{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T08:28:55Z","timestamp":1790497735272,"version":"4.1.0"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2019,3,10]],"date-time":"2019-03-10T00:00:00Z","timestamp":1552176000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:p>\n                    Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double\u2010blind, placebo\u2010controlled study, we tested the safety and efficacy of cilofexor (formerly GS\u20109674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large\u2010duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) &gt; 1.67 \u00d7 upper limit of normal and total bilirubin \u2264 2 mg\/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7\u03b1\u2010hydroxy\u20104\u2010cholesten\u20103\u2010one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U\/L (interquartile range 288\u2010439) and 0.7 mg\/dL (0.5\u20101.0), respectively. Dose\u2010dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction \u221221%;\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.029 versus placebo), gamma\u2010glutamyl transferase (\u221230%;\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    &lt; 0.001), alanine aminotransferase (ALT) (\u221249%;\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.009), and aspartate aminotransferase (\u221242%;\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid\u2013treated and untreated patients. At week 12, cilofexor\u2010treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma\u2010glutamyl transferase, tissue inhibitor of metalloproteinase 1, C\u2010reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo\u2010treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    In this 12\u2010week, randomized, placebo\u2010controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC.\n                  <\/jats:p>","DOI":"10.1002\/hep.30509","type":"journal-article","created":{"date-parts":[[2019,1,20]],"date-time":"2019-01-20T01:04:18Z","timestamp":1547946258000},"page":"788-801","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":257,"title":["The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS\u20109674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis"],"prefix":"10.1097","volume":"70","author":[{"given":"Michael","family":"Trauner","sequence":"first","affiliation":[{"name":"Medical University of Vienna,Vienna,Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliya","family":"Gulamhusein","sequence":"additional","affiliation":[{"name":"University of Toronto,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilal","family":"Hameed","sequence":"additional","affiliation":[{"name":"University of California,San Francisco School of Medicine,San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Caldwell","sequence":"additional","affiliation":[{"name":"University of Virginia,Charlottesville,VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell L.","family":"Shiffman","sequence":"additional","affiliation":[{"name":"Bon Secours Liver Institute,Richmond,VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Landis","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine,Seattle,WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertus","family":"Eksteen","sequence":"additional","affiliation":[{"name":"Aspen Woods Clinic,Calgary,AB,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosh","family":"Agarwal","sequence":"additional","affiliation":[{"name":"King\u2019s College,London,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Muir","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine,Durham,NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Rushbrook","sequence":"additional","affiliation":[{"name":"Norfolk and Norwich University Hospital,Norfolk,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Lu","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xu","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen\u2010Chieh","family":"Chuang","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Billin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Li","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuhan","family":"Chung","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Mani","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Myers","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Bowlus","sequence":"additional","affiliation":[{"name":"University of California Davis,Davis,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kris V.","family":"Kowdley","sequence":"additional","affiliation":[{"name":"Liver Care Network and Organ Care Research,Swedish Medical Center,Seattle,WA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,3,10]]},"reference":[{"key":"hep30509-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1056\/NEJMra1506330","article-title":"Primary sclerosing 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