Coskun, Tamer, Urva, Shweta, Roell, William C., Qu, Hongchang, Loghin, Corina, Moyers, Julie S., O'Farrell, Libbey S., Briere, Daniel A., Sloop, Kyle W., Thomas, Melissa K., Pirro, Valentina, Wainscott, David B., Willard, Francis S., Abernathy, Matthew, Morford, LaRonda, Du, Yu, Benson, Charles, Gimeno, Ruth E., Haupt, Axel, and Milicevic, Zvonko
With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro , LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction. In a phase 1 single ascending dose study, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing, and a reduction in body weight persisted up to day 43 after a single dose. These findings warrant further clinical assessment of LY3437943. [Display omitted] • LY3437943 has triple agonist activity at the glucagon, GIP, and GLP-1 receptors • LY3437943 caused greater body weight loss in obese mice than tirzepatide • LY3437943 increased energy expenditure through glucagon receptor activation • Safety and tolerability of LY3437943 were similar to other incretin-based drugs Coskun et al. demonstrate that LY3437943, a triple glucagon, GIP, and GLP-1 receptor agonist for the treatment of obesity and type 2 diabetes, can reduce body weight through increased energy expenditure and reduced calorie intake in obese mice. Its safety and tolerability in healthy participants were similar to other incretin-based therapies. [ABSTRACT FROM AUTHOR]