1684-P: A GLP-1 Analogue Optimized for cAMP-Biased Signaling Improves Weight Loss in Obese Mice

Introduction and Objective: Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism is foundational to obesity pharmacotherapies like semaglutide. These compounds were engineered for maximal G protein alpha(s) (Gsα) signaling potency and downstream cAMP production. However, this strategy requires reconsideration as partial, biased GLP-1R agonists characterized by decreased Gsα signaling and disproportionate reductions in β-arrestin recruitment relative to the native ligand provide greater weight loss than full, balanced agonists in preclinical models. Methods: We tested the hypothesis that in vitro signaling bias, which considers both cAMP signaling and β-arrestin recruitment, better predicts weight loss in diet induced obese (DIO) rodents than cAMP potency alone. Results: Our data demonstrates that the signaling bias metric β significantly correlates to GLP-1R agonist mediated weight loss in diet-induced obese mice. We further characterized a protracted GLP-1 analogue (NNC5840) which exhibits a partial, cAMP biased GLP-1R signaling profile in vitro and demonstrates superior maximal body weight reduction compared to semaglutide in DIO mice. The NNC5840 weight loss profile is characterized by reduced in vivo potency but increased maximal efficacy. Conclusion: These data suggest that drug discovery screening strategies which take a holistic approach to target receptor signaling may provide more efficacious candidate molecules. Disclosure J.D. Douros: Employee; Novo Nordisk. D. Perez-Tilve: Research Support; MBX Biosciences, Novo Nordisk A/S. Other Relationship; BlueWater LLC, Ghrelco LLC. Consultant; Eli Lilly and Company, Ampeptec. M. Capozzi: None. B.N. DuBois: Employee; Novo Nordisk. R. Rohlfs: Employee; Novo Nordisk. J. Mokrosinski: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. R. Augustin: None. S.A. Mowery: Employee; Novo Nordisk. M. Waldhoer: Consultant; Schrödinger. P.J. Knerr: Employee; Novo Nordisk A/S. Consultant; Toralgen, Inc. Funding This research was partially supported by Novo Nordisk and The European Union within the scope of the European Research Council ERC-CoG Trusted no.101044445, awarded to Timo D. Mueller.