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. 2022 Jan 4;34(1):59-74.e10.
doi: 10.1016/j.cmet.2021.12.005. Epub 2021 Dec 20.

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

Martin Bossart  1 , Michael Wagner  2 , Ralf Elvert  3 , Andreas Evers  2 , Thomas Hübschle  3 , Tim Kloeckener  3 , Katrin Lorenz  2 , Christine Moessinger  3 , Olof Eriksson  4 , Irina Velikyan  5 , Stefan Pierrou  6 , Lars Johansson  6 , Gabriele Dietert  7 , Yasmin Dietz-Baum  7 , Thomas Kissner  7 , Irene Nowotny  8 , Christine Einig  9 , Christelle Jan  10 , Faiza Rharbaoui  8 , Johann Gassenhuber  8 , Hans-Peter Prochnow  8 , Inoncent Agueusop  9 , Niels Porksen  11 , William B Smith  12 , Almut Nitsche  11 , Anish Konkar  13
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Free article

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

Martin Bossart et al. Cell Metab. .
Free article

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.

Trial registration: ClinicalTrials.gov NCT04521738.

Keywords: GCG; GIP; GLP-1; metabolic disease; pharmacodynamics; receptor occupancy; safety; triple GLP-1/GIP/GCG receptor agonist; type 2 diabetes.

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Conflict of interest statement

Declaration of interests M.B., M.W., R.E., A.E., T.H., T. Kloeckener, K.L., C.M., G.D., Y.D.-B., T. Kissner, I.N., C.E., C.J., F.R., J.G., H.-P.P., I.A., N.P., A.N., and A.K. were employees of Sanofi when the studies were conducted and may hold shares and/or stock options in the company. M.B., M.W., A.E., and K.L. are inventors on the patent application WO2018100135 containing SAR441255. O.E. and S.P. are employees of Antaros Medical AB, which received payment for the practical conduct of the PET study. Otherwise, they declare no competing interests. L.J. is co-founder, co-owner, and employee of Antaros Medical AB, which received payment for the practical conduct of the PET study. Otherwise, L.J. declares no competing interests. I.V. is an employee of Uppsala University Hospital, which received payment for the practical conduct of the PET study. I.V. declares no competing interests. W.B.S. was the principal investigator of the study conducted at the MDNOCCR Alliance for Multispecialty Research (AMR)/DBA NOCCR (New Orleans Center for Clinical Research), Knoxville, Tennessee, and received payment for the practical conduct of the study. No payment was received for the preparation of this manuscript. No other potential conflicts of interest relevant to this article were reported.

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