作者
Martin Bossart,Michael Wagner,Ralf Elvert,Andreas Evers,Thomas Hübschle,Tim Kloeckener,Katrin Lorenz,Christine Moessinger,Olof Eriksson,Irina Velikyan,Stefan Pierrou,L. E. B. Johansson,Gabriele Dietert,Yasmin Dietz-Baum,Thomas Kissner,Irene Nowotny,Christine Einig,Christelle Jan,Faïza Rharbaoui,Johann Gassenhuber,Hans-Peter Prochnow,Inoncent Agueusop,Niels Pörksen,William B. Smith,Almut Nitsche,Anish Konkar
摘要
Summary
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.