title: PF-05231023, a long-acting FGF21 analogue, decreases body weight by reduction of food intake in non-human primates.
abstract: PF-05231023, a long-acting FGF21 analogue, is a promising potential pharmacotherapy for the treatment of obesity and associated comorbidities. Previous studies have shown the potential of FGF21 and FGF21-like compounds to decrease body weight in mice, non-human primates, and humans; the precise mechanisms of action remain unclear. In particular, there have been conflicting reports on the degree to which FGF21-induced weight loss in non-human primates is attributable to a decrease in food intake versus an increase in energy expenditure. Here, we present a semi-mechanistic mathematical model of energy balance and body composition developed from similar work in mice. This model links PF-05231023 administration and washout to changes in food intake, which in turn drives changes in body weight. The model is calibrated to and compared with recently published data from cynomolgus macaques treated with PF-05231023, demonstrating its accuracy in describing pharmacotherapy-induced weight loss in these animals. The results are consistent with the hypothesis that PF-05231023 decreases body weight in cynomolgus macaques solely by a reduction in food intake, with no direct effect on energy expenditure.
authors.affiliation: Pfizer Inc, 610 Main Street, South Bldg, 4th Floor, Cambridge, MA, 02139, USA.|, 4916 Olde Millcrest Court, Raleigh, NC, 27609, USA.
authors.forename: W Clayton
authors.initials: WC
authors.lastname: Thompson
authors.affiliation: Pfizer Inc, 610 Main Street, South Bldg, 4th Floor, Cambridge, MA, 02139, USA.|Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA, 02115, USA.
authors.forename: Yingjiang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Pfizer Inc, 610 Main Street, South Bldg, 4th Floor, Cambridge, MA, 02139, USA.|Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA, 02115, USA.
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
authors.affiliation: Pfizer Inc, 610 Main Street, South Bldg, 4th Floor, Cambridge, MA, 02139, USA. cynthia.j.musante@pfizer.com.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Musante
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D061067:Antibodies, Monoclonal, Humanized; C000604284:PF-05231023; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
keywords: Body weight; Energy balance; FGF21; K-PD; Mathematical Model; Non-human primate; Obesity