A first-in-human pharmacodynamic and pharmacokinetic study of a fully human anti-glucagon receptor monoclonal antibody in normal healthy volunteers

Diabetes Obes Metab. 2018 Feb;20(2):283-291. doi: 10.1111/dom.13075. Epub 2017 Sep 14.

Abstract

Aims: Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 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-blinded trial.

Methods: Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 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 hyperglycaemia by serial glucagon challenges.

Results: REGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose-dependent increases in hepatic aminotransferases. No increase in LDL-C was observed. Hypoglycaemia, 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 hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration-time profiles suggest a 2-compartment disposition and marked nonlinearity, consistent with target-mediated clearance. REGN1193 inhibited the glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose area under the curve for 0 to 90 minutes (AUC0-90 minutes ) by 80% to 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.

Conclusion: 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 suggests an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown.

Keywords: GCGR; REGN1193; glucagon stimulation; phase 1.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Blocking / administration & dosage
  • Antibodies, Blocking / adverse effects
  • Antibodies, Blocking / blood
  • Antibodies, Blocking / pharmacology
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / pharmacokinetics*
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Humanized
  • Biomarkers / blood
  • Blood Glucose / analysis
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Half-Life
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology
  • Infusions, Intravenous
  • Lost to Follow-Up
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Patient Dropouts
  • Receptors, Glucagon / antagonists & inhibitors*
  • Receptors, Glucagon / metabolism
  • Young Adult

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • Blood Glucose
  • Hypoglycemic Agents
  • Receptors, Glucagon
  • crotedumab