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

Abstract 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.