Glucagon Receptor Antagonist LGD-6972 Significantly Lowers HbA1c and Is Well Tolerated after 12-Week Treatment in Patients with Type 2 Diabetes Mellitus (T2DM) on Metformin
Authors: PETTUS JEREMY , VAJDA ERIC G. , PIPKIN JAMES , WILLIAMSON GRETCHEN , ZANGMEISTER MIRIAM A. , LI YONG-XI , HENRY ROBERT R. , D'ALESSIO DAVID , FRIAS JUAN P. , ZHI LIN , MARSCHKE KEITH 
Published: June 2018

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&lt;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 &lt;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..