Phase I study of the oral GLP ‐1 receptor agonist DA ‐ 302168S : Safety, pharmacokinetics, and pharmacodynamics in healthy and overweight/obese adults

AIM: This first-in-human Phase I study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DA-302168S, a novel oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1RA). MATERIALS AND METHODS: The study comprised three parts: a single ascending dose (SAD) phase in healthy adults (Phase Ia; 2.5-50 mg), and two multiple ascending dose (MAD) phases-a 28-day study in healthy adults (Phase Ib) and a 28-day, weekly-titration study in overweight/obese adults (Phase Ic; 7.5-30 mg QD). All parts were randomised, double-blind, and placebo-controlled. Safety and tolerability were the primary endpoints. RESULTS: DA-302168S was generally well tolerated, with gastrointestinal events (primarily nausea) being the most common adverse events. PK profiles were dose proportional with moderate inter-individual variability across SAD and MAD phases. Robust, dose-dependent efficacy was observed in overweight/obese subjects (Phase Ic), with mean weight loss ranging from -5.67% to -7.26%, significantly exceeding placebo (-2.90%). This was accompanied by significant metabolic improvements, including reduced glucose fluctuations, lowered HbA1c, and optimised lipid profiles. CONCLUSIONS: DA-302168S demonstrates a favourable safety and PK profile, coupled with substantial, dose-dependent weight loss and metabolic benefits. These results strongly support its continued development as a promising once-daily oral therapy for obesity and type 2 diabetes.