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.