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DUET was a 12-week, randomized, double-blind, placebo-controlled, multicenter phase 2a study investigating the efficacy, safety and pharmacodynamics and pharmacokinetics of once-daily TERN-501 (THR\u03b2 agonist) as monotherapy or combined with TERN-101 (farnesoid X receptor agonist), in patients with presumed MASH. Overall, 162 patients were randomized to: TERN-501 monotherapy (1\u2009mg (<jats:italic>n<\/jats:italic>\u2009=\u200923), 3\u2009mg (<jats:italic>n<\/jats:italic>\u2009=\u200923) or 6\u2009mg (<jats:italic>n<\/jats:italic>\u2009=\u200922)), TERN-101 10-mg monotherapy (<jats:italic>n<\/jats:italic>\u2009=\u200924), TERN-501 (3\u2009mg (<jats:italic>n<\/jats:italic>\u2009=\u200923) or 6\u2009mg (<jats:italic>n<\/jats:italic>\u2009=\u200923)) plus TERN-101 10-mg combination therapy or placebo (<jats:italic>n<\/jats:italic>\u2009=\u200924). The primary endpoint was relative change from baseline at week\u200912 in liver fat content with TERN-501 monotherapy versus placebo, using magnetic resonance imaging proton density fat fraction (MRI-PDFF). Least squares mean (s.e.) changes from baseline at week\u200912 in MRI-PDFF with TERN-501 were: \u221215.4% (5.2%) with 1\u2009mg, \u221227.5% (5.7%) with 3\u2009mg (<jats:italic>P<\/jats:italic>\u2009=\u20090.0036) and \u221244.8% (5.9%) with 6\u2009mg (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001), versus \u22124.0% (5.4%) with placebo. The incidence of adverse events was similar with TERN-501 monotherapy or placebo. In conclusion, TERN-501 treatment resulted in dose-dependent, significant reductions from baseline in MRI-PDFF compared to placebo in patients with MASH. ClinicalTrials.gov registration: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT05415722\" ext-link-type=\"uri\">NCT05415722<\/jats:ext-link>.<\/jats:p>","DOI":"10.1038\/s41591-025-03722-7","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T05:03:45Z","timestamp":1749618225000},"page":"2297-2305","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2127-2040","authenticated-orcid":false,"given":"Mazen","family":"Noureddin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naim","family":"Alkhouri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Lawitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kris V.","family":"Kowdley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Loomba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lois","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4060-2252","authenticated-orcid":false,"given":"Amnon","family":"Schlegel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonya","family":"Marmon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kacey","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Quirk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8285-2204","authenticated-orcid":false,"given":"Stephen A.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"3722_CR1","doi-asserted-by":"publisher","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","volume":"62","author":"CD Byrne","year":"2015","unstructured":"Byrne, C. 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N.A. has received grant\/research support from 89bio, Akero Therapeutics, Arbutus Biopharma, AstraZeneca, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Corcept Therapeutics, CymaBay Therapeutics, DSM, Galectin Therapeutics, Genentech, Genfit, Gilead Sciences, Healio, Hepagene Therapeutics, Intercept Pharmaceuticals, Inventiva Pharma, Ionis Pharmaceuticals, Ipsen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Noom, NorthSea Therapeutics, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking Therapeutics and Zydus Pharmaceuticals; reports speaker\u2019s fees from AbbVie, Alexion Pharmaceuticals, Echosens, Gilead Sciences, Intercept Pharmaceuticals, Ipsen, Madrigal Pharmaceuticals, Perspectum and Theratechnologies; and reports consulting for 89bio, Boehringer Ingelheim, Echosens, Fibronostics, Gilead Sciences, Intercept Pharmaceuticals, Ipsen, Madrigal Pharmaceuticals, NorthSea Therapeutics, Novo Nordisk, Perspectum, Pfizer and Zydus Pharmaceuticals. E.J.L. has received research\/grant support from 89bio, Akero Therapeutics, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, DSM, Enanta Pharmaceuticals, ENYO Pharma, Exalenz Bioscience, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead Sciences, GSK, Hanmi Pharmaceuticals, Hightide Therapeutics, Intercept Pharmaceuticals, Inventiva Pharma, Janssen Pharmaceuticals, Lilly, Madrigal Pharmaceuticals, Merck & Co, NGM Biopharmaceuticals, NorthSea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet Biosciences, Takeda Pharmaceuticals, Terns Pharmaceuticals, Viking Therapeutics and Zydus Pharmaceuticals. K.V.K. is a consultant for 89bio, CymaBay Therapeutics, Enanta Pharmaceuticals, Genfit, Gilead, HighTide Therapeutics, Inipharm, Intercept Pharmaceuticals, Madrigal, Mirum, NGM Biopharmaceuticals, Pfizer and Zydus Pharmaceuticals; and reports research support from 89bio, Boston, Corcept Therapeutics, CymaBay Therapeutics, Genfit, Gilead, GSK, Hanmi Pharmaceuticals, Intercept Pharmaceuticals, Janssen Pharmaceuticals, Madrigal, Mirum, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Pliant, Terns Pharmaceuticals, Viking Therapeutics and Zydus Pharmaceuticals; and reports speaker\u2019s fees from AbbVie, Gilead and Intercept Pharmaceuticals; and stock options in Inipharm. R.L. is a consultant for 89bio, Aardvark Therapeutics, Alnylam\/Regeneron Pharmaceuticals, Altimmune, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Galmed Pharmaceuticals, Gilead Sciences, Glympse Bio, HighTide Therapeutics, Inipharm, Intercept Pharmaceuticals, Inventiva Pharma, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Lilly, Madrigal Pharmaceuticals, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck & Co, Pfizer, Sagimet Biosciences, Theratechnologies, Terns Pharmaceuticals and Viking Therapeutics; and reports research grants (paid to institution) from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead Sciences, Hanmi Pharmaceuticals, Intercept Pharmaceuticals, Inventiva Pharma, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Lilly, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals. R.L. is cofounder of LipoNexus. He receives funding support from NIDDK P30DK120515. L.L., A.S., Y.L. and E.Q. are former employees of Terns Pharmaceuticals. C.J. and K.A. are employees and shareholders of Terns Pharmaceuticals. T.M. is a consultant to Terns Pharmaceuticals. S.A.H. received grant support for research from Akero Therapeutics, Axcella Health, Bristol Myers Squibb, CiVi Biopharma, Conatus Pharmaceuticals, ENYO Pharma, Galectin Therapeutics, Genentech, Genfit, Gilead Sciences, Hepion Pharmaceuticals, HighTide Therapeutics, Immuron, Intercept Pharmaceuticals, Madrigal pharmaceuticals, NGM Biopharmaceuticals, NorthSea Therapeutics, Novo Nordisk, Pfizer, Poxel, Sagimet Biosciences, Second Genome and Viking Therapeutics; reported participation on an advisory board and\/or acting as a consultant to 89bio, Akero Therapeutics, Aligos Therapeutics, Altimmune, Arrowhead Pharmaceuticals, Asteroid Therapeutics, Axcella Health, Bluejay Therapeutics, Boxer Capital, Boehringer Ingelheim, BVF Partners, CiVi Biopharma, Corcept Therapeutics, ChronWell, Dexcom, Eccogene, Echosens, ENYO Pharma, Foresite Labs, Galectin Therapeutics, Galecto, Genfit, Gilead Sciences, GSK, Hepagene Therapeutics, Hepion Pharmaceuticals, Hepta Bio, HighTide Therapeutics, HistoIndex, Inipharm, Intercept Pharmaceuticals, Inventiva Pharma, Ionis Pharmaceuticals, Madrigal Pharmaceuticals, Medpace, MGGM Therapeutics, NeuroBo Pharmaceuticals, NGM Biopharmaceuticals, NorthSea Therapeutics, Novo Nordisk, PathAI, Pfizer, Piper Sandler, Poxel, Regeneron Pharmaceuticals, Sagimet Biosciences, Sonic Incytes, Takeda Pharmaceuticals, Terns Pharmaceuticals, Tramontane Therapeutics and Viking Therapeutics; and had stock and\/or options (self-managed) in Akero Therapeutics, ChronWell, Galectin Therapeutics, Genfit, Hepion Pharmaceuticals, Hepta Bio, HistoIndex, NGM Biopharmaceuticals, NorthSea Therapeutics and Sonic Incytes.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}