美国休斯顿卫理公会医院Mazen Noureddin团队研究了每周一次的Efruxifermin与安慰剂治疗代谢功能障碍相关脂肪性肝炎（HARMONY）中的安全性和有效性。相关论文于2025年8月16日发表在《柳叶刀》杂志上。

Efruxifermin是一种二价成纤维细胞生长因子21类似物，正在开发用于治疗代谢功能障碍相关脂肪性肝炎（MASH）。该试验旨在前瞻性评估对中度(ii期；F2)或严重(3期；F3)纤维化。

研究组进行了一项多中心、随机、双盲、安慰剂对照的2b期临床试验，在美国41个学术和社区中心进行。活检证实为MASH（定义为非酒精性脂肪肝疾病活动评分为4分或更高，脂肪变性、球囊化和小叶炎症评分为1分或更高），组织学分期为F2或F3纤维化的成年人（18-75岁），通过互动反应系统随机分配（1:1:1），每周一次皮下注射efruxifermin （28 mg或50 mg）或安慰剂。参与者、调查员、病理学家、现场工作人员和发起人按小组分配。主要终点是肝纤维化的改善（减少≥1期），在第24周时MASH没有恶化，这是先前报道的。第96周的治疗终点包括主要终点的最终评估，以及没有纤维化恶化的MASH缓解。

2021年3月22日至2022年2月7日，128名参与者被随机分配，126名参与者接受了至少一剂量的efruxifermin或安慰剂，并被纳入修改意向治疗分析。128名参与者中，女性79人（62%），男性49人（38%）。改良意向治疗人群中，在第96周出现≥1期纤维化改善且无MASH恶化的参与者比例为：安慰剂组43人中有8人（19%），28 mg组40人中有12人（30%）(与安慰剂相比差异：12个百分点；P = 0.19)， 50 mg组43人中有21人（49%）(差异：31个百分点[12 ~ 49]；p = 0·0030)。在88名进行第96周活检的参与者中，安慰剂组34名参与者中有8名（24%）观察到≥1期纤维化改善而没有MASH恶化，28 mg组26名参与者中有12名（46%）观察到(与安慰剂相比差异：22个百分点；P = 0.070)， 50 mg组28例中有21例（75%）(差异：52个百分点，[31 ~ 73]；术;0·0001)。28毫克组40名参与者中有38名（95%）报告了不良事件，50毫克组43名参与者中有43名（100%）报告了不良事件，安慰剂组43名中有42名（98%）报告了不良事件。轻度至中度胃肠道不良事件与安慰剂相比更常见。各组中没有药物性肝损伤或死亡的报告。

研究结果表明，在96周后，Efruxifermin比安慰剂对纤维化的改善更大，值得在3期试验中进一步研究。

附：英文原文

Title: Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial

Author: Mazen Noureddin, Juan P Frias, Guy W Neff, K Jean Lucas, Cynthia Behling, Pierre Bedossa, Julie Dubourg, Doreen Chan, Mark Burch, Erica Fong, Brittany de Temple, Matt Minerva, Kim Barrett, Reshma Shringarpure, Erik J Tillman, Timothy Rolph, Andrew Cheng, Kitty Yale

Issue&Volume: 2025/08/16

Abstract:

Background

Efruxifermin is a bivalent fibroblast growth factor 21 analogue in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This trial aimed to prospectively assess the safety and efficacy of efruxifermin administration for 96 weeks in individuals with MASH and moderate (stage 2; F2) or severe (stage 3; F3) fibrosis.

Methods

HARMONY is a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial conducted at 41 academic and community centres in the USA. Adults (aged 18–75 years) with biopsy-confirmed MASH (defined as non-alcoholic fatty liver disease activity score of 4 or higher and a score of 1 or higher for steatosis, ballooning, and lobular inflammation), with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive subcutaneous efruxifermin (28 mg or 50 mg) once per week or placebo. Participants, investigators, pathologists, site staff, and the sponsor were masked to group assignments. The primary endpoint was an improvement in liver fibrosis (decrease ≥1 stage) without worsening of MASH at week 24, which has been previously reported. End-of-treatment endpoints at week 96 included a final evaluation of the primary endpoint, as well as MASH resolution without fibrosis worsening. The trial is registered with ClinicalTrials.gov, NCT04767529, and is complete.

Findings

Between March 22, 2021, and Feb 7, 2022, 128 participants were randomly assigned and 126 received at least one dose of efruxifermin or placebo and were included in the modified intention-to-treat analysis. 79 (62%) of 128 participants were female and 49 (38%) were male. The proportion of participants in the modified intention-to-treat population with ≥1-stage fibrosis improvement without MASH worsening at week 96 was eight (19%) of 43 in the placebo group, 12 (30%) of 40 in the 28 mg group (difference vs placebo: 12 percentage points [95% CI –6 to 31]; p=0·19), and 21 (49%) of 43 in the 50 mg group (difference: 31 percentage points [12 to 49]; p=0·0030). Of 88 participants with week-96 biopsies, ≥1-stage fibrosis improvement without MASH worsening was observed in eight (24%) of 34 participants in the placebo group, 12 (46%) of 26 in the 28 mg group (difference vs placebo: 22 percentage points [95% CI –1 to 45]; p=0·070), and 21 (75%) of 28 in the 50 mg group (difference: 52 percentage points, [31 to 73]; p<0·0001). 38 (95%) of 40 participants in the 28 mg group, 43 (100%) of 43 in the 50 mg group, and 42 (98%) of 43 in the placebo group reported an adverse event. Mild to moderate gastrointestinal adverse events were more common with efruxifermin than placebo. There were no reports of drug-induced liver injury or deaths across the groups.

Interpretation

Efruxifermin resulted in greater improvements in fibrosis than placebo after 96 weeks, warranting further investigation in phase 3 trials.

DOI: 10.1016/S0140-6736(25)01073-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01073-6/abstract