Discovery and Preclinical Evaluation of TPM003: A Novel GLP-1/GIP/Glucagon Triple Hormone Receptor Agonist with Robust Efficacy in Obesity and NASH

Harnessing
the simultaneous activation of GLP-1R, GIPR, and GCGR
has emerged as a highly promising therapeutic paradigm for obesity
and related metabolic diseases, including nonalcoholic steatohepatitis
(NASH). Here, we report the discovery of TPM003, a novel unimolecular
GLP-1R/GIPR/GCGR triple agonist engineered by using a long-acting
PEG-fatty acid (PEG-FA) stapling technology. TPM003 exhibits balanced
triple receptor agonism and demonstrates an extended systemic half-life
across multiple species. In obese mice, TPM003 induced robust and
durable weight loss, accompanied by broad improvements in metabolic
parameters, outperforming current GLP-1RA standards. Importantly,
TPM003 also effectively reversed hepatic steatosis and improved markers
of liver function in multiple NASH models. Furthermore, TPM003 is
compatible with SNAC-based absorption enhancement, enabling oral delivery
in a tablet formulation. Collectively, these findings highlight the
therapeutic advantages of balanced GLP-1R/GIPR/GCGR agonism for obesity
and NASH and support TPM003 as a promising preclinical candidate with
translational potential.