20-OR: GPR142 Agonists Increase Glucose-Dependent Insulin Secretion and Differentially Regulate Hormone Secretion in Preclinical and Phase 1 Studies

Abstract

Agonists of G-protein-coupled receptor 142 (GPR142) are reported to increase insulin secretion and lower glucose in preclinical models. We identified a novel agonist, LY3325656 (LY) that selectively activates GPR142 in humans and mice. In preclinical models, LY increased glucose-dependent insulin secretion (GDIS) and secretion of glucagon and incretin hormones GLP-1 and GIP. To elucidate mechanisms of LY in humans, we designed a multi-part, single-dose study in 24 healthy volunteers (HV) and 12 patients with type 2 diabetes (T2D) (NCT03115099). LY was well tolerated through dose escalation up to 1950 mg in HV, with a median time to peak concentration of 4 hours and half-life of 4.59 hours. A graded glucose infusion evaluated GDIS, and LY demonstrated increased insulin secretion at higher doses (750-1950 mg). A 4-period, crossover design consisting of placebo (Pb), LY (1950mg), LY+DPP-IV inhibitor, and GLP-1R agonist treatment investigated glucose-lowering and incretin pharmacology in patients with T2D. LY significantly reduced post-meal glucose levels (2-hour glucose AUC) by >10% during a mixed meal tolerance test. Increases in post-meal GLP-1 AUC concentrations with LY compared to Pb were seen in a few, but not all patients with T2D. Serum glucagon levels were consistently increased by LY in patients with T2D and HV. We conclude that GPR142 activation in humans increases GDIS and augments glucagon secretion but does not substantively augment GIP or GLP-1 secretion. Our data suggest that acute stimulatory effects of GPR142 on insulin and glucagon secretion translate from preclinical models to man, unlike preclinical effects on gut peptide secretion. Innovative and efficient single-dose studies can provide key mechanistic understanding of the translatability of preclinical findings for the treatment of T2D. Disclosure E.J. Pratt: Employee; Self; Eli Lilly and Company. T. Oura: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. X. Ma: Employee; Self; Eli Lilly and Company. H.V. Lin: Employee; Self; Eli Lilly and Company, Forkhead BioTherapeutics, Inc. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Eli Lilly and Company, Forkhead BioTherapeutics, Inc. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Ma: None. A.M. Efanov: Employee; Self; Eli Lilly and Company. M.K. Thomas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.