A First-in-Human Pharmacodynamic and Pharmacokinetic Study of a Fully-Human Anti-Glucagon Receptor Monoclonal Antibody in Normal Healthy Volunteers

4 years ago

A First-in-Human Pharmacodynamic and Pharmacokinetic Study of a Fully-Human Anti-Glucagon Receptor Monoclonal Antibody in Normal Healthy Volunteers

Kuo-Chen Chan, Joyce B. Harp, Feng Yang, George D. Yancopoulos, Alexander T. King, Ana Kostic, Jesper Gromada

Aims Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and 2 diabetes. Here we report the safety, tolerability, pharmacokinetics [PK], and pharmacodynamics [PD] of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double blind trial. Materials and Methods Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 mg/kg to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability, and PK were assessed over 106 days. The glucose lowering effect of REGN1193 was assessed after induction of hyperglycemia by serial glucagon challenges. Results REGN1193 was generally well-tolerated. There were small (<3x upper limit of normal) and transient dose-dependent increases in hepatic aminotransferases. No increase in LDL-C was observed. Hypoglycemia, assessed as laboratory blood glucose ≤70 mg/dL occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycemia were asymptomatic, >50 mg/dL, and did not required treatment or medical assistance. Concentration-time profiles suggest a two-compartment disposition and marked non-linearity, consistent with target-mediated clearance. REGN1193 inhibited glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose AUC 0–90 minutes by 80-90% on days 3 and 15, while blunting the increase in C-peptide. REGN1193 dose-dependently increased total GLP-1, GLP-2, and glucagon with plasma levels returning to baseline by day 29 in all dose groups. Conclusions REGN1193, a GCGR-blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggest an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/dom.13075