{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:02:47Z","timestamp":1790960567747,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T00:00:00Z","timestamp":1674000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acad Dermatol Venereol"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>There remains an unmet need for oral medications that are safe and efficacious for long\u2010term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro\u2010inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The objective of this study was to examine the PDE4 enzymatic activity and anti\u2010inflammatory effects of orismilast in vitro<jats:italic>,<\/jats:italic> ex vivo<jats:italic>,<\/jats:italic> and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The PDE1\u201011 enzymatic activity of orismilast was tested in vitro using a single concentration of 308\u2009nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone\u2010induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor \u03b1 (TNF\u03b1), and the secretion of T\u2010helper (Th)1 (TNF\u03b1 and IFN\u03b3), Th17 (IL\u201022 and IL\u201023), and Th2 (IL\u20104, IL\u20105, and IL\u201013) related cytokines in PBMC. In vivo<jats:italic>,<\/jats:italic> 10 and 30\u2009mg\/kg doses of orismilast significantly reduced ear thickness and inflammation markers (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Orismilast displayed selective and potent PDE4 inhibition and broad\u2010spectrum anti\u2010inflammatory activity in several pre\u2010clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdv.18818","type":"journal-article","created":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T13:18:25Z","timestamp":1671283105000},"page":"721-729","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Pharmacology of orismilast, a potent and selective PDE4 inhibitor"],"prefix":"10.1111","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3686-7805","authenticated-orcid":false,"given":"Jonathan I.","family":"Silverberg","sequence":"first","affiliation":[{"name":"George Washington University School of Medicine and Health Sciences  District of Columbia Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4629-1486","authenticated-orcid":false,"given":"Lars E.","family":"French","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University (LMU) Munich, Munich, Germany. Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine  Florida Miami USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard B.","family":"Warren","sequence":"additional","affiliation":[{"name":"Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8394-2057","authenticated-orcid":false,"given":"Bruce","family":"Strober","sequence":"additional","affiliation":[{"name":"Yale University and Central Connecticut Dermatology  Connecticut Cromwell USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Kj\u00f8ller","sequence":"additional","affiliation":[{"name":"UNION therapeutics, A\/S  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten O. A.","family":"Sommer","sequence":"additional","affiliation":[{"name":"UNION therapeutics, A\/S  Hellerup Denmark"},{"name":"Novo Nordisk Foundation Center for Biosustainability Technical University of Denmark (DTU)  Kongens Lyngby Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Andres","sequence":"additional","affiliation":[{"name":"UNION therapeutics, A\/S  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Felding","sequence":"additional","affiliation":[{"name":"UNION therapeutics, A\/S  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Weiss","sequence":"additional","affiliation":[{"name":"UNION therapeutics, A\/S  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9390-6105","authenticated-orcid":false,"given":"Deniz","family":"Tutkunkardas","sequence":"additional","affiliation":[{"name":"UNION therapeutics, A\/S  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tine","family":"Skak\u2010Nielsen","sequence":"additional","affiliation":[{"name":"LEO Pharma A\/S  Ballerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9363-324X","authenticated-orcid":false,"given":"Emma","family":"Guttman","sequence":"additional","affiliation":[{"name":"Department of Dermatology Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2021.2007"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2018.08.028"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/2040622319830646"},{"issue":"12","key":"e_1_2_9_5_1","first-page":"28","article-title":"New and emerging topical therapies for psoriasis and atopic dermatitis","volume":"12","author":"Psomadakis CE","year":"2019","journal-title":"J Clin Aesthet Dermatol"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/09546634.2020.1729335"},{"issue":"4","key":"e_1_2_9_7_1","first-page":"189","article-title":"Manifestations and management of difficult\u2010to\u2010treat psoriasis","volume":"10","author":"Aldredge LM","year":"2018","journal-title":"JDNA"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13555-020-00409-4"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a005926"},{"issue":"1","key":"e_1_2_9_10_1","first-page":"1000326","article-title":"Cyclic adenosine monophosphate signalling in inflammatory skin disease","volume":"7","author":"Levy J","year":"2016","journal-title":"J Clin Exp Dermatol Res"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0121725"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.8.4820"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2016.01.007"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612823666170214105651"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/archdermatol.2012.812"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2014.12.014"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19103086"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-019-00284-1"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2000073"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2015.03.049"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S89849"},{"issue":"2","key":"e_1_2_9_22_1","first-page":"4","article-title":"Crisaborole 2% ointment (Eucrisa) for atopic dermatitis","volume":"24","author":"Woo TE","year":"2019","journal-title":"Skin Therapy Lett"},{"key":"e_1_2_9_23_1","volume-title":"FDA approves Otezla (Apremilast) for the treatment of adult patients with plaque psoriasis, regardless of severity level","author":"PR Newswire","year":"2021"},{"key":"e_1_2_9_24_1","first-page":"147","article-title":"Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD","volume":"4","author":"Giembycz MA","year":"2010","journal-title":"Drug dDes Devel Ther"},{"key":"e_1_2_9_25_1","unstructured":"GlobeNewswire.FDA Approves Arcutis' ZORYVE\u2122 (Roflumilast) Cream 0.3% For the Treatment of Plaque Psoriasis in Individuals Age 12 and Older. Available from:https:\/\/www.globenewswire.com\/news\u2010release\/2022\/07\/29\/2488966\/0\/en\/FDA\u2010Approves\u2010Arcutis\u2010ZORYVE\u2010Roflumilast\u2010Cream\u20100\u20103\u2010For\u2010the\u2010Treatment\u2010of\u2010Plaque\u2010Psoriasis\u2010in\u2010Individuals\u2010Age\u201012\u2010and\u2010Older.html"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01048"},{"key":"e_1_2_9_27_1","unstructured":"ClinicalTrials.gov. Identifier NCT02496546 An Explorative Trial Evaluating the Effect of LEO 32731 Cream in Adults With Mild to Moderate Atopic Dermatitis (AD).2017."},{"key":"e_1_2_9_28_1","unstructured":"ClinicalTrials.gov. Identifier: NCT04982432 Orismilast for the Treatment of Mild to Severe Hidradenitis Suppurativa (OSIRIS)2021."},{"key":"e_1_2_9_29_1","unstructured":"ClinicalTrials.gov. Study to Assess the Efficacy and Safety of Orismilast in Psoriasis (IASOS).2022."},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00778a018"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.06.047"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2014.05.014"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2019.09.003"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevEukarGeneExpr.v20.i2.10"},{"key":"e_1_2_9_35_1","unstructured":"Otelza [package insert].Celgene Corporation summit (NJ): Celgene Corporation;2019."},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00266-6"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14451"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.08.029"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2015.09.001"}],"container-title":["Journal of the European Academy of Dermatology and Venereology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jdv.18818","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jdv.18818","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jdv.18818","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T12:11:55Z","timestamp":1695211915000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jdv.18818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,18]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1111\/jdv.18818"],"URL":"https:\/\/doi.org\/10.1111\/jdv.18818","archive":["Portico"],"relation":{},"ISSN":["0926-9959","1468-3083"],"issn-type":[{"value":"0926-9959","type":"print"},{"value":"1468-3083","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,18]]},"assertion":[{"value":"2022-08-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}