as Th17 signaling may be targeted more robustly [241]. AD is classically not a Th17 centered disease like psoriasis, but a latent activation of accompanying pathways is seen in disease development [242].…”

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation

“…Because c-Jun N-terminal kinase (JNK) and spleen tyrosine kinase (SYK) play important roles in AD pathogenesis [ 39 , 40 , 41 , 42 ], we further tested whether CA-PH also inhibits their activity. CA-PH did not inhibit the activity of JNK and minimally inhibited the activity of SYK ( Supplemental Figure S1 ).…”

“…In particular, SYK has been investigated as a therapeutic target of skin inflammatory diseases such as AD [ 71 , 72 , 73 , 74 ]. ASN002, an oral dual JAK/SYK inhibitor, suppressed moderate to severe AD phenotypes in early clinical trials [ 41 , 42 ]. ASN002 reversed a lesional skin transcriptome toward a non-lesional phenotype [ 48 ].…”

“…ASN002 reversed a lesional skin transcriptome toward a non-lesional phenotype [ 48 ]. It also suppressed key inflammatory pathways related to AD pathogenesis, such as T H 2, T H 17/T H 22, and T H 1 axis [ 41 ]. In addition, polydatin (3, 4′, 5-trihydroxystilbene-3-β-mono-D-glucoside), a natural component extracted from Polygonum cuspidatum , directly inhibited activity of SYK and suppressed pro-inflammatory cytokine expression in mast cells [ 75 ].…”

<p>Emerging Role of Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis</p>

“…6,26 SYK aids in releasing cytokines IL-1B, IL-10, and IL-17 and impacts differentiation and proliferation of dendritic cells, keratinocytes, and B-lymphocytes. 28 JAK1 and JAK3 receptors modulate the pathway for cytokines IL-2 and IL-4 via phosphorylation of STAT3, STAT5, and STAT6. 6 IL-4 is a key player in antibody class switching and potentiates T helper type 2 (Th2) cell differentiation, stimulating the release of additional cytokines.…”