Wong Vincent Wai-Sun, Amin Neeta B, Takahashi Hirokazu, Darekar Amanda, Tacke Frank, Kiszko Jan, Rodriguez Hector, Nakajima Atsushi, Alkhouri Naim, Charlton Michael, Anstee Quentin M
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Pfizer Research and Development, Cambridge, MA, USA.
Lancet Gastroenterol Hepatol. 2025 Oct;10(10):924-940. doi: 10.1016/S2468-1253(25)00128-1. Epub 2025 Jul 31.
Ervogastat, a diacylglycerol acyltransferase 2 (DGAT2) inhibitor, and clesacostat, an acetyl-coenzyme A carboxylase (ACC) inhibitor, have shown promise in reducing hepatic steatosis. Increased circulating triglycerides, a mechanistic consequence of ACC inhibitors, has been shown to be downregulated by DGAT2 inhibitor co-administration. 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.
This phase 2 double-blind, double-dummy, randomised study was conducted at 198 clinical sites across 11 countries. 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. 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. Patients were analysed according to the treatment group they were assigned to. 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. This completed trial was registered with ClinicalTrials.gov (NCT04321031).
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. Thus, the primary endpoint was not met by any doses of ervogstat alone, but was met by both dose levels of ervogastat plus clesacostat. 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. 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. The most common adverse event was 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%]). 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%]).
The combined efficacy, safety, and tolerability data with ervogastat supports continued investigation for its use in MASH. Larger and longer trials are needed to further assess ervogastat and ervogastat plus clesacostat for MASH treatment.
Pfizer.
二酰甘油酰基转移酶2（DGAT2）抑制剂埃沃加司他和乙酰辅酶A羧化酶（ACC）抑制剂可司他已显示出在减轻肝脂肪变性方面的前景。ACC抑制剂的一个机制性后果是循环甘油三酯升高，而联合使用DGAT2抑制剂已显示可下调这种情况。我们评估了埃沃加司他单药以及埃沃加司他联合可司他对经活检确诊为代谢功能障碍相关脂肪性肝炎（MASH）且纤维化程度为2期或3期的成人患者的疗效和安全性。
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。使用计算机生成的随机编码（随机排列区组法）以相等比例将患者分配至治疗组，并根据纤维化程度（F2与F3）进行分层，通过交互式响应技术系统将患者分配至埃沃加司他（25毫克、75毫克、150毫克或300毫克）、埃沃加司他联合可司他（150毫克加5毫克或300毫克加10毫克）或安慰剂组，每日两次，共48周。主要终点是在第48周时实现MASH缓解且纤维化无恶化、至少有1期纤维化改善且MASH无恶化或两者兼具的患者比例。根据患者被分配的治疗组进行分析。主要终点基于全分析集（所有随机分配且至少服用一剂研究药物并提供可评估基线活检数据的患者）进行分析，其中未进行第48周活检的患者被视为无反应者。这项完成的试验已在ClinicalTrials.gov注册（NCT04321031）。
招募于2020年6月15日开始；随机分组于2023年2月22日完成，255名患者被随机分配并接受治疗（占计划样本量的73%；埃沃加司他25毫克组：N = 35；埃沃加司他75毫克组：N = 48；埃沃加司他150毫克组：N = 42；埃沃加司他300毫克组：N = 31；埃沃加司他150毫克加可司他5毫克组：N = 35；埃沃加司他300毫克加可司他10毫克组：N = 30；安慰剂组：N = 34）。安慰剂组中有13名（38%）患者达到复合主要终点，埃沃加司他25毫克组中有16名（46%）患者达到（达到主要终点的患者比例与安慰剂组的差异为0·08 [90% CI -0·11至0·27]），埃沃加司他75毫克组中有25名（52%）患者达到（0·14 [-0·04至0·32]），埃沃加司他150毫克组中有21名（50%）患者达到（0·12 [-0·07至0·30]），埃沃加司他300毫克组中有14名（45%）患者达到（0·07 [-0·12至0·27]）。埃沃加司他150毫克加可司他5毫克组中有23名（66%）患者（与安慰剂组的差异为0·27 [
