{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T07:04:22Z","timestamp":1768892662049,"version":"3.49.0"},"reference-count":24,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T00:00:00Z","timestamp":1613174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","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":[[2021,5]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>LY2775240 is a highly selective, potent and orally\u2010administered inhibitor of phosphodiesterase 4 (PDE4), and is being investigated as a treatment option for inflammatory disorders, such as psoriasis. LY2775240 was investigated in rodent and rhesus monkey nonclinical models. Treatment with LY2775240 led to significant reductions in TNF\u03b1 production, a marker of PDE4 engagement upon immune activation, in both nonclinical models. In the first part of a 2\u2010part first\u2010in\u2010human randomized study, a wide dose range of LY2775240 was safely evaluated and found to be well\u2010tolerated with common adverse events (AEs) of nausea, diarrhea, and headache. No serious AEs were reported. The pharmacokinetic profile of LY2775240 was well\u2010characterized, with a half\u2010life that can support once\u2010a\u2010day dosing. An ex vivo pharmacodynamic (PD) assay demonstrated dose\u2010dependent PDE4 target engagement as assessed by reduction in TNF\u03b1 production. A 20\u00a0mg dose of LY2775240 led to near\u2010maximal TNF\u03b1 inhibition in this PD assay in the first part of the study and was selected for comparison with the clinical dose of apremilast (30\u00a0mg) in the crossover, second part of this study. The 20\u00a0mg dose of LY2775240 demonstrated sustained maximal (50%\u201380%) inhibition of TNF\u03b1 over all timepoints over the 24\u2010h duration. The comparator apremilast achieved peak inhibition of ~\u00a050% at only 4 h postdose with a return to about 10% inhibition within 12 h of dosing. In summary, the nonclinical data and safety, tolerability, and PK\/PD data in healthy subjects supports further investigation of LY2775240 in inflammatory indications.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"box\" position=\"anchor\"><jats:caption><jats:title>Study Highlights<\/jats:title><\/jats:caption><jats:p>\n<jats:list list-type=\"simple\">\n\n<jats:list-item><jats:p>\n<jats:bold>WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?<\/jats:bold>\n<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p>Phosphodiesterase 4 (PDE4) inhibitors, such as apremilast, are currently approved to treat autoimmune disorders, such as psoriasis. LY2775240 is an oral PDE4 inhibitor being developed for treatment of a variety of inflammatory disorders. The degree of enzymatic inhibition achieved by PDE4 inhibitors clinically is poorly understood.\n<jats:list list-type=\"simple\">\n<jats:list-item><jats:p><jats:bold>WHAT QUESTION DID THIS STUDY ADDRESS?<\/jats:bold><\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p>This study investigated single ascending doses of LY2775240, a highly selective oral PDE4 inhibitor, in healthy subjects. LY2775240 was well\u2010tolerated over the dose range evaluated, and pharmacokinetic\/pharmacodynamic (PD) profiles were well\u2010characterized.\n<jats:list list-type=\"simple\">\n<jats:list-item><jats:p><jats:bold>WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?<\/jats:bold><\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p>This study evaluated different doses of LY2775240 and subsequently compared a selected LY2775240 dose with the clinical dose of apremilast with an ex vivo assay. This information builds a connection between target engagement and clinical efficacy.\n<jats:list list-type=\"simple\">\n<jats:list-item><jats:p><jats:bold>HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?<\/jats:bold><\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p>This is the first report of an ex vivo PD assay that has been systematically implemented in a PDE4 inhibitor Phase 1 study. Early investigation of exposure\u2010response relationships versus a comparator can support evaluation of clinically meaningful doses of investigational agents.<\/jats:p><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/cts.12968","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T22:38:57Z","timestamp":1609454337000},"page":"1037-1048","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Characterization of LY2775240, a selective phosphodiesterase\u20104 inhibitor, in nonclinical models and in healthy subjects"],"prefix":"10.1111","volume":"14","author":[{"given":"Dipak R.","family":"Patel","sequence":"first","affiliation":[{"name":"Clinical Services Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shweta","family":"Urva","sequence":"additional","affiliation":[{"name":"Global PK\/PD &amp; Pharmacometrics Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Ho","sequence":"additional","affiliation":[{"name":"Translational Sciences \u2010 Autoimmunity Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cody J.","family":"Buckman","sequence":"additional","affiliation":[{"name":"Immunology Discovery Research Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanfei","family":"Ma","sequence":"additional","affiliation":[{"name":"Immunology Discovery Research Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Lim","sequence":"additional","affiliation":[{"name":"Global PK\/PD &amp; Pharmacometrics \u2010 SG Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean E.","family":"Sissons","sequence":"additional","affiliation":[{"name":"Translational Sciences \u2010 Autoimmunity Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary S.","family":"Zuniga","sequence":"additional","affiliation":[{"name":"Translational Sciences \u2010 Autoimmunity Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diane","family":"Philips","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Cox","sequence":"additional","affiliation":[{"name":"Translational Sciences \u2010 Autoimmunity Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Dairaghi","sequence":"additional","affiliation":[{"name":"Immunology Discovery Research Lilly Corporate Center Eli Lilly and Co Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,2,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2018.08.025"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/key276"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-11-96"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00123"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2014.05.014"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2012.01.001"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)17708-3"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(05)03622-6"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3041"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/906349"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0771-6"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.14164"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-3083.2012.04716.x"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-205056"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S89849"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/pde.12780"},{"key":"e_1_2_8_18_1","unstructured":"Eli Lilly and Company.LY2775240: (2S)\u20102 3\u2010dihydroxy\u20101\u2010[(3S 4S)\u20103\u2010[(1R)\u20101\u2010hydroxyethyl]\u20104\u2010[4\u2010methoxy\u20103\u2010[1\u2010(5\u2010methyl\u20102\u2010pyridyl) azetidin\u20103\u2010yl] oxy\u2010phenyl]\u20103\u2010methyl\u2010pyrrolidin\u20101\u2010yl] propan\u20101\u2010one; WO 2014\/159012 A1 Eli Lilly and Company Priority March 13 2013 Filed March 7 2013. Published October 2 2014."},{"key":"e_1_2_8_19_1","unstructured":"ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29. Identifier NCT02963779 A Study of LY2775240 in Healthy Participants;2016Nov 15 [cited 2020 Aug 13]. Available from:http:\/\/clinicaltrials.gov\/ct2\/show\/NCT02963779?term=2775240&rank=1"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm900210d"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.256"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0074640"},{"key":"e_1_2_8_23_1","unstructured":"Celgene Corporation.OTEZLA (apremilast) [package insert]. U.S. Food and Drug Administration.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2014\/205437s000lbl.pdf. Accessed January 2021."},{"key":"e_1_2_8_24_1","unstructured":"AstraZeneca Pharmaceuticals LP.DALIRESP (roflumilast) [package insert]. U.S. Food and Drug Administration website.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2013\/022522s003lbl.pdf. Accessed January 2021."},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1185\/030079908X301866"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.12968","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.12968","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.12968","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T03:08:32Z","timestamp":1693364912000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.12968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,13]]},"references-count":24,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1111\/cts.12968"],"URL":"https:\/\/doi.org\/10.1111\/cts.12968","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,13]]},"assertion":[{"value":"2020-09-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}