89-LB: Oral Delivery of a GLP-1 Agonist with High Bioavailability in Dogs and Humans

Abstract

GLP-1 mimetics, which are highly efficacious as antidiabetic agents, are also proving to be effective for weight loss, albeit at higher doses. While most require injections due to poor oral bioavailability, Rybelsus® (semaglutide) is orally effective for glycemic control, however, its 1% bioavailability and high dose requirement limits its viability as an effective oral weight-loss medication. Here, we demonstrate high oral bioavailability of the GLP-1 agonist, exenatide, A) in canines using an orally ingestible robotic pill (RP) which painlessly injects drug transenterically in the proximal small bowel and B) in humans using an endoscopically guided transenteric injection which mimics RP delivery. Awake dogs received 10 µg of exenatide orally via RP (RT-104, N=4) or SC injection (Byetta®, N=5), while 5 healthy human volunteers received 10 µg of Byetta® via an endoscopic, transenteric injection and, after a 3-day washout, via a SC injection. Exenatide concentrations, determined via ELISA in serially collected plasma samples, yielded similar PK curves in both species (Figure) with oral bioavailability via RP or endoscopic injection calculated to be 79% in dogs and 81% in humans, respectively, compared to SC injections. These data provide the basis for further development of an orally ingestible GLP-1 mimetic (RT-104) which would provide the higher, efficacious exposures needed for both weight loss and glycemic control. Disclosure A. T. Vo: None. A. Yamaguchi: None. A. Dhalla: Employee; Rani Therapeutics. K. Horlen: Employee; Rani Therapeutics. L. Fung: None. B. Syed: None. M. Imran: Board Member; Neptune Medical, Other Relationship; InCube Ventures, Modulus, Inc. M. Hashim: None.