Evaluation of GSK1292263, a novel GPR119 agonist, in type 2 diabetes mellitus (T2DM): Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses

Abstract

GPR119 receptor agonists increase glucose-sensitive insulin secretion and circulating gut hormones in animal models of T2DM. GSK1292263 was investigated in 2 randomized, placebo-controlled studies with (i) drug-na{ï}ve T2DM patients and patients washed off prior anti-diabetic medications (NCT01119846), and (ii) T2DM patients on metformin monotherapy (NCT01128621). Safety, tolerability, PK and PD of GSK1292263 were evaluated when administered as single (25-800mg; n=45) or multiple doses (100-600mg/day for 14 days; n=96); sitagliptin 100mg/day for 14 days was used as a comparator. Subjects taking GSK1292263 or placebo alone for 14 days were co-dosed with 100mg sitagliptin on day 14. An oral glucose tolerance test (OGTT) and 24h profiles of glucose, insulin, C-peptide, glucagon, GLP-1, GIP and PYY were used to assess PD. All doses of GSK1292263 were generally well tolerated (no SAEs). The most common drug-related AEs were generally mild and similar in subjects administered GSK1292263, placebo or sitagliptin. GSK1292263 AUC and Cmax were less than dose-proportional over the range of doses evaluated. Food increased the systemic exposure of GSK1292263. Steady state was observed after ∼4 days of dosing, consistent with the mean half-life range of ∼12-18h. Co-administration of single-dose sitagliptin with steady-state GSK1292263 did not alter the PK of either drug. Following single doses of GSK1292263, there was a dose-dependent decrease in glucose AUC (0-3h) during the OGTT. After 14 days, GSK1292263 did not reduce AUCglucose (0-24h) when administered alone or when co-dosed with metformin or sitagliptin. There was an increase in circulating gut hormone levels during the prandial periods, especially for PYY. Combination with sitagliptin resulted in increased plasma active GLP-1 concentrations, but lower total GLP-1, GIP and PYY concentrations. Sitagliptin alone reduced AUCglucose (0-24h). This suggests that GPR119 agonism does not provide clinically meaningful glycemic improvement in T2DM patients, and efficacy is not increased when co-dosed with metformin or sitagliptin.