LY2599506, a novel glucokinase activator (GKA), improves fasting and postprandial glucose in patients with type 2 diabetes mellitus

Abstract

Background and aims: LY2599506 (licensed from Prosidion) is an orallyadministeredGKA. GKAs lower the plasma glucose threshold for insulin releaseand may modulate other hormonal and hepatic mechanisms of glucosehomeostasis. The primary objective of this Phase 1 study was to assessthe safety and tolerability of LY2599506 during multiple-dose administrationto healthy subjects and T2DM. Based on previous clinical data, LY2599506was expected to enhance glucose control for 1-4 hours after dosing;consequently, LY2599506 was given prior to each meal and at bedtime(four times a day [QID] dosing) to achieve glycemic control in bothpostprandial (PP) and post absorptive periods. Materials and methods:This 3-part study used a single-blind design with randomized assignmentto placebo or LY2599506 (Parts A and B) or study sequence (Part C).In Part A, healthy subjects (n=9) received ~50 mg LY2599506 or placeboQID for 7 days. In Part B, T2DM (n=18) underwent dose-titration ofLY2599506 or placebo QID for 12 days; in Part C, T2DM (n=11) receivedtwice-daily (BID) and QID LY2599506 dosing for 13 days each in a2-period crossover design. Planned LY2599506 dose levels were 50,100, 200, and 300 mg QID. Starting with 50 mg or 100 mg, doses wereincreased at 3 day intervals so that blood glucose (BG) thresholdsof 60 mg/dL (Part B) and 80 mg/ dL (Part C) were not exceeded. Standardizedmeals at breakfast, lunch, dinner, and bedtime were administeredto characterize blood glucose, insulin, and glucagon responses. Results:At baseline, mean HbA1c in T2DM was 7.4%; mean diabetes durationwas 7 years; and 80% were on stable metformin therapy. Mild or moderatehypoglycemia was the dose-limiting adverse event and was effectivelymanaged with food/drink. No severe hypoglycemia occurred, even withdosing at bedtime. QID dosing of LY2599506 achieved a relativelyflat 24-h exposure profile. Under inpatient conditions with dosereduction for BG <60 mg/dL (Part B), the maximum tolerated (non-hypoglycemic)dose of LY2599506 ranged from 50-1100 mg/day; under ambulatory conditionswith dose reduction for BG <80mg/dL (Part C), the maximum dose rangedfrom 60-530 mg/ day. In part B, fasting BG after 12 days of treatmentwas significantly lower during treatment with LY (Placebo: 129 (plusor minus) 26.6 mg/dL vs LY: 84.4 (plus or minus) 15.7 mg/ dL, p=0.0004)and significant reductions in 2-h PP BG were also observed aftereach of the main meals (Figure). In Part C, BID dosing was slightlyless effective in controlling BG following lunch than QID dosing(Figure). Although absolute differences in PP insulin levels werenot generally observed, the insulin/glucose ratios on Day 12 wereincreased at PP time points relative to placebo (Placebo: 0.36 (plusor minus) 0.38 vs LY: 0.71 (plus or minus) 0.33) which may suggestan improvement in beta cell function. No significant effects on glucagonwere observed. Conclusion: LY2599506 was well tolerated and improvedglycemic control in T2DM patients.(Figure presented).