Introduction and Objective: Amylin is an attractive target for obesity therapy. Eloralintide is a selective and potent once-weekly subcutaneously administered amylin analog peptide, which has demonstrated promising efficacy and safety profile in a 48-week clinical trial for obesity. ASC39 is a novel oral small molecule amylin receptor agonist development candidate. This study evaluates in vitro and in vivo pharmacological properties of ASC39 vs eloralintide.Methods: The cAMP activation of ASC39 vs eloralintide was assessed for human amylin receptors and human calcitonin receptor (hCTR). Weight-loss effects of ASC39 vs eloralintide were evaluated in diet-induced obese (DIO) rats by oral daily dosing of ASC39 (5 mg/kg) and subcutaneous once-every-three days (Q3D) dosing of eloralintide (3 nmol/kg).Results: In a head-to-head cAMP activation assay, EC50s for human amylin 1 receptor (hAMY1R) were 21.4 pM and 21.2 pM for ASC39 and eloralintide, respectively. EC50s for hCTR were 846.1 pM and 1350.8 pM for ASC39 and eloralintide, respectively. These data indicates ASC39 and eloralintide have 40-fold and 64-fold selectivity, respectively for hAMY1R over hCRT. In a head-to-head DIO rat study, oral administration of ASC39 resulted in significant weight loss which was as good as eloralintide.Conclusion: ASC39 is an eloralintide-like selective and potent oral small molecule amylin receptor agonist development candidate with a novel scaffold. Both ASC39 and eloralintide demonstrated a strong selectivity towards hAMY1R over hCTR and a comparable preclinical efficacy in DIO rats. Oral ASC39’s attractive pharmacological profile supports its advancement into human clinical trials, alone and in combination to offer a novel, convenient, accessible and differentiated obesity therapeutic option.
J.J. Wu: None. C. Wu: None.
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