{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:36:38Z","timestamp":1792503398518,"version":"4.5.0"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T00:00:00Z","timestamp":1730678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T00:00:00Z","timestamp":1730678400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>GLP\u20101 receptor agonists (GLP\u20101 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non\u2010clinical and first\u2010in\u2010human (FIH) evaluation of ECC5004\/AZD5004, an oral small\u2010molecule GLP\u20101 RA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>ECC5004 was profiled in cell lines overexpressing human GLP\u20101R, in glucose\u2010stimulated insulin secretion (GSIS) assays in a human \u03b2\u2010cell line and non\u2010human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9\u2009months and a phase I, double\u2010blind, placebo\u2010controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1\u2013300\u2009mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50\u2009mg) in patients with T2DM for 28\u2009days.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ECC5004 bound to the hGLP\u20101R (IC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u20092.4\u2009nM) augmented cAMP signalling without \u03b2\u2010arrestin\u20102 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC\u2010\u03b2H5 cells (EC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u20095.9\u2009nM) and in vivo in NHPs (EC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u20090.022\u2009nM). Dose\u2010dependent body weight changes compared to control were seen in the 9\u2010month NHP toxicity study. In the first\u2010in\u2010human study, ECC5004 was well tolerated with no serious adverse events. Dose\u2010dependent reductions in glucose and body weight were observed with a dose\u2010proportional exposure at doses \u226525\u2009mg.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      ECC5004 engaged the GLP\u20101R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP\u20101 RAs, along with a pharmacokinetic profile compatible with once\u2010daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity.\n                      <jats:italic>Clinical trial registration<\/jats:italic>\n                      : NCT05654831.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.16047","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T10:00:27Z","timestamp":1730714427000},"page":"551-562","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Non\u2010clinical and first\u2010in\u2010human characterization of\n                    <scp>ECC5004<\/scp>\n                    \/\n                    <scp>AZD5004<\/scp>\n                    , a novel once\u2010daily, oral small\u2010molecule\n                    <scp>GLP<\/scp>\n                    \u20101 receptor agonist"],"prefix":"10.1111","volume":"27","author":[{"given":"Amina Z.","family":"Haggag","sequence":"first","affiliation":[{"name":"Anaheim Clinical Trials LLC  Anaheim California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Eccogene Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Butcher","sequence":"additional","affiliation":[{"name":"Eccogene Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Pagnussat","sequence":"additional","affiliation":[{"name":"QPS MRA LLC  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Davies","sequence":"additional","affiliation":[{"name":"Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&amp;D, AstraZeneca  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Lundqvist","sequence":"additional","affiliation":[{"name":"Assays, Profiling and Cell Sciences, Discovery Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Data Sciences and Quantitative Biology, Discovery Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Van Zuydam","sequence":"additional","affiliation":[{"name":"Data Sciences and Quantitative Biology, Discovery Sciences BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Nelander","sequence":"additional","affiliation":[{"name":"Cardiovascular, Renal and Metabolism Biometrics, Late Cardiovascular, Renal and Metabolism BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aruni","family":"Jha","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&amp;D, AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtao","family":"Yu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences R&amp;D, AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Boianelli","sequence":"additional","affiliation":[{"name":"DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bosse","family":"Lindmark","sequence":"additional","affiliation":[{"name":"DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ollerstam","sequence":"additional","affiliation":[{"name":"Cardiovascular, Renal and Metabolism Safety, Clinical Pharmacology and Safety Sciences R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Eccogene (Shanghai) Co. 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