733-P: Efficacy of a Novel Oral Amylin Analog and the Development of an Oral GLP-1/Amylin Coformulated Tablet to Produce High In Vivo Plasma Exposures

by sugaradmin



Introduction and Objective: GLP-1 and amylin peptide hormones independently reduce food intake, delay gastric emptying, and decrease glucagon release. Combination of GLP-1 and amylin analogs promotes greater weight loss and glycemic control than either agent alone. Here we assessed the in vivo efficacy of a novel oral amylin analog (VRB103) in rodent models, as well as pharmacokinetics (PK) of the first oral co-formulation of GLP-1, amylin, and a proprietary permeation enhancer (T2026), showing improved oral bioavailability in cynomolgus monkeys.Methods: VRB103 was administered via single daily subcutaneous injection either alone or in combination with VRB101 (GLP-1 analog Ecnoglutide) in Sprague-Dawley (SD) rats to evaluate its efficacy in reducing body weight (BW). Separately, an oral co-formulated tablet of VRB103, VRB101, and T2026 was dosed daily in cynomolgus monkey for 7 days and PK samples were collected and analyzed.Results: In SD rats, VRB103 alone decreased BW by 0.3%, 3.8% and 9%, 24 hours after a single subcutaneous injection of 5 nmol/kg, 25 nmol/kg and 125 nmol/kg, respectively, while the control group gained 4.7% in BW. Combination of 5 nmol/kg VRB103 and 5 nmol/kg VRB101 induced a 7.4% BW loss in the same model, demonstrating superior efficacy of the GLP-1/amylin combination. Oral PK study with a co-formulated tablet containing VRB103, VRB101 and T2026 was conducted in cynomolgus monkeys. After once-daily dosing for 7 days, similarly high plasma exposures were achieved for VRB103 (AUC0-168h = 79,352 h*ng/ml) and VRB101 (AUC0-168h = 93,249 h*ng/ml).Conclusion: In a preclinical model, the combination of the amylin analog VRB103 and VRB101 demonstrated a synergistic effect on body weight reduction. Both VRB103 and VRB101 achieved high plasma exposures in cynomolgus monkeys when dosed orally from a single co-formulated tablet containing VRB103, VRB101, and T2026, supporting continued development of the oral GLP-1/amylin combination for the treatment of obesity and type 2 diabetes.

Disclosure

H. Zou: Employee; Sciwind Biosciences. X. Wu: Employee; Sciwind Biosciences. W. Guo: Employee; Sciwind Biosciences. J. Deng: None. C.L. Jones: Employee; Sciwind Biosciences, Verdiva Bio. S. Trieu: Advisory Panel; Novo Nordisk. Employee; Verdiva Bio. R. Ho: Employee; Verdiva Bio. Consultant; Beacon Therapeutics, Aiolos Bio. M. Eid: Employee; Verdiva Biosciences, Boehringer-Ingelheim. J. Hughes: Employee; GlaxoSmithKline plc. W. Zhong: None. M. Fenaux: None.



Source link