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.

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).