BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy

•BI 456906 is a novel, acylated GCGR/GLP-1R dual agonist containing a C18 fatty acid.•BI 456906 doses produced greater bodyweight reductions compared with semaglutide.•Increased energy expenditure and decreased food intake drove BI 456906-induced weight loss.•GLP-1R engagement was shown through glucose tolerance, food intake and gastric emptying.•Liver Nnmt expression and plasma amino acids and FGF-21 demonstrated GCGR engagement.