Efficacy and safety of ervogastat alone and in combination with clesacostat in patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and F2-F3 fibrosis (MIRNA): results from a phase 2, randomised, double-blind, double-dummy study.

Increased circulating triglycerides, a mechanistic consequence of ACC inhibitors, has been shown to be downregulated by DGAT2 inhibitor co-administration.

ACC抑制剂的机制性后果，即循环甘油三酯的增加，已被证明可以通过联合使用DGAT2抑制剂来下调。

We assessed the efficacy and safety of ervogastat alone and ervogastat plus clesacostat in adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stage 2 or 3.

我们评估了ervogastat单独使用以及ervogastat联合clesacostat在经活检证实患有代谢功能障碍相关脂肪性肝炎（MASH）且纤维化分期为2或3的成年患者中的疗效和安全性。

Methods

This phase 2 double-blind, double-dummy, randomised study was conducted at 198 clinical sites across 11 countries.

这项2期双盲、双模拟、随机研究在11个国家的198个临床地点进行。

A computer-generated randomisation code (random permuted blocks method) was used to allocate patients to treatment groups in equal ratios, and stratified based on degree of fibrosis (F2 vs F3), using an interactive response technology system to ervogastat (25 mg, 75 mg, 150 mg, or 300 mg), ervogastat plus clesacostat (150 mg plus 5 mg or 300 mg plus 10 mg), or placebo, twice daily for 48 weeks.

使用计算机生成的随机化代码（随机排列块方法）以等比例将患者分配到治疗组，并根据纤维化程度（F2 vs F3）进行分层，使用交互式响应技术系统进行ervogastat（25 mg，75 mg，150 mg或300 mg），ervogastat加clesacostat（150 mg加5 mg或300 mg加10 mg）或安慰剂的治疗，每日两次，持续48周。

The primary endpoint was the proportion of patients achieving MASH resolution without fibrosis worsening, at least 1 stage fibrosis improvement without MASH worsening, or both, at week 48.

主要终点是第48周时，患者达到MASH消退且纤维化未恶化，至少1级纤维化改善且MASH未恶化，或两者兼有的比例。

Patients were analysed according to the treatment group they were assigned to.

患者根据他们被分配的治疗组进行分析。

The primary endpoint was analysed based on the full analysis set (all randomly assigned patients who took at least one dose of study treatment who provided evaluable baseline biopsy data) in which patients missing a week 48 biopsy were considered non-responders.

主要终点是基于完整分析集进行分析的（所有随机分配的患者，至少接受了一次研究治疗，并提供了可评估的基线活检数据），其中缺失第48周活检的患者被视为无应答者。

This completed trial was registered with ClinicalTrials.gov (NCT04321031).

该已完成的试验已在ClinicalTrials.gov注册（NCT04321031）。

Results

Recruitment began June 15, 2020; randomisation was completed Feb 22, 2023, with 255 patients randomly assigned and given treatment (73% of planned sample size; ervogastat 25 mg: N=35; ervogastat 75 mg: N=48; ervogastat 150 mg: N=42; ervogastat 300 mg: N=31; ervogastat 150 mg plus clesacostat 5 mg: N=35; ervogastat 300 mg plus clesacostat 10 mg: N=30; placebo: N=34). 13 (38%) patients in the placebo group achieved the composite primary endpoint, as did 16 (46%) in the ervogastat 25 mg group (difference from placebo in the proportion of patients achieving the primary endpoint 0·08 [90% CI -0·11 to 0·27]), 25 (52%) in the ervogastat 75 mg group (0·14 [-0·04 to 0·32]), 21 (50%) in the ervogastat 150 mg group (0·12 [-0·07 to 0·30]), and 14 (45%) in the ervogastat 300 mg group (0·07 [-0·12 to 0·27]). 23 (66%) patients in the ervogastat 150 mg plus clesacostat 5 mg group (difference from placebo 0·27 [90% CI 0·07 to 0·43]) and 19 (63%) of those in the ervogastat 300 mg plus clesacostat 10 mg group (0·25 [0·04 to 0·42]) achieved the composite primary endpoint.

招募始于2020年6月15日；随机分组于2023年2月22日完成，共有255名患者被随机分配并接受了治疗（计划样本量的73%；ervogastat 25 mg：N=35；ervogastat 75 mg：N=48；ervogastat 150 mg：N=42；ervogastat 300 mg：N=31；ervogastat 150 mg加clesacostat 5 mg：N=35；ervogastat 300 mg加clesacostat 10 mg：N=30；安慰剂：N=34）。

Thus, the primary endpoint was not met by any doses of ervogstat alone, but was met by both dose levels of ervogastat plus clesacostat.

因此，单独使用ervogstat的任何剂量均未达到主要终点，但ervogstat加clesacostat的两种剂量水平均达到了主要终点。

All experimental groups showed greater effects on MASH resolution without worsening of fibrosis than with placebo alone; improvement in fibrosis by one stage or more without worsening of MASH was not greater in any experimental group compared with placebo.

所有实验组在MASH消退方面的效果均优于仅使用安慰剂的组别，且未加重纤维化；与安慰剂相比，任何实验组在纤维化改善一个阶段或以上而MASH未加重方面的效果并未更优。

Most adverse events were mild or moderate in severity and did not increase in frequency or severity with increasing dose; however, ervogastat plus clesacostat was associated with a likely undesirable fasting lipid and apolipoprotein profile.

大多数不良事件的严重程度为轻度或中度，并且随着剂量的增加，其频率或严重程度并未增加；然而，ervogastat 加上 clesacostat 与可能不理想的空腹脂质和载脂蛋白谱相关。

The most common adverse eventwas inadequate control of diabetes (placebo: 4/34 [12%]; ervogastat 25 mg: 6/35 [17%]; ervogastat 75 mg: 5/48 [10%]; ervogastat 150 mg: 3/42 [7%]; ervogastat 300 mg: 2/31 [6%]; ervogastat 150 mg plus clesacostat 5 mg: 2/35 [6%]; ervogastat 300 mg plus clesacostat 10 mg: 2/30 [7%]).

最常见的不良事件是糖尿病控制不足（安慰剂：4/34 [12%]；ervogastat 25 mg：6/35 [17%]；ervogastat 75 mg：5/48 [10%]；ervogastat 150 mg：3/42 [7%]；ervogastat 300 mg：2/31 [6%]；ervogastat 150 mg 加上 clesacostat 5 mg：2/35 [6%]；ervogastat 300 mg 加上 clesacostat 10 mg：2/30 [7%]）。

There were no fatal events; 19/255 (7%) patients reported 20 serious adverse events (placebo: 1/34 [3%]; ervogastat 25 mg: 1/35 [3%]; ervogastat 75 mg: 5/48 [10%]; ervogastat 150 mg: 1/42 [2%]; ervogastat 300 mg: 4/31 [13%]; ervogastat 150 mg plus clesacostat 5 mg: 5/35 [14%]; ervogastat 300 mg plus clesacostat 10 mg: 2/30 [7%]).

没有发生致命事件；19/255（7%）的患者报告了20例严重不良事件（安慰剂：1/34 [3%]；ervogastat 25 mg：1/35 [3%]；ervogastat 75 mg：5/48 [10%]；ervogastat 150 mg：1/42 [2%]；ervogastat 300 mg：4/31 [13%]；ervogastat 150 mg 加 clesacostat 5 mg：5/35 [14%]；ervogastat 300 mg 加 clesacostat 10 mg：2/30 [7%]）。

interpretation

The combined efficacy, safety, and tolerability data with ervogastat supports continued investigation for its use in MASH.

ervogastat的综合疗效、安全性和耐受性数据支持继续研究其在MASH中的应用。

Larger and longer trials are needed to further assess ervogastat and ervogastat plus clesacostat for MASH treatment.

需要更大规模和更长期的试验来进一步评估ervogastat及其与clesacostat联合用于MASH治疗的效果。

funding

Pfizer.

辉瑞制药。