Long-acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys.
Fibroblast growth factor 21 (FGF21), a hormone with short half-life, has consistently shown strong pharmacological efficacy. We first assessed the efficacy of murine recombinant FGF21 in C57BL6 lean mice for 5 wk. We then generated a long-acting FGF21 molecule by fusing a Fc to a variant of human recombinant FGF21 (hrFGF21) that contained two engineered mutations [L98R, P171G; Fc-FGF21(RG)] and tested it in C57BL6 diet-induced obese mice and obese rhesus monkeys. We compared its metabolic properties with those of the hrFGF21. Groups of diet-induced obese mice were treated for 36 d with different doses of hrFGF21 (01, 0.3, and 1 mg/kg twice daily) and with Fc-FGF21(RG) (2.3 mg/kg, every 5 d). Body weight, glucose, insulin, cholesterol, and triglyceride levels were decreased after treatment with either compound. A glucose tolerance test (GTT) was also improved. Obese rhesus monkeys were treated with hrFGF21 (once a day) and Fc-FGF21(RG) (once a week) in a dose-escalation fashion. Doses started at 0.1 and 0.3 mg/kg and ended at 3 and 5 mg/kg for hrFGF21 and Fc-FGF21(RG), respectively. Doses were escalated every 2 wk, and animals were followed up for a washout period of 3 wk. Body weight, glucose, insulin, cholesterol, and triglyceride levels and the GTT profile were decreased to a greater extent with Fc-FGF21(RG) than with hrFGF21. The PK-PD relationship of Fc-FGF21(RG) exposure and triglyceride reduction was also conducted with a maximum response model. In conclusion, in more than one species, Fc-FGF21(RG) chronically administered once a week showed similar or greater efficacy than hrFGF21 administered daily.
Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. mveniant@amgen.com
Murielle M
MM
Véniant
Renee
R
Komorowski
Ping
P
Chen
Shanaka
S
Stanislaus
Katherine
K
Winters
Todd
T
Hager
Lei
L
Zhou
Russell
R
Wada
Randy
R
Hecht
Jing
J
Xu
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight; D004334:Drug Administration Schedule; D005346:Fibroblast Growth Factors / Q000008:administration & dosage* / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy*; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors