The oral IRAK4 inhibitors zabedosertib and BAY1830839 suppress local and systemic immune responses in a randomized trial in healthy male volunteers
© 2024 Bayer AG and Centre for Human Drug Research. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics..
This study evaluated and characterized the pharmacological activity of the orally administered interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors BAY1834845 (zabedosertib) and BAY1830839 in healthy male volunteers. Participants received one of either IRAK4 inhibitors or a control treatment (prednisolone 20 mg or placebo) twice daily for 7 days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment. The inflammatory response was evaluated by laser speckle contrast imaging (skin perfusion) and multispectral imaging (erythema). At Day 7, participants received 1 ng/kg intravenous lipopolysaccharide (LPS). Circulating inflammatory proteins, leukocyte differentiation, acute phase proteins, and clinical parameters were evaluated before and after the systemic LPS challenge. Treatment with BAY1834845 significantly reduced the mean IMQ-induced skin perfusion response (geometric mean ratio [GMR] vs. placebo: 0.69 for BAY1834845, 0.70 for prednisolone; both p < 0.05). Treatment with BAY1834845 and BAY1830839 significantly reduced IMQ-induced erythema (GMR vs. placebo: 0.75 and 0.83, respectively, both p < 0.05; 0.86 for prednisolone, not significant). Both IRAK4 inhibitors significantly suppressed the serum TNF-α and IL-6 responses (≥80% suppression vs. placebo, p < 0.05) and inhibited C-reactive protein, procalcitonin, and IL-8 responses to intravenous LPS. This study demonstrated the pharmacological effectiveness of BAY1834845 and BAY1830839 in suppressing systemically and locally induced inflammatory responses in the same range as prednisolone, underlining the potential value of these IRAK4 inhibitors as future therapies for dermatological or other immune-mediated inflammatory diseases.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Clinical and translational science - 17(2024), 3 vom: 18. März, Seite e13771 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jodl, Stefan J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 17.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1111/cts.13771 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Jodl, Stefan J |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The oral IRAK4 inhibitors zabedosertib and BAY1830839 suppress local and systemic immune responses in a randomized trial in healthy male volunteers |
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| 520 | |a © 2024 Bayer AG and Centre for Human Drug Research. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. | ||
| 520 | |a This study evaluated and characterized the pharmacological activity of the orally administered interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors BAY1834845 (zabedosertib) and BAY1830839 in healthy male volunteers. Participants received one of either IRAK4 inhibitors or a control treatment (prednisolone 20 mg or placebo) twice daily for 7 days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment. The inflammatory response was evaluated by laser speckle contrast imaging (skin perfusion) and multispectral imaging (erythema). At Day 7, participants received 1 ng/kg intravenous lipopolysaccharide (LPS). Circulating inflammatory proteins, leukocyte differentiation, acute phase proteins, and clinical parameters were evaluated before and after the systemic LPS challenge. Treatment with BAY1834845 significantly reduced the mean IMQ-induced skin perfusion response (geometric mean ratio [GMR] vs. placebo: 0.69 for BAY1834845, 0.70 for prednisolone; both p < 0.05). Treatment with BAY1834845 and BAY1830839 significantly reduced IMQ-induced erythema (GMR vs. placebo: 0.75 and 0.83, respectively, both p < 0.05; 0.86 for prednisolone, not significant). Both IRAK4 inhibitors significantly suppressed the serum TNF-α and IL-6 responses (≥80% suppression vs. placebo, p < 0.05) and inhibited C-reactive protein, procalcitonin, and IL-8 responses to intravenous LPS. This study demonstrated the pharmacological effectiveness of BAY1834845 and BAY1830839 in suppressing systemically and locally induced inflammatory responses in the same range as prednisolone, underlining the potential value of these IRAK4 inhibitors as future therapies for dermatological or other immune-mediated inflammatory diseases | ||
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| 700 | 1 | |a Rohde, Beate |e verfasserin |4 aut | |
| 700 | 1 | |a Moerland, Matthijs |e verfasserin |4 aut | |
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