785-P: Preclinical Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) Assessments of Sustained-Released Formulation of Once-Monthly Injectable Semaglutide (PT403)

Objective: Advancements in GLP-1RA research, shifting from daily to weekly injectables, have improved therapeutic outcomes and expanded market potential, paving the way for monthly injectable drug development. This study evaluates the clinical potential of PLGA-encapsulated once-monthly injectable semaglutide through extensive non-clinical assessments, including safety profiling and pharmacokinetic/pharmacodynamic evaluations. Methods: Semaglutide was solubilized in acetic acid with a diverse biodegradable PLGA polymer mixture and processed using ultrasonic spray-drying to create microspheres encapsulating semaglutide. The optimized formulation, PT403, with a proper drug loading and no initial burst was developed. Subsequent assessments, including PK, PD, and toxicology, were conducted in mouse, rat, and/or minipig. Results: PT403 exhibits favorable physicochemical properties, including uniform microsphere size (20μm), one-year stability, and extended release up to 70 days in minipigs. In a Single Ascending Dose (SAD) study in mice, PT403 induced a 20% body weight reduction at doses ranging from 24 to 192 mg/kg. No other notable critical signs were observed, ensuring a safe profile even up to 192 mg/kg. Moreover, simulated release profiles suggest PT403's potential as a once-a-month injectable, with a Peak-to-Trough ratio of 1.4. Both semaglutide and PT403 demonstrated consistent reductions in body weight (30%) and cumulative food intake across 28 repeated injections of semaglutide and double injections of PT403. Conclusion: PT403, featuring uniform microsphere size and favorable drug loading, exhibited safety in mice at the highest dose. Simulations support this formulation, and consistent pharmacodynamic effects across semaglutide and PT403 groups in repeated injections suggest its promise for clinical development as a monthly injectable for diabetes and obesity. Disclosure J. Lee: None. J. Cho: None. E. Jang: None. M. Kim: None. J. Bae: None. M. Choi: None. S. Chang: None. J. Jung: None.