Abstract 9918: Novel and Profound Lipid Effects of GSK1292263, a Potent and Selective GPR119 Agonist, in Dyslipidemic Subjects

Abstract

GSK1292263 (GSK263), a GPR119 agonist, improves glucose regulation in animal models of diabetes, but has no effect on plasma glucose in type 2 diabetics. Unexpectedly, GSK263 lowered fasting LDLc and triglycerides (TG), while increasing HDLc in these diabetic subjects. The study aim was to determine whether GSK263 improves lipid profiles in dyslipidemic, non-diabetic subjects when dosed alone or with atorvastatin (NCT# 01218204). Eligible subjects on statin/Vytorin therapy were washed off these drugs for 4 weeks. After washout, they were randomized to receive (i) 100mg (n=11), 300mg (n=12) or 800mg (n=13) QD of GSK263 or placebo (n=11) for 2 weeks; or (ii) 10mg atorvastatin (A10) or 80mg atorvastatin (A80) for a 4-week Run-in period. After the atorvastatin Run-in, (i) A10 was co-dosed with: 100mg (n=11), 300mg (n=11), 800mg (n=11) QD GSK263, placebo (n=12) or 10mg ezetimibe (n=13), and (ii) A80 was co-dosed with: 800mg (n=12) QD GSK263 or placebo (n=13). Fasting plasma lipids and NMR lipoprotein particles (LipoProfile) were measured at baseline and after 2 weeks of dosing. By ANCOVA (change from baseline), 800mg GSK263 significantly increased fasting HDLc by 20.7% (95% CI 9.8 to 31.6%), reduced fasting LDLc by 21.8% (95% CI -32.1 to -11.2%), and reduced fasting TGs by 54.8% (95% CI -70.8 to -38.9%) when compared to placebo. TG AUCs (wm 0-24h) fell by 41.3% (95% CI -61.9 to -20.8%). Similar effects were seen when co-dosed with A10 and A80. The lipid effects were dose-dependent, with GSK263 100mg having minimal effect. GSK263 may reduce apoB100, apoE and CRP, but had no clear effect on apoA1. NMR analysis suggests that GSK263 (i) reduced VLDL and chylomicron particle number and VLDL particle size, (ii) reduced LDL and IDL particle number and increased LDL particle size, and (iii) increased HDL particle number and size, especially when co-administered with atorvastatin. GSK263 was generally well tolerated over the dose range of 100mg to 800mg QD administered for 14 days. The majority of AEs associated with GSK1292263 were mild in intensity. GSK263 has significant effects on plasma lipids and lipoprotein particles in dyslipidemic patients when dosed alone and with atorvastatin. Studies are on-going to investigate the novel mechanisms underlying these lipid effects.