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.
Zheng et al. (Wed,) studied this question.