18. Glucagon Receptor Antibody LY2786890 Reduced Glucose Levels in Type 2 Diabetes Mellitus Patients (106-LB)

Glucagon levels are often elevated in type 2 diabetes mellitus (T2DM) and may contribute to hyperglycemia. LY2786890 (LY) is a humanized IgG4 monoclonal glucagon receptor antibody that displays antagonistic activity against the human glucagon receptor. A Phase 1, randomized, double-blind, placebo-controlled study examined the safety and efficacy of single doses of LY in healthy subjects (n = 10, intravenous [IV] 0.05 mg/kg) and T2DM patients (n = 44; IV 0.05, 0.1, 0.3, 0.55 mg/kg; subcutaneous [SC] 0.1, 0.55 mg/kg; mean fasting blood glucose [FBG] 126 mg/dL; hemoglobin A1c 7.3%). LY was safe and well tolerated. Hypoglycemia was infrequent and mild. Dose dependent elevations in aminotransferase levels were seen in T2DM patients; levels returned to baseline during follow up with no clinical signs of liver injury or significant elevations in bilirubin or alkaline phosphatase. Pharmacokinetic and pharmacodynamic (PD) profiles of LY supported once weekly SC dosing. The half-life (4 to 26 days) and PD time-action were concentration dependent. Absolute bioavailability after SC administration was estimated to be 50%. In T2DM patients, LY significantly reduced FBG (Fig ure) and increased plasma glucagon up to approximately 3-fold by day 2. As seen with oral glucagon receptor an tagonists, these data demonstrate that blocking glucagon action effectively lowers blood glucose in T2DM subjects.