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

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

Affiliations

  • 1 Synthetic Medicinal Modalities, Integrated Drug Discovery Germany, Sanofi, Frankfurt, Germany. Electronic address: martin.bossart@sanofi.com.
  • 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: konkar_anish@lilly.com.
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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