Glp-1 Agonist Based Therapies: Engineering Considerations And Development Of Dulaglutide, A GLP1-Fc
Wolfgang Glaesner
Chief Scientific Officer,AME, Eli Lilly and Co
Targeting the incretin system via GLP-1 receptor agonism has become a powerful tool to treat type 2 diabetes. Exenatide is currently available in 2 different formulations, soluble as twice daily injection (Byetta, Amylin Pharmaceuticals) and as depot formulation for once weekly injections(Bydureon, Amylin Pharmaceuticals). Liraglutide is available as soluble once daily injection (Victoza, Novo Nordisk). Multiple GLP-1 analogs and long-acting formulations are currently in development to provide more convenient and less frequent administration. One of these novel analogs is dulaglutide, a long-acting GLP-1 analog based on the fusion of a DPP-IV protected GLP-1 moiety and an IgG4-Fc carrier protein. Dulaglutide is a potent insulinotropic agent in vitro in rat and cynomolgus monkey cell-based systems and demonstrates prolonged time-action in rodents and primates. Dulaglutide has also been designed for improved safety, which is based on removal of potential T-cell epitopes through de-immunization and the elimination of FcyR interaction to decrease the potential for ADCC activity. Dulaglutide is currently in phase 3 clinical evaluation as once-weekly treatment of type 2 diabetes.