1766-P: VRB-103 Is a Potent, Orally Bioavailable Amylin Analog with a Strong Selectivity towards Human Amylin Receptors vs. Calcitonin Receptor

Introduction and Objective: Amylin is a peptide hormone secreted from pancreatic beta-cells that reduces appetite, delays gastric emptying, and decreases glucagon release. Amylin functions by activating human amylin receptors (hAMY1R, hAMY2R and hAMY3R), which consist of the calcitonin receptor (hCTR) in complex with receptor activity modifying proteins (RAMP1-3). Clinical stage amylin analogs, such as cagrilintide and eloralintide, have demonstrated distinct profiles for tolerability and body weight reduction with weekly subcutaneous administrations. Amylin analogs vary in their selectivity for hAMY1R-3R relative to hCTR, which may have implications for clinical efficacy and tolerability. VRB-103 is a novel amylin analog designed to be optimized for oral administration. Here we evaluated the in vitro potency of VRB-103 for activation of hAMY1R-3R and hCTR, and the relative selectivity on hAMY1R-3R vs hCTR. Methods: VRB-103 was tested in CHO cell lines stably overexpressing hAMY1R, hAMY2R, hAMY3R, or hCTR. Eloralintide and cagrilintide were used as comparators. Results: VRB-103 demonstrated potent in vitro activities against hAMY1R, hAMY2R and hAMY3R with EC50s of 0.057 nM, 0.146 nM, and 0.011 nM, respectively. VRB-103 showed lower activity against hCTR compared to the amylin receptors. When normalized to cagrilintide, this resulted in hAMY1R, hAMY1R, and hAMY3R selectivity relative to hCTR of 20.6, 5.5 and 4.4-fold, respectively. By comparison, eloralintide showed normalized relative lower selectivity for hAMY1R, hAMY2Rand hAMY3R activation versus hCTR of 5.0, 0.8 and 1.4-fold, respectively. Conclusion: VRB-103 is a potent and orally bioavailable amylin analog with a strong selectivity towards human amylin receptors relative to hCTR. The amylin receptor selectivity of VRB-103 was more pronounced than that of the comparators analyzed. VRB-103 is currently in development as a once-weekly oral tablet for obesity. Disclosure M. Fenaux: None. C.L. Jones: Employee; Current; Verdiva Bio. W. Zhong: None. Y. Li: Employee; Current; Sciwind Biosciences. S. Hao: Employee; Current; Sciwind Biosciences. Z. Li: Employee; Current; Sciwind Biosciences. Y. Wang: Employee; Current; Sciwind Biosciences. J. Zhao: Employee; Current; Sciwind Biosciences. J. Francis: Employee; Current; Verdiva Bio. H. Zou: Employee; Current; Sciwind Biosciences. X. Wu: Employee; Current; Sciwind Biosciences. R. Zhu: Employee; Current; Sciwind Biosciences.