TY - JOUR
T1 - Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis
AU - Pavel, Ana B.
AU - Song, Teresa
AU - Kim, Hyun Je
AU - Del Duca, Ester
AU - Krueger, James G.
AU - Dubin, Celina
AU - Peng, Xiangyu
AU - Xu, Hui
AU - Zhang, Ning
AU - Estrada, Yeriel D.
AU - Denis, Louis
AU - Rao, Niranjan
AU - Gupta, Sandeep
AU - Zammit, David J.
AU - Bissonnette, Robert
AU - Guttman-Yassky, Emma
N1 - Funding Information:
Disclosure of potential conflict of interest: A. B. Pavel, H. J. Kim, E. Del Duca, X. Peng, H. Xu, N. Zhang, and Y. D. Estrada are employees of Mount Sinai. L. Denis, N. Rao, S. Gupta, and D. J. Zammit are employees of Asana BioSciences. J. G. Krueger has received research support from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. R. Bissonnette is an investigator, consultant, advisory board member, speaker for, and/or receives honoraria from Abbvie, Aquinox Pharma, AntibioTx, Asana BioSciences, Astellas, Boehringer Ingelheim, Brickell Biotech, Eli Lilly, Dermavant, Dermira, Dignity Sciences, Galderma, Glenmark, GSK Stiefel, Hoffman LaRoche Posay, Kiniksa, Leo Pharma, Neokera, Pfizer, Regeneron, Ralexar, Sanofi, Sienna, and Vitae and is an employee and shareholder of Innovaderm Research. E. Guttman-Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from Abbvie , Celgene , Eli Lilly , Janssen , MedImmune / AstraZeneca , Novartis , Pfizer , Regeneron , Vitae , Glenmark , Galderma , Asana , Innovaderm , Dermira , and UCB and is a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. The rest of the authors declare that they have no relevant conflicts of interest.
Funding Information:
This study was funded by Asana BioSciences .
Funding Information:
This study was funded by Asana BioSciences.Disclosure of potential conflict of interest: A. B. Pavel, H. J. Kim, E. Del Duca, X. Peng, H. Xu, N. Zhang, and Y. D. Estrada are employees of Mount Sinai. L. Denis, N. Rao, S. Gupta, and D. J. Zammit are employees of Asana BioSciences. J. G. Krueger has received research support from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. R. Bissonnette is an investigator, consultant, advisory board member, speaker for, and/or receives honoraria from Abbvie, Aquinox Pharma, AntibioTx, Asana BioSciences, Astellas, Boehringer Ingelheim, Brickell Biotech, Eli Lilly, Dermavant, Dermira, Dignity Sciences, Galderma, Glenmark, GSK Stiefel, Hoffman LaRoche Posay, Kiniksa, Leo Pharma, Neokera, Pfizer, Regeneron, Ralexar, Sanofi, Sienna, and Vitae and is an employee and shareholder of Innovaderm Research. E. Guttman-Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from Abbvie, Celgene, Eli Lilly, Janssen, MedImmune/AstraZeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB and is a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. The rest of the authors declare that they have no relevant conflicts of interest.
Publisher Copyright:
© 2019 American Academy of Allergy, Asthma & Immunology
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
KW - ASN002
KW - Atopic dermatitis
KW - Janus kinase
KW - Janus kinase inhibitors
KW - T17
KW - T2
KW - T22
KW - barrier
KW - spleen tyrosine kinase
KW - spleen tyrosine kinase inhibitors
KW - tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=85071072223&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2019.07.013
DO - 10.1016/j.jaci.2019.07.013
M3 - Article
C2 - 31356921
AN - SCOPUS:85071072223
SN - 0091-6749
VL - 144
SP - 1011
EP - 1024
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 4
ER -