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Herein we report therapeutic efficacy of EDP\u2010305, in direct comparison with the first\u2010in\u2010class FXR agonist obeticholic acid (OCA), in mouse models of liver disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>EDP\u2010305 (10 and 30\u00a0mg\/kg\/day) or OCA (30mg\/kg\/day) was tested in mouse models of pre\u2010established biliary fibrosis (BALBc.<jats:italic>Mdr2<\/jats:italic>\u2010\/\u2010, n\u00a0=\u00a09\u201012\/group) and steatohepatitis induced by methionine\/choline\u2010deficient diet (MCD, n\u00a0=\u00a07\u201012\/group). Effects on biliary epithelium were evaluated in vivo and in primary EpCAM\u00a0+\u00a0hepatic progenitor cell (HPC) cultures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In a BALBc.<jats:italic>Mdr2\u2010\/\u2010<\/jats:italic> model, EDP\u2010305 reduced serum transaminases by up to 53% and decreased portal pressure, compared to untreated controls. Periportal bridging fibrosis was suppressed by EDP\u2010305 at both doses, with up to a 39% decrease in collagen deposition in high\u2010dose EDP\u2010305. In MCD\u2010fed mice, EDP\u2010305 treatment reduced serum ALT by 62% compared to controls, and profoundly inhibited perisinusoidal \u2018chicken wire\u2019 fibrosis, with over 80% reduction in collagen deposition. In both models, treatment with 30mg\/kg OCA reduced serum transaminases up to 30%, but did not improve fibrosis. The limited impact on fibrosis was mediated by cholestasis\u2010independent worsening of ductular reaction by OCA in both disease models; OCA but not EDP\u2010305 at therapeutic doses promoted ductular proliferation in healthy mice and favoured differentiation of primary HPC towards cholangiocyte lineage in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>EDP\u2010305 potently improved pre\u2010established liver injury and hepatic fibrosis in murine biliary and metabolic models of liver disease, supporting the clinical evaluation of EDP\u2010305 in fibrotic liver diseases including cholangiopathies and non\u2010alcoholic steatohepatitis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14490","type":"journal-article","created":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T14:05:42Z","timestamp":1587737142000},"page":"1655-1669","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["A novel non\u2010bile acid FXR agonist EDP\u2010305 potently suppresses liver injury and fibrosis without worsening of ductular reaction"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0018-2233","authenticated-orcid":false,"given":"Ping","family":"An","sequence":"first","affiliation":[{"name":"Divison of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA"},{"name":"Division of Gastroenterology and Hepatology Renmin Hospital Wuhan University Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyan","family":"Wei","sequence":"additional","affiliation":[{"name":"Divison of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA"},{"name":"Department of Radiation Oncology The First Affiliated Hospital Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8339-9701","authenticated-orcid":false,"given":"Pinzhu","family":"Huang","sequence":"additional","affiliation":[{"name":"Divison of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA"},{"name":"Department of Colon and Rectum Surgery The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenda","family":"Li","sequence":"additional","affiliation":[{"name":"Divison of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA"},{"name":"Department of Hepatobiliary Surger Sun Yat-sen Memorial Hospital Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Qi","sequence":"additional","affiliation":[{"name":"Divison of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA"},{"name":"Institute of Portal Hypertension The First Hospital of Lanzhou University Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lin","sequence":"additional","affiliation":[{"name":"Divison of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kahini A.","family":"Vaid","sequence":"additional","affiliation":[{"name":"Divison of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery Renmin Hospital Wuhan University Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shucha","family":"Zhang","sequence":"additional","affiliation":[{"name":"Enanta Pharmaceuticals, Inc. 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