近日，美国加州大学圣迭戈分校Rohit Loomba团队研究了反义寡核苷酸DGAT-2抑制剂ION224治疗代谢功能障碍相关脂肪性肝炎的疗效与安全性。2025年8月23日出版的《柳叶刀》杂志发表了这项成果。

ION224是一种肝脏定向的二酰基甘油O-酰基转移酶2 （DGAT2）的反义抑制剂，可抑制新生脂肪生成，这是代谢功能障碍相关脂肪性肝炎（MASH）中与脂肪毒性、潜在炎症、肝细胞损伤和纤维化相关的重要代谢途径。该研究旨在前瞻性评估ION224在MASH和纤维化患者中的安全性和有效性。

ION224-CS2是一项适应性、两部分、多中心、随机、双盲、安慰剂对照的2期临床试验，在美国和波多黎各的43个临床点进行，患者年龄为18-75岁，活检证实为MASH和纤维化（F1、F2和F3期），基线肝脂肪变性≥10%。在第一部分中，参与者被随机分配（1:1:1）到皮下注射ION224 60mg， 90mg或120mg，或安慰剂，每月一次。在第2部分中，在预先指定的安全性和有效性（肝脂肪变性）的中期分析后，参与者被随机分配（2:1）到ION224 90mg和120mg或安慰剂组。主要终点是非酒精性脂肪性肝病活动度评分（NAS）降低≥2分，肝细胞球囊或小叶炎症改善≥1分，且在第51周无纤维化恶化。主要分析是在一个预定义的方案集中进行的，该方案集包括接受了13剂研究药物中至少10剂的患者，没有连续错过3剂，并在治疗结束时完成了最终的肝活检。

在2021年6月8日至2022年12月27日期间，160名参与者被随机分配接受ION224 60 mg (n=23), 90 mg （n=45）或120 mg （n=46）或安慰剂（n=46），其中123人被纳入每个方案集。90毫克组的39名参与者中有18名（46%）达到了主要终点（预测风险为46.2%，风险差为27.4%,p= 0.0094）， 120毫克组的34名参与者中有20名（59%）达到了主要终点（58.8% [43.2 - 75.4];40.1% [18.7 - 64.1],p= 0.0002），而安慰剂组的32名参与者中有6名（19%）达到了主要终点（预测风险为18.7%）。ION224安全且耐受性良好。在接受ION224治疗的参与者中，有107人（94%）报告了不良事件，46名接受安慰剂治疗的参与者中有41人（89%）报告了不良事件。无死亡，无治疗相关的严重不良事件。

研究结果表明，这项研究首次提供了临床证据，证明ION224反义介导的DGAT2抑制可能是治疗MASH的一种安全有效的策略。观察到的组织学改善与体重变化无关，提示可能与其他疗法（如基于GLP-1的治疗）联合使用。

附：英文原文

Title: Antisense oligonucleotide DGAT-2 inhibitor, ION224, for metabolic dysfunction-associated steatohepatitis (ION224-CS2): results of a 51-week, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Author: Rohit Loomba, Erin Morgan, Keyvan Yousefi, Dan Li, Richard Geary, Sanjay Bhanot, Naim Alkhouri

Issue&Volume: 2025/08/23

Abstract:

Background

ION224, a liver-directed antisense inhibitor of diacylglycerol O-acyltransferase 2 (DGAT2), suppresses de novo lipogenesis, an important metabolic pathway associated with lipotoxicity and the underlying inflammation, hepatocellular injury, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to prospectively assess the safety and efficacy of ION224 in patients with MASH and fibrosis.

Methods

ION224-CS2 was an adaptive, two-part, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial conducted at 43 clinical sites in the USA and Puerto Rico in patients aged 18–75 years with biopsy-confirmed MASH and fibrosis (stages F1, F2, and F3) and baseline liver steatosis ≥10%. In part 1, participants were randomly assigned (1:1:1) to subcutaneous injections of ION224 60 mg, 90 mg, or 120 mg, or placebo, once per month. In part 2, participants were randomly assigned (2:1) to ION224 90 mg and 120 mg or placebo after a pre-specified interim analysis of safety and efficacy (liver steatosis). The primary endpoint was ≥2-point reduction in Non-Alcoholic Fatty Liver Disease Activity Score Activity Score (NAS) with ≥1-point improvement in hepatocellular ballooning or lobular inflammation, and without worsening of fibrosis at week 51. The primary analysis was in a predefined per-protocol set that included patients who received at least ten of 13 doses of the study drug without missing three consecutive doses and completed the final liver biopsy at the end of treatment. ION224-CS2 was registered at ClinicalTrials.gov (NCT04932512) and is closed.

Findings

Between June 8, 2021, and Dec 27, 2022, 160 participants were randomly assigned to receive ION224 60 mg (n=23), 90 mg (n=45), or 120 mg (n=46), or placebo (n=46), of whom 123 were included in the per-protocol set. The primary endpoint was met in 18 (46%) of 39 participants in the 90-mg group (predicted risk 46·2% [95% CI 30·5–61·8]; risk difference 27·4% [95% CI 6·7–48·1], p=0·0094) and 20 (59%) of 34 in the 120-mg group (58·8% [42·3–75·4]; 40·1% [18·7– 61·4], p=0·0002) compared with six (19%) of 32 in the placebo group (predicted risk 18·7% [95% CI 5·2–32·3]). ION224 was safe and well tolerated. Adverse events were reported in 107 (94%) of participants treated with ION224 and 41 (89%) of 46 participants treated with placebo. There were no deaths and no treatment-related serious adverse events.

Interpretation

This study provides the first clinical evidence that antisense-mediated inhibition of DGAT2 with ION224 could be a safe and efficacious strategy for the treatment of MASH. The observed histological improvements were independent of changes in bodyweight, suggesting potential to combine with other therapies such as GLP-1 based treatments.

DOI: 10.1016/S0140-6736(25)00979-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00979-1/abstract