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

• Published in: Cell metabolism Vol. 34; no. 1; pp. 59 - 74.e10
• Main Authors: Bossart, Martin, Wagner, Michael, Elvert, Ralf, Evers, Andreas, Hübschle, Thomas, Kloeckener, Tim, Lorenz, Katrin, Moessinger, Christine, Eriksson, Olof, Velikyan, Irina, Pierrou, Stefan, Johansson, Lars, Dietert, Gabriele, Dietz-Baum, Yasmin, Kissner, Thomas, Nowotny, Irene, Einig, Christine, Jan, Christelle, Rharbaoui, Faiza, Gassenhuber, Johann, Prochnow, Hans-Peter, Agueusop, Inoncent, Porksen, Niels, Smith, William B., Nitsche, Almut, Konkar, Anish
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.01.2022
• Subjects: Animals; Gastric Inhibitory Polypeptide; GCG; GCG GIP GLP-1 metabolic disease pharmacodynamics receptor occupancy safety triple GLP-1/GIP/GCG receptor agonist type 2 diabetes; GIP; GLP-1; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glycemic Control; Humans; Incretins - pharmacology; metabolic disease; Peptides - pharmacology; pharmacodynamics; receptor occupancy; Receptors, Gastrointestinal Hormone - agonists; Receptors, Glucagon - agonists; safety; triple GLP-1/GIP/GCG receptor agonist; type 2 diabetes; Weight Loss - drug effects; GLP-1; type 2 diabetes; pharmacodynamics; safety; receptor occupancy; GCG; triple GLP-1/GIP/GCG receptor agonist; metabolic disease; GIP
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2021.12.005

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 engagement of the three receptors by SAR441255 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.