781-P: Sustained-Release Formulation Development and Preclinical Evaluations of Monthly or Bimonthly Injectable Semaglutide and Tirzepatide

Objective: Accumulated real-world data indicates strong tendencies to develop long-acting formulating drug. This study aimed for optimization and preclinical development of the sustained-release formulation of Semaglutide (PT403) and Tirzepatide (PT404) to explore whether they are applicable for bi-monthly (once every two months) injectable drugs. Methods: Semaglutide or Tirzepatide dissolved in acetic acid with diverse combination of biodegradable PLGA polymers was applied to the ultrasonic spray dryer that produces API-encapsulated microspheres. The pharmacokinetic profiles of PT403 and PT404 were tested in rats and minipigs after a single subcutaneous injection. Results: Both optimized formulation of PT403 and PT404 have demonstrated favorable physicochemical properties, showing uniformly sized microspheres (20±3 μm). Furthermore, the aggregation issue of Semaglutide, which was not observed in PT404, was solved by applying PROW technology. Also, increased encapsulation rates and higher drug loading (~8%) showed higher bioavailability, no initial burst and a short lag phase (<3 days). Additionally, the release of PT403 initiated from 3 days to 70 days in minipigs, which potentially indicates every two months injectable (Q8W) in humans, compared to the once-a-weekly (QW) Semaglutide and Tirzepatide. Lastly, double injection of PT403 can easily reached the therapeutic window with 1.4 of the Peak-to-Through ratio, based on simulated PK profiles in repeated injection in human. Conclusion: Evidence from recent formulation studies of PT403 and PT404 indicates that Peptron's SmartDepot technology is strongly applicable for long-acting drugs. The comprehensive results of formulation development, preclinical data, and mass production will provide the basis for successful clinical development of PT403 and PT404 as monthly or bi-monthly injectable diabetes and obesity drugs. Disclosure J.Jung: None. S.Chang: None.