Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor PF-06700841 Reveal Reduction of Skin Inflammation in Plaque Psoriasis.

Abstract

The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus kinase 1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus kinase 1 for signal transduction.

• Authors: Karen M Page, Mayte Suarez-Farinas, Maria Suprun, Weidong Zhang, Sandra Garcet, Judilyn Fuentes-Duculan, Xuan Li, Matthew Scaramozza, Elizabeth Kieras, Christopher Banfield, James D Clark, Andrew Fensome, James G Krueger, Elena Peeva
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 140 Issue 8 Pg. 1546-1555.e4 (08 2020) ISSN: 1523-1747 [Electronic] United States
• PMID: 31972249 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• IL12B protein, human
• IL17A protein, human
• IL17F protein, human
• Interleukin-12 Subunit p40
• Interleukin-17
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• PF-06700841
• JAK1 protein, human
• Janus Kinase 1
• TYK2 Kinase
• TYK2 protein, human

Topics

• Adult
• Biopsy
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Humans
• Interleukin-12 Subunit p40 (metabolism)
• Interleukin-17 (metabolism)
• Janus Kinase 1 (antagonists & inhibitors, metabolism)
• Male
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage, adverse effects)
• Psoriasis (drug therapy, immunology, pathology)
• Pyrazoles (administration & dosage, adverse effects)
• Pyrimidines (administration & dosage, adverse effects)
• Signal Transduction (drug effects, immunology)
• Skin (drug effects, immunology, pathology)
• TYK2 Kinase (antagonists & inhibitors, metabolism)
• Th17 Cells (drug effects, immunology)
• Treatment Outcome
• Young Adult