Abstract 9791: GPR119 Agonism Affects Lipoprotein Particle Remodeling in Dyslipidemic Monkeys

Abstract

GSK1292263 (GSK263), a small molecule agonist of G-protein coupled receptor 119 (GPR119), significantly increases fasting HDLc, and decreases triglyceride (TG), and LDLc concentrations in both diabetic and dyslipidemic patients. The mechanism of these improvements is unclear, as no other GPR119 agonists have been reported to show similar lipid effects. Studies in non-primate preclinical models have not recapitulated the breadth of lipid effects seen in patients with GSK263. Thus, the purpose of the current study was (i) to determine if dyslipidemic non-human primates respond to GSK263 and (ii) to evaluate if the lipid improvements are a GPR119 class effect by testing another potent agonist (GSK706) as a comparator. We used a 3-period crossover design with 2 weeks active treatment followed by a 2 week washout period to evaluate the effects of Vehicle, GSK263 (25 mg/kg, comparable exposure to a clinically efficacious dose), and GSK706 (10 mg/kg, to achieve bio-equivalent GPR119 agonism to GSK263) in hypertriglyceridemic cynomolgus monkeys (N=15). Drug was administered once daily in a piece of fruit which was voluntarily consumed. For each treatment period, fasting plasma lipids and lipoproteins (by FPLC and NMR, LipoProfile®) were assessed at baseline and after 14 days of dosing. Neither GSK263 nor GSK706 had significant effects on LDLc or fasting TG, but both robustly increased HDLc by ∼20%, similar in magnitude to that seen in patients. NMR analysis shows that treatment with GSK263 and GSK706 (i) decreased number of LDL particles by ∼20%, decreased number of small, dense LDL particles by ∼36%, increased LDL size by ∼1%; (ii) increased HDL size by ∼3%, increased number of large HDL particles by ∼23%, decreased number of small HDL particles by ∼32%; (iii) decreased number of large VLDL/chylomicrons by ∼30% and tended to increase the number of small VLDL particles. Two selective GPR119 agonists have been shown to shift lipoprotein particle remodeling in the direction of potential cardiovascular benefit in monkeys. The effects of GSK263 on lipoprotein metabolism in the dyslipidemic monkey are largely concordant with the human clinical results and may suggest a receptor class effect, since both GPR119 agonists confer the same lipid improvements.