Zhang Hong, Li Qianqian, Chen Hong, Guo Lingfeng, Li Jing, Xie Can, Yan Jiangyu, Ding Yanhua
Phase I Clinical Research Center, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
Dongguan HEC Biopharmaceutical R&D Co., Ltd, Dongguan, China.
BioDrugs. 2025 May;39(3):477-486. doi: 10.1007/s40259-025-00715-3. Epub 2025 Apr 3.
HEC88473 is a novel long-acting dual agonist of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) receptors. It is a Fc fusion protein containing a fibroblast growth factor 21 and a GLP-1 moiety, fused to the N-terminal and C-terminal of the Fc fragment, respectively.
This study aimed to evaluate the clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of HEC88473.
The clinical safety, tolerability, pharmacokinetics, and preliminary pharmacodynamics of HEC88473 (0.5-62.9 mg) were evaluated in a phase I, single-ascending dose trial with healthy and obese subjects. Serum glucose, lipid, and adiponectin levels were evaluated.
HEC88473 was slowly absorbed and metabolized into Fc-GLP-1 and Fc-FGF21 after dosing. In healthy participants, the median times to observed maximum serum concentration of HEC88473, Fc-GLP-1, and Fc-FGF21 were all in the range of 12.00-14.00 h, and their geomean half-lives were 16.2-22.6, 66.5-119.5, and 28.4-41.6 h, respectively. Their systemic exposure increased slightly more than proportionally to the dose. In healthy subjects, serum glucose decreased from baseline (day 1) in the oral glucose tolerance test at days 3 and 7 after HEC88473 administration with doses ≥ 5.1 mg, and the largest reduction occured in the 47.6-mg dose group, which was -1.829 mmol/L after baseline and placebo adjustment. At doses of ≥ 10.2 mg, adiponectin levels showed an upward trend with the dose and treatment time, and the average percentage increase of adiponectin from baseline was up to 90.71% in the 62.9-mg dose group. At doses of ≥ 17.0 mg, triglyceride levels showed a significant reduction from baseline in a certain dose-dependent manner, and the average percentage of triglyceride decrease from baseline was up to - 43.01% in the 62.9-mg dose group. HEC88473 was well tolerated, with the majority of treatment-related adverse events being gastrointestinal disorders of mild severity.
HEC88473 is well tolerated in healthy and obese subjects, and it shows glucose-lowering and lipid-lowering efficacies. The data support further clinical evaluations of HEC88473 for the treatment of metabolic diseases.
This study was registered at ClinicalTrials.gov (registration number: NCT05943886).
HEC88473是一种新型的胰高血糖素样肽1（GLP-1）和成纤维细胞生长因子21（FGF21）受体长效双激动剂。它是一种Fc融合蛋白，分别在Fc片段的N端和C端融合了一个成纤维细胞生长因子21和一个GLP-1部分。
本研究旨在评估HEC88473的临床安全性、耐受性、药代动力学和药效学。
在一项针对健康和肥胖受试者的I期单剂量递增试验中，评估了HEC88473（0.5 - 62.9 mg）的临床安全性、耐受性、药代动力学和初步药效学。评估了血清葡萄糖、脂质和脂联素水平。
给药后，HEC88473吸收缓慢，并代谢为Fc-GLP-1和Fc-FGF21。在健康受试者中，观察到的HEC88473、Fc-GLP-1和Fc-FGF21血清浓度最大值的中位时间均在12.00 - 14.00小时范围内，其几何平均半衰期分别为16.2 - 22.6小时、66.5 - 119.5小时和28.4 - 41.6小时。它们的全身暴露量随剂量增加略有超比例增加。在健康受试者中，在给予剂量≥5.1 mg的HEC88473后第3天和第7天的口服葡萄糖耐量试验中，血清葡萄糖较基线（第1天）降低，最大降幅出现在47.6 mg剂量组，经基线和安慰剂调整后为-1.829 mmol/L。在剂量≥10.2 mg时，脂联素水平随剂量和治疗时间呈上升趋势，在62.9 mg剂量组中，脂联素较基线的平均百分比增加高达90.71%。在剂量≥17.0 mg时，甘油三酯水平从基线开始以一定的剂量依赖性方式显著降低，在62.9 mg剂量组中，甘油三酯较基线降低的平均百分比高达-43.01%。HEC88473耐受性良好，大多数与治疗相关的不良事件为轻度胃肠道疾病。
HEC88473在健康和肥胖受试者中耐受性良好，并显示出降糖和降脂功效。这些数据支持对HEC88473治疗代谢性疾病进行进一步的临床评估。
本研究已在ClinicalTrials.gov注册（注册号：NCT05943886）。
