{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:23:08Z","timestamp":1792714988936,"version":"4.5.0"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T00:00:00Z","timestamp":1710979200000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004326","name":"Bayer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004326","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>This study evaluated and characterized the pharmacological activity of the orally administered interleukin\u20101 receptor\u2010associated 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\u2009mg or placebo) twice daily for 7\u2009days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3\u2009days, 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\u2009ng\/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\u2010induced skin perfusion response (geometric mean ratio [GMR] vs. placebo: 0.69 for BAY1834845, 0.70 for prednisolone; both <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Treatment with BAY1834845 and BAY1830839 significantly reduced IMQ\u2010induced erythema (GMR vs. placebo: 0.75 and 0.83, respectively, both <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; 0.86 for prednisolone, not significant). Both IRAK4 inhibitors significantly suppressed the serum TNF\u2010\u03b1 and IL\u20106 responses (\u226580% suppression vs. placebo, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and inhibited C\u2010reactive protein, procalcitonin, and IL\u20108 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\u2010mediated inflammatory diseases.<\/jats:p>","DOI":"10.1111\/cts.13771","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T10:42:15Z","timestamp":1711017735000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The oral <scp>IRAK4<\/scp> inhibitors zabedosertib and <scp>BAY1830839<\/scp> suppress local and systemic immune responses in a randomized trial in healthy male volunteers"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4268-3588","authenticated-orcid":false,"given":"Stefan J.","family":"Jodl","sequence":"first","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7241-2889","authenticated-orcid":false,"given":"Wouter","family":"ten Voorde","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Klein","sequence":"additional","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9648-4318","authenticated-orcid":false,"given":"Andrea","family":"Wagenfeld","sequence":"additional","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank S.","family":"Zollmann","sequence":"additional","affiliation":[{"name":"Pharma Consult  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4316-2398","authenticated-orcid":false,"given":"Maximilian","family":"Feldm\u00fcller","sequence":"additional","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi B.","family":"Klarenbeek","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Digna T.","family":"de Bruin","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-1807","authenticated-orcid":false,"given":"Manon A. A.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5867-9090","authenticated-orcid":false,"given":"Robert","family":"Rissmann","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden Academic Centre for Drug Research  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Rohde","sequence":"additional","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthijs","family":"Moerland","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151074"},{"key":"e_1_2_10_3_1","first-page":"S459","article-title":"Identification of highly potent and selective interleukin\u20101 receptor\u2010associated kinase 4 inhibitors for the treatment of rheumatic diseases. Poster presented at 76th annual meeting of the American College of Rheumatology","volume":"64","author":"Chaudhary D","year":"2012","journal-title":"Arthritis Rheum"},{"issue":"10","key":"e_1_2_10_4_1","first-page":"2909","article-title":"Efficacy and safety of the selective interleukin\u20101 receptor associated kinase 4 inhibitor, PF\u201006650833, in patients with active rheumatoid arthritis and inadequate response to methotrexate","volume":"71","author":"Danto S","year":"2019","journal-title":"Arthritis Rheum"},{"key":"e_1_2_10_5_1","unstructured":"ClinicalTrials.gov NCT04772885.A single and multiple ascending dose trial of KT\u2010474 in healthy adult volunteers and patients with atopic dermatitis (AD) or hidradenitis suppurativa (HS).2021. 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