679-P: The Novel GIP, GLP-1, and Glucagon Triple Receptor Agonist LY3437943 Exhibits Robust Efficacy in Preclinical Models of Obesity and Diabetes

Abstract

The ever-growing prevalence of obesity and its associated comorbidities (T2D, NASH/NAFLD) is driving the need to discover new therapies for improving metabolic health. Recently, multi-receptor agonists have offered promise for meeting this need. Here, we characterize LY3437943, a novel single agent tri-agonist at the GIP, GLP-1, and glucagon (Gcg) receptors (R). Pharmacologic analysis of LY3437943 in cAMP assays using recombinant cell lines expressing the individual receptors indicated a potency balance favoring GIPR agonism (1.7- and 2.5-fold less potent at the GLP-1R and GcgR, respectively, but 7-fold more potent at the GIPR; all potencies in relation to the native ligands). In endogenous cells, LY3437943 regulated adipocyte lipolysis and hepatocyte glucose output. In vivo studies demonstrated regulation of multiple metabolic endpoints. Acute treatment with LY3437943 dose-dependently inhibited semi-liquid gastric emptying in mice and enhanced glucose dependent insulin secretion in rat IVGTT experiments. Chronic studies in diet induced obese mice reduced food intake and body weight (45% weight loss primarily via reduced fat mass) superior to other GIPR and GLP-1R agonists. In these experiments, LY3437943 lowered blood glucose and plasma insulin, indicating improved insulin sensitivity. Additionally, chronic administration improved biomarkers of liver health, decreasing both plasma alanine aminotransferase and liver triglycerides. Rodent and cynomolgus monkey PK modeling also suggested the potential for weekly dosing in humans. Taken these findings together, LY3437943 is a novel tri-agonist at the GIPR, GLP-1R, and GcgR, producing superior weight loss and glycemic control compared with other incretin receptor-targeting molecules and offers additional benefit for liver health. These findings prompt evaluation of the potential clinical benefit of LY3437943 in patients with obesity and metabolic diseases. Disclosure T. Coskun: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. F. S. Willard: Employee; Self; Eli Lilly and Company. J. V. Ficorilli: None. O. Cabrera: None. S. Urva: Employee; Self; Eli Lilly and Company. F. Norouziyan cooper: None. L. Guo: Employee; Self; Eli Lilly and Company. J. Alsina-fernandez: None. H. Qu: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. J. S. Moyers: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. W. C. Roell: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. L. O’farrell: None. A. Regmi: Employee; Self; Eli Lilly and Company. X. Ruan: None. A. D. Showalter: None. K. Sloop: Employee; Self; Eli Lilly and Company. D. B. Wainscott: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company, Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Funding Eli Lilly and Company