Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 after single subcutaneous administration in healthy subjects

Aims: To evaluate the pharmacodynamics, pharmacokinetics and safety of single subcutaneous (s.c.) injection of ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in healthy subjects. Methods: A total of 51 healthy volunteers were enrolled in this double-blind, placebo-controlled study investigating RG7697 doses ranging from 0.03 to 5 mg. Adverse events (AEs) were monitored and drug concentrations, fasting glycaemic variables, vital signs, ECG, antibody formation and routine laboratory variables were assessed. A meal tolerance test (MTT) was performed at the same time on day -1 (baseline) and day 1. Results: RG7697 was generally well tolerated in healthy participants after s.c. injections up to 3.6 mg. Tolerability was limited by gastrointestinal AEs (nausea and vomiting) at the highest dose. There was a small dose-dependent increase in heart rate. No episodes of hypoglycaemia occurred. RG7697 concentrations peaked at 2 to 4 hours post-dose with a half-life of 19 to 25 hours. During MTT, RG7697 at doses >= 1.8 mg, reduced glucose maximum plasma concentration (Cmax;-46%) without affecting overall glucose area under the curve (AUC). Its effect on insulin was more pronounced, with reductions in both Cmax (-64%) and AUC (-51%). Pharmacodynamic variables were well correlated to RG7697 average plasma concentration during MTT, with IC50 (average concentration required for 50% reduction) values of 49 and 24.5 ng/mL for glucose and insulin, respectively. Conclusion: Single s.c. injections of RG7697 up to 3.6 mg were generally well tolerated. Evidence of glycaemic effect and pharmacokinetic profiles consistent with once-daily dosing render this drug candidate suitable to be further tested in multiple-dose clinical trials in patients with type 2 diabetes.