Spleen tyrosine kinase inhibition ameliorates airway inflammation through modulation of NLRP3 inflammosome and Th17/Treg axis

Patel, Divyesh; Gaikwad, Sagar; Challagundla, Naveen; Nivsarkar, Manish; Agrawal-Rajput, Reena

doi:10.1016/j.intimp.2017.11.026

Cited by 38 publications

(22 citation statements)

References 46 publications

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“…[33][34][35][36][37][38][39][40][41] In mice SYK inhibition was shown to inhibit T H 17 pathway signaling and improve terminal epidermal differentiation. [41][42][43] Thus dual JAK-SYK inhibition might broaden the range of cytokines targeted to successfully resolve AD across the different disease subtypes. 9,10,12,21,[44][45][46][47][48] ASN002 is the first oral dual JAK/SYK inhibitor tested in patients with AD.…”

Section: Abbreviations Usedmentioning

confidence: 99%

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

Pavel

Song

Kim

et al. 2019

Journal of Allergy and Clinical Immunology

103

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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.

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Section: Abbreviations Usedmentioning

confidence: 99%

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

Pavel

Song

Kim

et al. 2019

Journal of Allergy and Clinical Immunology

103

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“…Spleen tyrosine kinases (SYKs) are involved in the release of cytokines during the proinflammatory process, including IL-1b, IL-10 and IL-17, and regulate DCs, B lymphocytes and keratinocyte differentiation, suggesting that SYK inhibitors could improve inflammatory skin diseases with aberrant differentiation, such as AD [78,79]. ASN002 is a potent, dual inhibitor of JAK and SYK kinases [47].…”

Section: Upadacitinib Baricitinib and Asn002: Jak Inhibitorsmentioning

confidence: 99%

Novel topical and systemic therapies in atopic dermatitis

Suga

Sato

2019

Immunological Medicine

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Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD.

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“…For example, Th17 activation has been shown to be higher in children and Asian patients . SYK is involved in several cytokine signalling pathways, including the Th17 pathway . It induces the production of CCL20, which attracts Th17 cells to the skin .…”

Section: Discussionmentioning

confidence: 99%

“…Spleen tyrosine kinase (SYK) and Janus kinase (JAK) are tyrosine kinases (TYKs) that play important roles in inflammatory processes . SYK is involved in the release of cytokines during the proinflammatory process, including IL‐1β, IL‐10 and IL‐17, and regulates dendritic cells, B lymphocytes and keratinocyte differentiation, suggesting that SYK inhibitors could improve inflammatory skin diseases with aberrant differentiation, such as AD . The JAK kinases family (JAK1, JAK2, JAK3 and TYK2) is also involved in signalling pathways of several cytokines involved in AD, such as IL‐4, IL‐13, IL‐31 and IL‐33 .…”

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confidence: 99%

The oral Janus kinase/spleen tyrosine kinase inhibitorASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate‐to‐severe atopic dermatitis: results from a randomized double‐blind placebo‐controlled study

Bissonnette

Maari

Forman³

et al. 2019

Br J Dermatol

104

105

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SummaryBackground ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways.ObjectivesThe objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate‐to‐severe AD. Methods A total of 36 patients with moderate‐to‐severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28‑day period (20 mg, 40 mg and 80 mg once daily).Results ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg −1·3 ± 2·1, P = 0·81; 40 mg −3·1 ± 2·7, P = 0·27; 80 mg −4·7 ± 2·1, P = 0·01; placebo −1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose‐dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis‐associated biomarker E selectin/SELE.ConclusionsIn patients with moderate‐to‐severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

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Spleen tyrosine kinase inhibition ameliorates airway inflammation through modulation of NLRP3 inflammosome and Th17/Treg axis

Cited by 38 publications

References 46 publications

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

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

Novel topical and systemic therapies in atopic dermatitis

The oral Janus kinase/spleen tyrosine kinase inhibitorASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate‐to‐severe atopic dermatitis: results from a randomized double‐blind placebo‐controlled study

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