OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes

Dec 6, 2023European journal of pharmacology

OXM-104 as a potential treatment for obesity, fatty liver disease, and type 2 diabetes

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Abstract

OXM-104, a dual GLP-1 and glucagon receptor agonist, demonstrated significant reductions in body weight and improved glucose control in mouse models.

OXM-104 activated only the GLP-1 and glucagon receptors without affecting the GIP receptor.
Both OXM-104 and cotadutide showed greater hepatoprotective effects compared to semaglutide, including reductions in liver fat and fibrosis.
All three agents, OXM-104, cotadutide, and semaglutide, resulted in marked weight loss and enhanced glucose regulation.
The improved NAFLD activity score with OXM-104 and cotadutide highlights the significance of glucagon receptor activation in metabolic health.

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OBJECTIVE: Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104.

METHODS: The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH).

RESULTS: OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor.

CONCLUSION: These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.

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OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes

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