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

Bossart M, Wagner M, Elvert R, Evers A, Hübschle T, Kloeckener T, Lorenz K, Moessinger C, Eriksson O, Velikyan I, Pierrou S, Johansson L, Dietert G, Dietz-Baum Y, Kissner T, Nowotny I, Einig C, Jan C, Rharbaoui F, Gassenhuber J, Prochnow HP, Agueusop I, Porksen N, Smith WB, Nitsche A, Konkar A

Cell Metab. 34 (1) 59-74.e10 [2022-01-04; online 2021-12-20]

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.

Olof Eriksson

SciLifeLab Fellow

PubMed 34932984

DOI 10.1016/j.cmet.2021.12.005

Crossref 10.1016/j.cmet.2021.12.005

pii: S1550-4131(21)00624-0
ClinicalTrials.gov: NCT04521738

Publications 9.5.0