BI 456906: a dual glucagon-like peptide-1/glucagon agonist promoting bodyweight reduction

Glucagon and glucagon-like peptide-1 (GLP-1) are hormones involved in energy homeostasis. GLP-1 receptor (GLP-1R) agonism reduces food intake and delays gastric emptying, and glucagon receptor (GCGR) agonism increases energy expenditure by thermogenesis. BI 456906 is a subcutaneous, once-weekly injectable dual GLP-1R/GCGR agonist in development for the treatment of obesity or non-alcoholic steatohepatitis. Here we show that BI 456906 is a potent dual agonist with an extended half-life in human plasma. Key GLP-1R-mediated mechanisms of reduced food intake, delayed gastric emptying and improved glucose tolerance were confirmed in GLP-1R knockout mice. GCGR activity was confirmed by reduced plasma amino acids, increased hepatic expression of nicotinamide N-methyltransferase and increased energy expenditure. BI 456906 produced greater bodyweight reductions than maximally efficacious semaglutide doses and modulated gene expression, including genes involved in amino acid metabolism. BI 456906 is a potent dual agonist that produces bodyweight-lowering effects through both GLP-1R and GCGR agonism. Overall design: Male C57BL6/J mice pre-fed with 60% high-fat diet were obtained from The Jackson Laboratories (Bar Harbour, ME, USA) at >16 weeks of age. Upon arrival, mice were single-housed to obtain accurate and individual food intake measurements for each animal. During the entire study, animals had ad libitum access to food (high-fat diet D12492; Research Diets, Inc., New Brunswick, NJ, USA) and tap water. Before the start of the study, animals were randomised based on their bodyweight measured 1 week prior to the start of treatment (n=11/group). At the study start, the age of mice was 22 weeks. Mice were administered chronic repeated SC dosing of vehicle, BI 456906 (3, 10, 20 or 30 nmol/kg) or semaglutide (20 or 100 nmol/kg) daily for 30 days, with bodyweight and food intake measured every day.