The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection.
This paper describes the preclinical pharmacological profiling and biomarker-guided selection process used to identify survodutide (BI 456906) as a clinical development candidate from a library of 19 dual glucagon receptor (GCGR)/GLP-1R agonists. Researchers assessed receptor potency using cAMP assays in CHO-K1 cells expressing human GCGR and GLP-1R, as well as in insulinoma (MIN6) cells and rat primary hepatocytes for endogenous receptor activity. In vivo target engagement was evaluated in lean mice using oral glucose tolerance tests (GLP-1R biomarker) and plasma FGF21 and liver NNMT mRNA expression (GCGR biomarkers). Efficacy was further tested in diet-induced obese (DIO) mice for body weight reduction and in diabetic db/db mice for glucose lowering. A strong correlation was found between in vitro and in vivo GCGR and GLP-1R biomarkers, enabling candidate ranking. Survodutide demonstrated balanced dual agonism, producing greater body weight reduction than selective GLP-1R agonists while maintaining comparable antidiabetic effects. Key limitations include that all efficacy data are from rodent models, and human pharmacological profiling is not reported in this paper. Survodutide is now in Phase 3 clinical trials for obesity.
Why this grade: All pharmacological profiling and efficacy data are derived from in vitro cell assays and rodent models (lean mice, DIO mice, db/db mice); no human clinical data are presented in this paper.
Aim To describe the biomarker strategy that was applied to select survodutide (BI 456906), BI 456908 and BI 456897 from 19 dual glucagon receptor (GCGR)/ glucagon-like peptide-1 receptor (GLP-1R) agonists for in-depth pharmacological profiling, which led to the qualification of survodutide as the clinical development candidate. Materials and methods Potencies to increase cyclic adenosine monophosphate (cAMP) were determined in Chinese hamster ovary (CHO)-K1 cells stably expressing human GCGR and GLP-1R. Agonism for endogenously expressed receptors was investigated in insulinoma cells (MIN6) for mouse GLP-1R, and in rat primary hepatocytes for the GCGR. In vivo potencies to engage the GLP-1R or GCGR were determined, measuring improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma fibroblast growth factor-21 (FGF21) and liver nicotinamide N-methyltransferase (NNMT) mRNA expression (100 nmol/kg), respectively. Body weight- and glucose-lowering efficacies were investigated in diet-induced obese (DIO) mice and diabetic db/db mice, respectively. Results Upon acute dosing in lean mice, target engagement biomarkers for the GCGR and GLP-1R demonstrated a significant correlation (Spearman correlation coefficient with p Conclusions Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP-1R pharmacology, engaging the GCGR for robust body weight-lowering efficacy exceeding that of selective GLP-1R agonists, while achieving antidiabetic efficacy that was comparable to selective GLP-1R agonism. Survodutide is currently being investigated in Phase 3 clinical trials in people living with obesity.
Educational summary of published research — not medical advice. License: cc by-nc-nd. Full text is shown only where licensing permits.