Scholarlink

Background <p>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.</p> Objectives <p>This study aimed to evaluate the clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of HEC88473.</p> Methods <p>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.</p> Results <p>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&#xa0;h, and their geomean half-lives were 16.2–22.6, 66.5–119.5, and 28.4–41.6&#xa0;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 ≥&#xa0;5.1 mg, and the largest reduction occured in the 47.6-mg dose group, which was −1.829&#xa0;mmol/L after baseline and placebo adjustment. At doses of ≥&#xa0;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 ≥&#xa0;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 −&#xa0;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.</p> Conclusions <p>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.</p> Clinical Trial Registration <p>This study was registered at ClinicalTrials.gov (registration number: NCT05943886).</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

First-in-Human Study on Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Escalating Doses of HEC88473, a Novel Dual GLP-1 and FGF21 Receptor Agonist in Healthy and Obese Chinese Subjects

  • 期刊论文

  • 发表日期：

    2025年4月3日

查看全文
  • Hong Zhang,
  • Qianqian Li,
  • Hong Chen,
  • Lingfeng Guo,
  • Jing Li,
  • Can Xie,
  • Jiangyu Yan,
  • Yanhua Ding

摘要

Background

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.

Objectives

This study aimed to evaluate the clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of HEC88473.

Methods

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.

Results

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.

Conclusions

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.

Clinical Trial Registration

This study was registered at ClinicalTrials.gov (registration number: NCT05943886).