Xiang Lin, Wang Guixia, Zhuang Yulei, Luo Lin, Yan Jiangyu, Zhang Hong, Li Xiaojiao, Xie Can, He Qingwei, Peng Yuyu, Chen Hong, Li Qianqian, Li Xiaoping, Guo Linfeng, Lv Guoyue, Ding Yanhua
Phase I Clinical Trial Center, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China.
Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China.
J Hepatol. 2025 Jun;82(6):967-978. doi: 10.1016/j.jhep.2024.12.006. Epub 2024 Dec 19.
BACKGROUND & AIMS: Glucagon-like peptide-1 (GLP-1) and fibroblast growth factor 21 (FGF21) are key regulators of glucose and lipid metabolism. In the present study, we assessed the safety and efficacy of a novel GLP-1/FGF21 dual agonist HEC88473 for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) combined with type 2 diabetes mellitus (T2DM).
This was a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase Ib/IIa trial. Sixty patients with MASLD and T2DM were randomized (10:2) to receive HEC88473 (5.1, 15.3, 30.6, 45.9, or 68.0 mg) or placebo via weekly subcutaneous injection for 5 weeks.
After 5 weeks of treatment with HEC88473, MRI-proton density fat fraction (MRI-PDFF) was reduced in a dose-proportional manner. The largest relative mean change reached -47.21% (p = 0.0143) in the 30.6 mg cohort, compared with -15.05% in the placebo group, with a higher proportion of >30% relative reductions in patients with baseline PDFF >8%. The 5-week treatment with HEC88473 significantly reduced levels of HbA1c (glycated hemoglobin), as well as fasting and postprandial glucose levels. The largest mean change in HbA1c was -1.10% in the 68.0 mg cohort, compared with -0.31% in the placebo group. Improvement was also observed in participants' lipid profiles. Most adverse events were mild to moderate in severity. The most frequently reported adverse events were gastrointestinal disorders (n = 29, 48.3%).
Herein, we report the clinical safety and proof-of-concept data for the GLP-1/FGF21 dual agonist HEC88473. A 5-week treatment with HEC88473 was generally safe and well tolerated, with multiple positive effects observed, including reduced liver fat, and improved glycemic control, insulin resistance and lipid metabolism, together indicating comprehensive improvement in metabolic syndrome.
In this randomized, double-blind, placebo-controlled phase Ib/IIa study, we assessed clinical safety, pharmacodynamic and pharmacokinetic data of the GLP-1/FGF21 dual agonist HEC88473 in patients with MASLD (metabolic dysfunction-associated steatotic liver disease) and T2DM (type 2 diabetes mellitus). HEC88473 was generally safe and well tolerated. The GLP-1/FGF21 dual agonist significantly reduced the hepatic fat fraction assessed using MRI-proton density fat fraction, and improved glycemic control and lipid profiles with only 5 weeks' treatment, leading to comprehensive improvement in metabolic syndrome. The present results suggest that HEC88473 could be a promising treatment option in this patient population.
Chinese Drug Trial Identifier (http://www.chinadrugtrials.org.cn/index.html): CTR20211088.
GOV: NCT05943886.
胰高血糖素样肽-1（GLP-1）和成纤维细胞生长因子21（FGF21）是葡萄糖和脂质代谢的关键调节因子。在本研究中，我们评估了新型GLP-1/FGF21双重激动剂HEC88473治疗代谢功能障碍相关脂肪性肝病（MASLD）合并2型糖尿病（T2DM）的安全性和有效性。
这是一项随机、双盲、安慰剂对照、多剂量递增的Ib/IIa期试验。60例MASLD和T2DM患者被随机分组（10:2），通过每周皮下注射接受HEC88473（5.1、15.3、30.6、45.9或68.0mg）或安慰剂治疗，为期5周。
用HEC88473治疗5周后，磁共振成像质子密度脂肪分数（MRI-PDFF）呈剂量依赖性降低。在30.6mg剂量组中，最大相对平均变化达到-47.21%（p=0.0143），而安慰剂组为-15.05%，基线PDFF>8%的患者中相对降低>30%的比例更高。用HEC88473进行5周治疗可显著降低糖化血红蛋白（HbA1c）水平以及空腹和餐后血糖水平。在68.0mg剂量组中，HbA1c的最大平均变化为-1.10%，而安慰剂组为-0.31%。参与者的血脂谱也有改善。大多数不良事件的严重程度为轻度至中度。最常报告的不良事件是胃肠道疾病（n=29，48.3%）。
在此，我们报告了GLP-1/FGF21双重激动剂HEC88473的临床安全性和概念验证数据。用HEC88473进行5周治疗总体上是安全的且耐受性良好，观察到多种积极效果，包括肝脏脂肪减少、血糖控制改善、胰岛素抵抗改善和脂质代谢改善，共同表明代谢综合征得到全面改善。
在这项随机、双盲、安慰剂对照的Ib/IIa期研究中，我们评估了GLP-1/FGF21双重激动剂HEC88473在MASLD（代谢功能障碍相关脂肪性肝病）和T2DM（2型糖尿病）患者中的临床安全性、药效学和药代动力学数据。HEC88473总体上是安全的且耐受性良好。GLP-1/FGF21双重激动剂仅治疗5周就能显著降低用MRI质子密度脂肪分数评估的肝脏脂肪分数，并改善血糖控制和血脂谱，从而使代谢综合征得到全面改善。目前的结果表明，HEC88473可能是该患者群体中有前景的治疗选择。
中国药物试验标识符（http://www.chinadrugtrials.org.cn/index.html）：CTR20211088。
美国国立医学图书馆临床试验数据库：NCT05943886。
