755-P: Metabolic Adaptation of Liver with Treatment of HM15275, a Long-Acting GLP-1/GIP/Glucagon Triple Agonist, Supporting Lean Mass Preservation

Introduction and Objective: Weight-loss quality (WLQ) has emerged as a challenge in developing GLP-1-based therapies. Previous nonclinical studies demonstrated that HM15275 achieved superior WLQ compared to Tirzepatide (TZP), a GLP-1/GIP dual agonist. This study aimed to extract mechanistic insights of different WLQ from altered metabolic pathways influenced by either treatment. Methods: RNA sequencing was conducted on liver from diet-induced obese (DIO) mice treated with HM15275 or TZP for 11 days. Biological processes affected by the treatment were identified using Gene Set Variation Analysis (GSVA) and pathways from MSigDB, including Hallmark, KEGG, Reactome, Wikipathways, and Gene Ontology. Results: HM15275 sustained fat metabolic pathways, including fatty acid beta-oxidation and transport, while down-regulated in TZP, contributing to greater fat mass loss under fasting-related metabolic challenges. HM15275 suppressed amino acid catabolic pathways relative to TZP, supporting lean mass preservation. HM15275 activated pathways related with glucose generation greater than TZP revealed by enrichment of gluconeogenesis and lactate recycling pathway, however, fasting blood glucose remained lower than vehicle treated implying limited effect on glucose intolerance. Furthermore, HM15275 downregulated ketone body synthesis compared to TZP, priming production of glucose rather than ketone body. Conclusion: HM15275 induces significant metabolic adaptations in liver, explaining improved WLQ compared with TZP. By preserving fat metabolism, suppressing amino acid catabolism, and enhancing gluconeogenesis and lactate recycling, HM15275 promotes greater fat mass loss with preserving lean mass. Furthermore, by prioritizing glucose generation over ketogenesis, HM15275 supports efficient energy metabolism without causing glucose intolerance. These findings imply heterogenous metabolic adaptation under different anti-obesity drugs explaining their WLQ. Disclosure H. Lee: Employee; Hanmi Pharm. Co., Ltd. S. Park: None. Y. Kim: None. Y. Kim: None. J. Kim: None. D. Lee: None. J.A. Kim: None. S. Bae: None. S. Lee: None. H. Chon: Employee; Hanmi Pharm. Co., Ltd. I. Choi: None.