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

  • Cell Metab. 2022 Jan 4;34(1):59-74.e10. doi: 10.1016/j.cmet.2021.12.005.
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
Affiliations
  • 1. Synthetic Medicinal Modalities, Integrated Drug Discovery Germany, Sanofi, Frankfurt, Germany. Electronic address: [email protected].
  • 2. Synthetic Medicinal Modalities, Integrated Drug Discovery Germany, Sanofi, Frankfurt, Germany.
  • 3. TA Diabetes, Sanofi, Frankfurt, Germany.
  • 4. Antaros Medical AB, Mölndal, Sweden; Science For Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
  • 5. Science For Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden; PET Centre, Centre for Medical Imaging, Uppsala University Hospital, Uppsala, Sweden.
  • 6. Antaros Medical AB, Mölndal, Sweden.
  • 7. Preclinical Safety, Sanofi, Frankfurt, Germany.
  • 8. Translational Medicine & Early Development, Sanofi, Frankfurt, Germany.
  • 9. Clinical Sciences & Operations, Sanofi, Frankfurt, Germany.
  • 10. Clinical Sciences & Operations, Sanofi, Chilly-Mazarin, France.
  • 11. Diabetes Development, Sanofi, Frankfurt, Germany.
  • 12. NOCCR Alliance for Multispecialty Research (AMR), Knoxville, TN, USA.
  • 13. TA Diabetes, Sanofi, Frankfurt, Germany. Electronic address: [email protected].
PMID: 34932984 DOI: 10.1016/j.cmet.2021.12.005
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.

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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