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

Abstract

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.

• Authors: Martin Bossart, Michael Wagner, Ralf Elvert, Andreas Evers, Thomas Hübschle, Tim Kloeckener, Katrin Lorenz, Christine Moessinger, Olof Eriksson, Irina Velikyan, Stefan Pierrou, Lars Johansson, Gabriele Dietert, Yasmin Dietz-Baum, Thomas Kissner, Irene Nowotny, Christine Einig, Christelle Jan, Faiza Rharbaoui, Johann Gassenhuber, Hans-Peter Prochnow, Inoncent Agueusop, Niels Porksen, William B Smith, Almut Nitsche, Anish Konkar
• Journal: Cell metabolism (Cell Metab) Vol. 34 Issue 1 Pg. 59-74.e10 (01 04 2022) ISSN: 1932-7420 [Electronic] United States
• PMID: 34932984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Glucagon-Like Peptide-1 Receptor
• Incretins
• Peptides
• Receptors, Gastrointestinal Hormone
• Receptors, Glucagon
• Gastric Inhibitory Polypeptide
• Glucagon-Like Peptide 1
• gastric inhibitory polypeptide receptor

Topics

• Animals
• Gastric Inhibitory Polypeptide
• Glucagon-Like Peptide 1
• Glucagon-Like Peptide-1 Receptor (agonists)
• Glycemic Control
• Humans
• Incretins (pharmacology)
• Peptides (pharmacology)
• Receptors, Gastrointestinal Hormone (agonists)
• Receptors, Glucagon (agonists)
• Weight Loss (drug effects)