Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist.

Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism. [Display omitted] • SAR441255 showed substantial body weight loss in diabetic obese monkeys • SAR441255 also improved glucose control in diabetic obese monkeys • PET imaging in monkeys confirmed high receptor occupancy with SAR441255 • In healthy subjects, biomarkers confirmed simultaneous SAR441255 receptor engagement Bossart et al. designed a unimolecular triple GLP-1R/GCGR/GIPR agonist with substantial metabolic activity in preclinical animal models. In a single-dose study in human subjects, SAR441255 lowered plasma glucose during a mixed-meal tolerance test with a decrease in plasma biomarker levels supportive of engagement at all three targeted receptors. [ABSTRACT FROM AUTHOR]