A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects

被引：416

作者：

Talukdar, Saswata ^{[1
]}

Zhou, Yingjiang ^{[1
]}

Li, Dongmei ^{[1
]}

Rossulek, Michelle ^{[1
]}

Dong, Jennifer ^{[1
]}

Somayaji, Veena ^{[1
]}

Weng, Yan ^{[2
]}

Clark, Ronald ^{[1
]}

Lanba, Adhiraj ^{[1
]}

Owen, Bryn M. ^{[4
]}

Brenner, Martin B. ^{[1
]}

Trimmer, Jeffrey K. ^{[1
]}

Gropp, Kathryn E. ^{[3
]}

Chabot, Jeffrey R. ^{[2
]}

Erion, Derek M. ^{[1
]}

Rolph, Timothy P. ^{[1
]}

Goodwin, Bryan ^{[1
]}

Calle, Roberto A. ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Cardiovasc Metab & Endocrine Dis Res Unit, 610 Main St, Cambridge, MA 02139 USA

[2] Pfizer Worldwide Res & Dev, Pharmacokinet Dynam & Metab, 610 Main St, Cambridge, MA 02139 USA

[3] Pfizer Inc, Drug Safety Res & Dev, Groton, CT 06340 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

来源：

CELL METABOLISM | 2016年 / 23卷 / 03期

基金：

英国惠康基金;

关键词：

ENERGY-EXPENDITURE; GLUCOSE-HOMEOSTASIS; INSULIN SENSITIVITY; GROWTH; BONE; METABOLISM; UTILITY; LIVER;

D O I：

10.1016/j.cmet.2016.02.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

FGF21 plays a central role in energy, lipid, and glucose homeostasis. To characterize the pharmacologic effects of FGF21, we administered a longacting FGF21 analog, PF-05231023, to obese cynomolgus monkeys. PF-05231023 caused a marked decrease in food intake that led to reduced body weight. To assess the effects of PF-05231023 in humans, we conducted a placebo-controlled, multiple ascending-dose study in overweight/obese subjects with type 2 diabetes. PF-05231023 treatment resulted in a significant decrease in body weight, improved plasma lipoprotein profile, and increased adiponectin levels. Importantly, there were no significant effects of PF-05231023 on glycemic control. PF-05231023 treatment led to dose-dependent changes in multiple markers of bone formation and resorption and elevated insulin-like growth factor 1. The favorable effects of PF-05231023 on body weight support further evaluation of this molecule for the treatment of obesity. Longer studies are needed to assess potential direct effects of FGF21 on bone in humans.

引用

页码：427 / 440

页数：14

共 38 条

[1] LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys [J].

Adams, Andrew C. ;

Halstead, Carolyn A. ;

Hansen, Barbara C. ;

Irizarry, Armando R. ;

Martin, Jennifer A. ;

Myers, Sharon R. ;

Reynolds, Vincent L. ;

Smith, Holly W. ;

Wroblewski, Victor J. ;

Kharitonenkov, Alexei .

PLOS ONE, 2013, 8 (06)

[2] Fundamentals of FGF19 & FGF21 Action In Vitro and In Vivo [J].

Adams, Andrew C. ;

Coskun, Tamer ;

Rovira, Armando R. Irizarry ;

Schneider, Michael A. ;

Raches, David W. ;

Micanovic, Radmila ;

Bina, Holly A. ;

Dunbar, James D. ;

Kharitonenkov, Alexei .

PLOS ONE, 2012, 7 (05)

[3] FGF21 regulates metabolism and circadian behavior by acting on the nervous system [J].

Bookout, Angie L. ;

de Groot, Marleen H. M. ;

Owen, Bryn M. ;

Lee, Syann ;

Gautron, Laurent ;

Lawrence, Heather L. ;

Ding, Xunshan ;

Elmquist, Joel K. ;

Takahashi, Joseph S. ;

Mangelsdorf, David J. ;

Kliewer, Steven A. .

NATURE MEDICINE, 2013, 19 (09) :1147-1152

[4] Weight loss-induced changes in adipose tissue proteins associated with fatty acid and glucose metabolism correlate with adaptations in energy expenditure [J].

Camps, Stefan G. J. A. ;

Verhoef, Sanne P. M. ;

Roumans, Nadia ;

Bouwman, Freek G. ;

Mariman, Edwin C. M. ;

Westerterp, Klaas R. .

NUTRITION & METABOLISM, 2015, 12

[5] βKlotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism [J].

Ding, Xunshan ;

Boney-Montoya, Jamie ;

Owen, Bryn M. ;

Bookout, Angie L. ;

Coate, Katie Colbert ;

Mangelsdorf, David J. ;

Kliewer, Steven A. .

CELL METABOLISM, 2012, 16 (03) :387-393

[6] FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis [J].

Fisher, Ffolliott M. ;

Kleiner, Sandra ;

Douris, Nicholas ;

Fox, Elliott C. ;

Mepani, Rina J. ;

Verdeguer, Francisco ;

Wu, Jun ;

Kharitonenkov, Alexei ;

Flier, Jeffrey S. ;

Maratos-Flier, Eleftheria ;

Spiegelman, Bruce M. .

GENES & DEVELOPMENT, 2012, 26 (03) :271-281

[7] Treating Diabetes and Obesity with an FGF21-Mimetic Antibody Activating the βKlotho/FGFR1c Receptor Complex [J].

Foltz, Ian N. ;

Hu, Sylvia ;

King, Chadwick ;

Wu, Xinle ;

Yang, Chaofeng ;

Wang, Wei ;

Weiszmann, Jennifer ;

Stevens, Jennitte ;

Chen, Jiyun Sunny ;

Nuanmanee, Noi ;

Gupte, Jamila ;

Komorowski, Renee ;

Sekirov, Laura ;

Hager, Todd ;

Arora, Taruna ;

Ge, Hongfei ;

Baribault, Helene ;

Wang, Fen ;

Sheng, Jackie ;

Karow, Margaret ;

Wang, Minghan ;

Luo, Yongde ;

McKeehan, Wallace ;

Wang, Zhulun ;

Veniant, Murielle M. ;

Li, Yang .

SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (162)

[8] The Effects of LY2405319, an FGF21 Analog, in Obese Human Subjects with Type 2 Diabetes [J].

Gaich, Gregory ;

Chien, Jenny Y. ;

Fu, Haoda ;

Glass, Leonard C. ;

Deeg, Mark A. ;

Holland, William L. ;

Kharitonenkov, Alexei ;

Bumol, Thomas ;

Schilske, Holger K. ;

Moller, David E. .

CELL METABOLISM, 2013, 18 (03) :333-340

[9] GENERATION OF ANALYTIC PLASMA-LIPOPROTEIN PROFILES USING 2 PREPACKED SUPEROSE-6B COLUMNS [J].

GERDES, LU ;

GERDES, C ;

KLAUSEN, IC ;

FAERGEMAN, O .

CLINICA CHIMICA ACTA, 1992, 205 (1-2) :1-9

[10] FGF21-based pharmacotherapy - potential utility for metabolic disorders [J].

Gimeno, Ruth E. ;

Moller, David E. .

TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2014, 25 (06) :303-311

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