Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2016-08, Vol.18 (8), p.795-802
• Main Authors: Kazierad, D. J., Bergman, A., Tan, B., Erion, D. M., Somayaji, V., Lee, D. S., Rolph, T.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alanine Transaminase - metabolism; Amino acids; Amino Acids - metabolism; Aspartate Aminotransferases - metabolism; beta-Alanine - administration & dosage; beta-Alanine - analogs & derivatives; Blood Glucose - metabolism; C-Peptide - metabolism; Cholesterol; Cholesterol, LDL - metabolism; clinical trial; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Dosage; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glucagon; Glucagon - metabolism; glucagon antagonist; Glucagon-Like Peptide 1 - metabolism; Glucose; Glycated Hemoglobin A - metabolism; Humans; Hypoglycemia; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - therapeutic use; Insulin - metabolism; Low density lipoprotein; Male; Metformin; Metformin - therapeutic use; Middle Aged; Peptides; Pharmacodynamics; Pharmacokinetics; phase I-II study; Placebos; Pyrazoles - administration & dosage; randomized trial; Receptors, Glucagon - antagonists & inhibitors; Sulfonylurea Compounds - therapeutic use; type 2 diabetes
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12672

Aims To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF‐06291874 in patients with type 2 diabetes mellitus (T2DM). Methods Patients were randomized to oral PF‐06291874 or placebo on a background of either metformin (Part A, Cohorts 1–5: 5–150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1–2: 15 or 30 mg once daily) for 14–28 days. A mixed‐meal tolerance test (MMTT) was administered on days −1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. Results PF‐06291874 exposure was approximately dose‐proportional with a half‐life of ∼19.7–22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose‐dependent manner, with placebo‐corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose‐dependent increases in glucagon and total glucagon‐like peptide‐1 (GLP‐1) were observed, although no meaningful changes were noted in insulin, C‐peptide or active GLP‐1 levels. Small dose‐dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF‐06291874 were well tolerated. Conclusion PF‐06291874 was well tolerated, has a pharmacokinetic profile suitable for once‐daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia.