Pharmacokinetic and dose-finding studies on efpeglenatide in patients with type 2 diabetes

Aim: To assess the efficacy, safety and pharmacokinetic/pharmacodynamic properties of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes (T2D). Research design and methods: Two randomized, double-blind, placebo-controlled phase 2 trials were conducted. The single-dose study (n = 48) was a first-in-patient, sequential dose-escalation study. Patients received a single subcutaneous injection of efpeglenatide (2–100 μg/kg) or placebo. The repeated-dose study (n = 71) was a multiple-ascending-dose trial. Patients received weekly (1, 2 or 4 mg once weekly; 8-week period) or monthly (8, 12 or 16 mg once monthly; 9-week period) subcutaneous injections of efpeglenatide or placebo (without titration). Results: Both studies demonstrated dose-proportional increases in efpeglenatide serum concentrations. The median time to attain maximum serum concentration (t_max) for efpeglenatide ranged from 72 to 144 hours in the single-dose study and from 48 to 120 hours in the repeated-dose study (following final dose). Geometric mean t_1/2 ranged from 135 to 180 hours across studies. Peak-to-trough ratios in the repeated-dose study ranged from 1.3 to 1.4 with once-weekly dosing and from 5.9 to 12.9 with once-monthly dosing. Following a single dose of efpeglenatide 14–100 μg/kg, fasting plasma glucose and postprandial plasma glucose levels were decreased at week 1 and remained below baseline levels for ≥3 weeks post-dosing. Repeated doses of efpeglenatide led to significant reductions in glycated haemoglobin vs placebo. In both studies, efpeglenatide was generally well tolerated. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events in efpeglenatide-treated patients. Conclusions: The delayed t_max, long half-life, and low peak-to-trough ratios observed demonstrate potential for improved efficacy and dosing flexibility, with good tolerability of efpeglenatide in patients with T2D.