Abstract
Pharmacological administration of FGF21 analogues has shown robust body weight reduction and lipid profile improvement in both dysmetabolic animal models and metabolic disease patients. Here we report the design, optimization, and characterization of a long acting glyco-variant of FGF21. Using a combination of N-glycan engineering for enhanced protease resistance and improved solubility, Fc fusion for further half-life extension, and a single point mutation for improving manufacturability in Chinese Hamster Ovary cells, we created a novel FGF21 analogue, Fc-FGF21[R19V][N171] or PF-06645849, with substantially improved solubility and stability profile that is compatible with subcutaneous (SC) administration. In particular, it showed a low systemic clearance (0.243 mL/hr/kg) and long terminal half-life (~200 hours for intact protein) in cynomolgus monkeys that approaches those of monoclonal antibodies. Furthermore, the superior PK properties translated into robust improvement in glucose tolerance and the effects lasted 14 days post single SC dose in ob/ob mice. PF-06645849 also caused greater body weight loss in DIO mice at lower and less frequent SC doses, compared to previous FGF21 analogue PF-05231023. In summary, the overall PK/PD and pharmaceutical profile of PF-06645849 offers great potential for development as weekly to twice-monthly SC administered therapeutic for chronic treatment of metabolic diseases.
Highlights
Pharmacological administration of Fibroblast growth factor 21 (FGF21) analogues has shown robust body weight reduction and lipid profile improvement in both dysmetabolic animal models and metabolic disease patients
Fibroblast growth factor 21 (FGF21) is a fasting-induced hormone originally identified as a protein that increased glucose uptake in adipocytes[1]
While both molecules showed improved pharmaceutical properties compared to Wild type (WT) FGF21, one still required daily SC dosing as a result of a short half-life, and the other required twice weekly intravenous (IV) dosing as a result of poor SC bioavailability and proteolytic instability within the C-terminus of FGF2112,19–21
Summary
Yan Weng[1], Tetsuya Ishino[1], Annette Sievers[1], Saswata Talukdar[5], Jeffrey R. Using a combination of N-glycan engineering for enhanced protease resistance and improved solubility, Fc fusion for further half-life extension, and a single point mutation for improving manufacturability in Chinese Hamster Ovary cells, we created a novel FGF21 analogue, Fc-FGF21[R19V][N171] or PF-06645849, with substantially improved solubility and stability profile that is compatible with subcutaneous (SC) administration It showed a low systemic clearance (0.243 mL/hr/kg) and long terminal half-life (~200 hours for intact protein) in cynomolgus monkeys that approaches those of monoclonal antibodies. A hyperglycosylated analogue of huEPO was successfully developed and marketed as Aranesp that has a threefold increase in serum circulating half-life, allowing for less frequent dosing in patients compared to rhEPO24 We extended this methodology to FGF21 as part of a combination approach to improve its properties. Optimization, and characterization of a long acting glyco-variant of FGF21, PF-06645849, with a PK profile that allows for once weekly to bi-weekly dosing, and a pharmaceutical profile that supports SC administration
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