Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

• Published in: The Lancet (British edition) 2019-11, Vol.394 (10213), p.2012-2024
• Main Authors: Harrison, Stephen A, Bashir, Mustafa R, Guy, Cynthia D, Zhou, Rong, Moylan, Cynthia A, Frias, Juan P, Alkhouri, Naim, Bansal, Meena B, Baum, Seth, Neuschwander-Tetri, Brent A, Taub, Rebecca, Moussa, Sam E
• Format: Article
• Language: English
• Subjects: Adult; Alanine Transaminase - blood; Biomarkers; Biomarkers - blood; Biopsy; Cholesterol; Clinical trials; Diarrhea; Diarrhea - chemically induced; Double-Blind Method; Double-blind studies; Drug dosages; Fat metabolism; Fatty liver; FDA approval; Female; Fibrosis; Histology; Humans; Hypothyroidism; Inflammation; Inflammation - pathology; Lipids; Lipids - blood; Liver; Liver - diagnostic imaging; Liver - enzymology; Liver - pathology; Liver Cirrhosis - diagnostic imaging; Liver Cirrhosis - pathology; Liver diseases; Low density lipoprotein; Magnetic Resonance Imaging; Male; Metabolic syndrome; Middle Aged; Nausea; Nausea - chemically induced; Non-alcoholic Fatty Liver Disease - diagnostic imaging; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - pathology; Proton density (concentration); Pyridazines - adverse effects; Pyridazines - therapeutic use; Randomization; Reduction; Safety; Steatosis; Thyroid; Thyroid gland; Thyroid Hormone Receptors beta - agonists; Triglycerides; Uracil - adverse effects; Uracil - analogs & derivatives; Uracil - therapeutic use; Weight control
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(19)32517-6

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1–3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260. 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (−32·9% resmetirom vs −10·4% placebo; least squares mean difference −22·5%, 95% CI −32·9 to −12·2; p