Inappropriately elevated levels of glucagon are thought to contribute to increased hepatic glucose production in people with T2DM and exacerbate hyperglycemia. LGD-6972 is an orally bioavailable, small molecule glucagon receptor antagonist. In a Phase 2, double-blind, placebo-controlled study, the safety and efficacy of LGD-6972 was evaluated in subjects with T2DM (HbA1c ≥7.0%-≤10.5%) on a stable dose of metformin. Patients were randomized to 5 mg (n = 43), 10 mg (n = 40), 15 mg (n = 42) LGD-6972, or placebo (n = 41) daily for 12 weeks. Mean HbA1c at baseline was 8.2% and did not differ among groups. A statistically significant decrease from baseline in HbA1c (p<0.0001) was observed at all LGD-6972 doses during 12 weeks of treatment [-0.90% (5 mg), -0.92% (10 mg), and -1.20% (15 mg) compared with placebo (-0.15%)]. All doses of LGD-6972 significantly decreased fasting plasma glucose (-30.1 to -39.3 mg/dL from baseline) and reduced glucose AUC0-4h during an OGTT. LGD-6972 treatment also increased fasting glucagon (1.9-3.1-fold) and total and active GLP-1 (1.3-1.4-fold and 1.1-1.4-fold, respectively) from baseline. LGD-6972 treatment was safe and well tolerated with a low incidence of hypoglycemia (8 mild, patient-reported events) and no severe hypoglycemia. Mild increases in aminotransferase levels (ALT and AST) were observed with LGD 6972 treatment (group means <ULN), that were reversible, not dose related or associated with increases in bilirubin or other liver function parameters. There was no consistent time- or dose-related change from baseline in lipids, blood pressure or body weight observed in LGD-6972 dose groups compared to placebo. These findings indicate that glucagon receptor antagonism with LGD 6972 significantly lowers HbA1c and fasting plasma glucose levels, and may be a promising new option to treat T2DM. The combination of safety and efficacy support further clinical development of LGD-6972.

Disclosure

J. Pettus: Advisory Panel; Self; Sanofi, Novo Nordisk Inc.. Consultant; Self; MannKind Corporation. Advisory Panel; Self; Insulet Corporation. Consultant; Self; Senseonics. E.G. Vajda: Employee; Self; Ligand Pharmaceuticals, Inc. J. Pipkin: Employee; Self; Ligand Pharmaceuticals, Inc.. G. Williamson: None. M.A. Zangmeister: None. Y. Li: None. R.R. Henry: Consultant; Self; Abbott, Alere Inc., AstraZeneca. Research Support; Self; AstaReal. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Hitachi, Ltd.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Johnson & Johnson Services, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Viacyte, Inc.. Consultant; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis. D. D'Alessio: Consultant; Self; Intarcia Therapeutics, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc. L. Zhi: Employee; Self; Ligand Pharmaceuticals, Inc. K. Marschke: Employee; Self; Ligand Pharmaceuticals, Inc..

© 2018 by the American Diabetes Association.
2018
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.