723-P: The Dual Glucagon and Glucagon-Like Peptide-1 Receptor (GCGR/GLP-1R) Agonist BI 4569Reduces Body Weight in Diet-Induced Obese Mice Based on Food Intake Reduction and an Increase in Energy Expenditure

BI 4569 is a synthetic peptide optimized to simultaneously engage the GCGR and GLP-1R. BI 4569 contains a fatty acid-based half-life extension that supports once-weekly subcutaneous injection in humans, and is currently in clinical investigation in patients with obesity or NASH. BI 4569 activates the human GCGR and GLP-1R in 100% human plasma with a potency (EC₅₀) of 6.3 nM and 1 nM, respectively. BI 4569 potently increases glucose-stimulated insulin secretion from mouse islets (EC₅₀ 5.7 nM) and insulin secretion from perifused human islets. On single injection in lean mice, BI 4569 dose-dependently reduced food intake (FI) , gastric emptying (GE) and improved oral glucose tolerance (oGTT) with an ED₅₀ of 90, 41, and 2.1 nmol/kg, respectively. Based on dose-dependent changes in liver NNMT mRNA and plasma amino acids, BI 4569 engages the GCGR, unlike semaglutide. Receptor-specificity of target engagement was further shown in GLP-1R knockout mice (FI, GE, oGTT) . The bodyweight-lowering efficacy of BI 4569 (3, 10, 20, 30 nmol/kg) was compared with semaglutide (20, 100 nmol/kg) in diet-induced obese mice. After 4 weeks of daily dosing, BI 4569 showed a superior bodyweight-lowering efficacy (32% at 30 nmol/kg, p≤0.0vs. vehicle) compared with a maximally effective dose of semaglutide (27% at 100 nmol/kg; p≤0.0vs. vehicle) . This greater bodyweight-lowering efficacy of BI 4569 was associated with changes in GCGR target engagement biomarkers, such as liver lipids, NNMT mRNA, plasma glucagon, FGF21, and cholesterol. Mechanistically, the superior bodyweight-lowering efficacy of BI 4569 was attributed to an increase in energy expenditure (measured at and 20 nmol/kg) .

In summary, the preclinical characterization of the novel dual GCGR/GLP-1R agonist BI 4569 provides strong evidence for its clinical benefit in patients with obesity and associated comorbidities.