Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dual glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide‐1 agonist RG 7697 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 RG 7697, 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 RG 7697 doses ranging from 0.03 to 5 mg. Adverse events ( AE s) 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 RG 7697 was generally well tolerated in healthy participants after s.c. injections up to 3.6 mg. Tolerability was limited by gastrointestinal AE s (nausea and vomiting) at the highest dose. There was a small dose‐dependent increase in heart rate. No episodes of hypoglycaemia occurred. RG 7697 concentrations peaked at 2 to 4 hours post‐dose with a half‐life of 19 to 25 hours. During MTT , RG 7697 at doses ≥1.8 mg, reduced glucose maximum plasma concentration ( C max ; −46%) without affecting overall glucose area under the curve ( AUC ). Its effect on insulin was more pronounced, with reductions in both C max (−64%) and AUC (−51%). Pharmacodynamic variables were well correlated to RG 7697 average plasma concentration during MTT , with IC 50 (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 RG 7697 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.