3065-LB: Nonclinical Profile of AMB-702, a Potent and Novel Oral GLP-1 Receptor Agonist

Introduction and Objective: Oral, small-molecule GLP-1RA receptor agonists hold significant promise to provide durable weight loss and improved long-term outcomes for those living with obesity, Type 2 diabetes or other chronic cardiometabolic disorders. The objective of this research was to demonstrate the differentiated profile of the oral GLP-1 receptor agonist and development candidate, AMB-702, with respect to: in vitro potency and selectivity, favorable pharmacokinetic properties and in vivo efficacy in mice and nonhuman primates. Methods: In vitro assays included cellular agonist activity and ADME profiling (permeability, transporter and CYP activity, microsome stability). In vivo studies included pharmacokinetics in mouse and cynomolgus monkey; acute pharmacodynamic studies in transgenic humanized GLP-1R mice food intake and glycemic control (IPGTT) and 7-day studies in cynomolgus monkeys assessing weight loss, food intake and tolerability. Results: AMB-702 demonstrated 1 nM potency in the GLP-1R cAMP assay, no beta arrestin activity and high permeability with low predicted clearance. In vivo oral exposure in mouse and monkey showed cellular EC50 target coverage at 24 hrs (fraction unbound, Ctrough). After a single dose in mice, significant decreases in food intake occurred. In an IPGTT, a 50% decrease in glucose AUC and a 3-fold increase in insulin secretion was seen. In the cynomolgus monkey, 1 or 2 mg/kg (PO, QD x 7d) resulted in body weight loss of 10.5% or 12.6%, respectively. Corresponding decreases in food intake occurred. Tolerability was demonstrated with minimal GI effects and serum chemistry and hematology parameters within normal limits after 7 days of dosing. Conclusion: AMB-702 demonstrated exquisite potency, desirable ADME and oral pharmacokinetic properties with robust efficacy in transgenic humanized GLP-1R mice and in the cynomolgus monkey. These data support the potential of AMB-702 as a treatment for obesity and type 2 diabetes. IND-enabling toxicology and safety studies are in progress to support clinical development. Disclosure P.A.Lee: Employee; Current; Ambrosia Biosciences. R.Linwood: Employee; Current; Ambrosia Biosciences. S.C.Peck: Employee; Current; Ambrosia Biosciences. N.Traggis: Employee; Current; Ambrosia Biosciences. K.D.Brown: Employee; Current; Ambrosia Biosciences. E.Hicken: Employee; Current; Ambrosia Biosciences. D.S.Backos: Employee; Current; Ambrosia Biosciences. D.Kahn: n/a. R.Pipal: None. B.Campos: None. M.C.Hilton: None. M.Martinson: Employee; Current; Ambrosia Biosciences Inc.