From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham (P.N.N.) - all in the United Kingdom; Pinnacle Clinical Research, San Antonio (S.A.H., M.R.), South Texas Research Institute, Edinburg (R.P.), and Houston Methodist Hospital, Houston Research Institute, Houston (M.N.) - all in Texas; Liverpat and University of Paris (P.B.), INSERM, Unité Mixte de Recherche Scientifique (UMRS) 1139, Centre de Recherche sur l'Inflammation (L.C.), and Sorbonne Université, ICAN Institute for Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux de Paris (APHP), INSERM, UMRS 1138, Centre de Recherche des Cordeliers (V.R.), Paris, and Université Paris-Cité, Department of Hepatology, Beaujon Hospital, APHP, Clichy (L.C.) - all in France; Duke University Health System, Durham, NC (C.D.G.); the Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of Johannes Gutenburg University Mainz, Mainz (J.M.S.), the Department of Internal Medicine II, Saarland University Medical Center, Homburg (J.M.S.), and Klinikum St. Georg Leipzig, Leipzig (I.S.) - all in Germany; MASLD Research Center, the Division of Gastroenterology and Hepatology, University of California, San Diego, La Jolla (R.L.); Madrigal Pharmaceuticals, West Conshohocken, PA (R.T., D.L.); University of Arizona for Medical Sciences (S.E.M.) and Arizona Liver Health (N.A.) - both in Tucson; Covenant Metabolic Specialists, Sarasota (G.W.N.), and Flourish Research, Boca Raton (S.J.B.) - both in Florida; the Transplant Institute, Department of Medicine, University of Chicago Pritzker School of Medicine, and the Transplant Institute, Center for Liver Diseases, University of Chicago Biological Sciences - both in Chicago (M.E.R., M.R.C.); the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN (M.F.A.); the Department of Medicine, Inova Fairfax Medical Campus, Falls Church (Z.Y.), and Virginia Commonwealth University, Richmond (A.J.S.) - both in Virginia; the Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem (S.F.), and Cliniques Universitaires Saint-Luc, Service d'Hépato-gastroentérologie, UCLouvain, Brussels (N.L.) - both in Belgium; the Liver Unit at the IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy (A.M.); the Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (J.M.P.); and the Division of Liver Diseases, Icahn School of Medicine at Mt. Sinai, New York (M.B.B.).
N Engl J Med. 2024 Feb 8;390(6):497-509. doi: 10.1056/NEJMoa2309000.
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).
背景：非酒精性脂肪性肝炎（NASH）是一种进展性肝脏疾病，目前尚无获批的治疗方法。Resmetirom 是一种正在开发用于治疗伴有纤维化的 NASH 的口服、肝脏靶向、甲状腺激素受体β选择性激动剂。
方法：我们正在进行一项正在进行的 3 期临床试验，涉及活检证实患有 NASH 且纤维化分期为 F1B、F2 或 F3 的成年人（分期范围从 F0[无纤维化]到 F4[肝硬化]）。患者以 1:1:1 的比例随机分配接受每日一次 80mg 或 100mg resmetirom 或安慰剂治疗。主要终点为 52 周时 NASH 缓解（包括非酒精性脂肪性肝病[NAFLD]活动评分降低≥2 分；评分范围为 0 至 8，分数越高表示疾病越严重）且纤维化无恶化，以及纤维化至少改善一个阶段且 NAFLD 活动评分无恶化。
结果：共有 966 名患者构成主要分析人群（80mg resmetirom 组 322 名，100mg resmetirom 组 323 名，安慰剂组 321 名）。80mg resmetirom 组和 100mg resmetirom 组 NASH 缓解且纤维化无恶化的患者比例分别为 25.9%和 29.9%，而安慰剂组为 9.7%（与安慰剂相比，均 P<0.001）。80mg resmetirom 组和 100mg resmetirom 组纤维化至少改善一个阶段且 NAFLD 活动评分无恶化的患者比例分别为 24.2%和 25.9%，而安慰剂组为 14.2%（与安慰剂相比，均 P<0.001）。80mg resmetirom 组和 100mg resmetirom 组从基线到 24 周时低密度脂蛋白胆固醇水平的变化分别为-13.6%和-16.3%，而安慰剂组为 0.1%（与安慰剂相比，均 P<0.001）。与安慰剂相比，Resmetirom 更常引起腹泻和恶心。各组严重不良事件的发生率相似：80mg resmetirom 组为 10.9%，100mg resmetirom 组为 12.7%，安慰剂组为 11.5%。
结论：80mg 剂量和 100mg 剂量的 Resmetirom 在 NASH 缓解和至少改善一个阶段的肝纤维化方面均优于安慰剂。（由 Madrigal 制药公司资助；MAESTRO-NASH 临床试验.gov 编号，NCT03900429。）
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