SUN-691 Permeate: A Novel Platform for Enhanced Incretin Peptide Bioavailability

Abstract Disclosure: P.D. Susilo: None. M. Kanelli: None. O. Petropulos: None. C. Dial: None. K. Kadasia: None. M. Buzo Mena: None. J. Liang: None. A. Hayward: None. K.A. Gaspie: None. S.M. Barron: None. R.R. Basani: None. A. Lopes: None. A. Yu: None. Introduction: Incretin peptide therapies have revolutionized obesity and diabetes treatment, yet overcoming oral delivery challenges—such as rapid gastrointestinal transit and limited intestinal absorption—is crucial to improving patient adherence, accessibility, and real-world effectiveness. To address these barriers, we developed the Peroral Mucosal Epithelium Absorption Enhancer (PERMEATE) method, which integrates synthetic tissue lining (SYNT) platform with proprietary permeation enhancers (PEs) to improve intestinal residence time and drive higher absorption. This proof-of-concept study demonstrates PERMEATE's ability to both create and significantly enhance the oral bioavailability of semaglutide (SEMA) in pig and rat models. Methods: A high-throughput ex vivo screen identified single and combination PEs with synergistic effects on SEMA permeation across porcine intestinal tissue. Ex vivo Franz experiments optimized formulation components and ratios to maximize colocalization of SEMA and PEs onto the intestinal tissue. Saline buffer washes were implemented to mimic a dynamic environment physiologically relevant to digestion. Lead formulations were tested in vivo in anesthetized Yorkshire pigs, a physiologically relevant gastrointestinal model, with plasma SEMA concentrations measured via LC-MS/MS over 168 hours. The area under the curve (AUC) was normalized by dose and compared to intravenous SEMA administration (n=4) to determine absolute bioavailability. To enhance replicates and rigor, formulations were also delivered via oral gavage to male rats (650-750 g, n=5-6 per group), with bioavailability assessed over 24 hours using the same methods. Results: Glycocholic acid (GCA) and ammonium carbonate (NHCO) were identified as the most effective PE combination with SEMA and SYNT, achieving a 15.5-fold increase in permeation compared to SEMA control in ex vivo tests. Optimized PERMEATE formulations improved colocalization of SEMA by 71.5-fold compared to a SEMA+PE control, after two washes, highlighting the ability of PERMEATE to create a localized depot and achieve prolonged residence time. In vivo, PERMEATE demonstrated a SEMA bioavailability of 2.4±1.6% in Yorkshire pigs (n=4), representing a significant 6-fold increase over the SEMA+PE control (0.4±0.3%, n=5; p=0.0316) and SEMA-Only control (0%, n=1). Improved bioavailability compared to controls was also observed in rats, highlighting translatability across multiple mammalian models. Conclusions: The PERMEATE platform, powered by SYNT™, significantly enhances the bioavailability of semaglutide (SEMA) in preclinical models, demonstrating up to a 6-fold improvement compared to controls. These findings underscore the potential of PERMEATE as a transformative platform for optimizing the oral delivery of macromolecule therapeutics. Presentation: Sunday, July 13, 2025