What does this research mean for the field?

The novel unimolecular GLP-1 and amylin receptor agonist ZT009 reduces body weight and food intake with superior efficacy and pharmacokinetic properties compared to amycretin in preclinical models. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to evaluate the efficacy and pharmacokinetic properties of ZT009, a novel unimolecular dual agonist for treating obesity.

June 7, 2026

2552-P: Preclinical Proof of Concept of ZT009, a Novel Unimolecular Long-Acting GLP-1 and Amylin Receptor Agonist

Key Points

This research aims to evaluate the efficacy and pharmacokinetic properties of ZT009, a novel unimolecular dual agonist for treating obesity.
In vitro assessments were performed using BHK and CHO cell lines for receptor activity evaluation.
In vivo efficacy was tested in lean rats and diet-induced obese rats, comparing ZT009 to amycretin.
Pharmacokinetic parameters were measured in rats, minipigs, and monkeys to assess stability and half-life.
ZT009 enhanced AMY3R activity by 5.1-fold compared to amycretin and reduced GLP-1 activity to 0.6-fold of amycretin.
Both lean and DIO rats showed significant body weight and food intake reduction with ZT009 compared to amycretin.
ZT009 exhibited a prolonged half-life and improved GI tolerability, showing reduced peak-to-trough variability.

Abstract

Introduction and Objective: Combination of GLP 1 and amylin analogs has emerged as next generation therapeutics for the treatment of obesity. We developed ZT009, a novel, long-acting unimolecular GLP-1 and Amylin receptor agonist, aiming to provide better efficacious and convenient treatment for obesity. Here, we report preclinical data supporting its therapeutic potential. Methods: In vitro activities of ZT009 on GLP-1 and amylin were assessed using a BHK cell line that overexpresses the human GLP-1 receptor, and a CHO cell line co-overexpressing the human amylin receptor-3 (AMY3R), respectively. In vivo tests were carried out in both lean rats and diet-induced obese (DIO) rats to demonstrate the pharmacological efficacy of ZT009 as compared to amycretin. The pharmacokinetic (PK) parameters were measured in rats, minipigs and monkeys. Results: ZT009 is an engineered peptide conjugate comprising GLP-1 and amylin analogs linked via a peptide linker and acylated with a fatty acid for time-action extension. It demonstrated high solubility and stability at neutral pH. In cell-based assays, ZT009 was designed to enhance AMY3R activity by 5.1-fold compared to amycretin, maximizing beneficial metabolic effects. Additionally, it was designed to moderately reduce GLP-1 activity to 0.6-fold that of amycretin, thereby minimizing GI side effects, while maintaining a wide safety margin. In lean rats and DIO rats, ZT009 dose-dependently reduced body weight and food intake with effects exceeding those of amycretin at same dose. Importantly, ZT009 exhibited a significantly prolonged half-life and delayed Tmax across all species tested compared to amycretin, suggesting reduced peak-to-trough variability and enhanced GI tolerability in clinical translation. Conclusion: These preclinical data demonstrate that ZT009 is a potent, long-acting dual GLP-1 and amylin receptor agonist with superior pharmacology and pharmacokinetic properties. ZT009 represents a promising next-generation candidate for obesity therapy, supporting further clinical development. Disclosure Y. Zhang: None. B. Wu: None. B. Zhang: None. X. Zhao: None. X. Chen: None. M. Wang: None. H. Jiang: None. P. Gao: None. S. Lin: None. X. Zhang: None. Y. Zhang: None.

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