Resmetirom（MGL-3196）治疗非酒精性脂肪性肝炎：一项多中心、随机、双盲、安慰剂对照的 2 期临床试验。

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

机构信息

Pinnacle Clinical Research, San Antonio, TX, USA; Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Department of Radiology, Center for Advanced Magnetic Resonance Development, Department of Pathology, and Division of Hepatology, Duke University Medical Center, Durham, NC, USA.

出版信息

Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6. Epub 2019 Nov 11.

DOI:10.1016/S0140-6736(19)32517-6

PMID:31727409

Abstract

BACKGROUND

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.

METHODS

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.

FINDINGS

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<0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom.

INTERPRETATION

Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging.

FUNDING

Madrigal Pharmaceuticals.

摘要

背景

非酒精性脂肪性肝炎（NASH）的特征是肝脂肪变性、炎症、肝细胞损伤和进行性肝纤维化。雷美替胺（MGL-3196）是一种肝脏靶向的、口服活性的、选择性甲状腺激素受体-β激动剂，旨在通过增加肝脂肪代谢和减少脂肪毒性来改善 NASH。我们旨在评估雷美替胺在 NASH 患者中的安全性和疗效。

方法

MGL-3196-05 是一项在美国 25 个中心进行的 36 周随机、双盲、安慰剂对照研究。符合条件的患者为通过 MRI 质子密度脂肪分数（MRI-PDFF）基线时肝活检证实为 NASH（纤维化 1-3 期）且肝脂肪分数至少为 10%的成年人。患者通过基于计算机的系统以 2:1 的比例随机分配接受雷美替胺 80mg 或匹配安慰剂，每日口服一次。在第 12 周和第 36 周进行连续肝脂肪测量，并在第 36 周进行第二次肝活检。主要终点是在基线和第 12 周均有 MRI-PDFF 检查的患者中，与安慰剂相比，第 12 周时 MRI-PDFF 评估肝脂肪的相对变化。该试验在 ClinicalTrials.gov 上注册，编号为 NCT02912260。

结果

348 名患者接受了筛选，84 名患者在 18 个美国地点被随机分配至雷美替胺组（n=78）和安慰剂组（n=41）。雷美替胺治疗的患者（n=78）与安慰剂组（n=38）相比，在第 12 周（雷美替胺 -32.9%[n=78] vs 安慰剂 -10.4%[n=38]；最小二乘均值差-22.5%，95%CI-32.9 至-12.2；p<0.0001）和第 36 周（雷美替胺 -37.3%[n=74] vs 安慰剂 -8.5%[n=34]；-28.8%，-42.0 至-15.7；p<0.0001）时肝脂肪明显减少。不良事件大多为轻度或中度，且在两组之间平衡，除了雷美替胺组一过性轻度腹泻和恶心的发生率较高。