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

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 (AUC_{0-90 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.

Figure 1

Study design schema. Dose escalation cohorts treated with placebo or REGN1193 (at 0.05, 0.1, 0.3 and 0.6 mg/kg) in group A (A) and group B combined with serial glucagon stimulations on day −1, day 3, day 8, day 15 and day 22 (B) as well as an “early onset” cohort treated with placebo or REGN1193 (at 0.3 mg/kg) with glucagon challenges on day −1, day 1 at 6 hours post‐dosing and day 8 (B*). Subjects in group A were admitted to the clinic on day −1 and subjects in group B on day −2. All subjects were discharged on day 4

Figure 2

Mean (± standard error [SE]) time‐concentration profile of functional REGN1193 following a single IV dose of REGN1193 in all study subjects (regardless of glucagon stimulation)

Figure 3

Effect of REGN1193 treatment in group A on glucagon, total GLP‐1, and GLP‐2 (A, B, and C, respectively) in the dose escalation portion of the study. X‐axes show discreet time points, y‐axes show median ± range; Reference ranges are 1.3 to 16.9, <13.9, and <22.2 pmol/L, for glucagon, total GLP‐1, and GLP‐2, respectively

Figure 4

Effect of REGN1193 treatment in group B on C‐peptide in the dose escalation portion of the study. X‐axis shows discreet time points (0, 6 and 15 indicating pre‐glucagon stimulation, 6 and 15 minutes post‐glucagon stimulation, respectively), y‐axis shows median ± range, the reference range is 1.1 to 4.4 ng/mL

Figure 5

Time‐dependent pharmacokinetics‐pharmocodynamics (PK/PD) of REGN1193 concentrations versus glucose‐lowering effect after glucagon challenge in group B for the 0.3 and 0.6 mg/kg dose cohorts (A). Time‐dependent pharmacokinetics‐pharmocodynamics (PK/PD) of REGN1193 concentrations versus glucagon (B), total GLP‐1 (C) and GLP‐2 (D) in group A for the 0.3 mg/kg and 0.6 mg/kg dose cohorts