Journal Article

LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys

Irizarry, Armando R., Reynolds, Vincent L., Wroblewski, Victor J., Kharitonenkov, Alexei, Hansen, Barbara C., Halstead, Carolyn A., Adams, Andrew C., Smith, Holly W., Martin, Jennifer A., Myers, Sharon R.

2013

Overview

Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that represents a promising target for the treatment of several metabolic diseases. Administration of recombinant wild type FGF21 to diabetic animals leads to a dramatic improvement in glycaemia and ameliorates other systemic measures of metabolic health. Here we report the pharmacologic outcomes observed in non-human primates upon administration of a recently described FGF21 analogue, LY2405319 (LY). Diabetic rhesus monkeys were treated subcutaneously with LY once daily for a period of seven weeks. The doses of LY used were 3, 9 and 50 mg/kg each delivered in an escalating fashion with washout measurements taken at 2, 4, 6 and 8 weeks following the final LY dose. LY therapy led to a dramatic and rapid lowering of several important metabolic parameters including glucose, body weight, insulin, cholesterol and triglyceride levels at all doses tested. In addition, we observed favorable changes in circulating profiles of adipokines, with increased adiponectin and reduced leptin indicative of direct FGF21 action on adipose tissue. Importantly, and for the first time we show that FGF21 based therapy has metabolic efficacy in an animal with late stage diabetes. While the glycemic efficacy of LY in this animal was partially attenuated its lipid lowering effect was fully preserved suggesting that FGF21 may be a viable treatment option even in patients with advanced disease progression. These findings support continued exploration of the FGF21 pathway for the treatment of metabolic disease.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipokines - blood / Adiponectin / Adipose tissue / Animals / Anticholesteremic agents / Biology / Blood glucose / Blood Glucose - analysis / Body weight / Care and treatment / Cholesterol / Development and progression / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - metabolism / Disease Progression / Dose-Response Relationship, Drug / Drug dosages / Endocrinology / Energy Intake - drug effects / Fibroblast growth factors / Fibroblast Growth Factors - pharmacokinetics / Fibroblast Growth Factors - pharmacology / Fibroblasts / Glucose / Glucose metabolism / Growth factors / Homeostasis / Insulin / Insulin - blood / Laboratories / Leptin / Lipids / Macaca mulatta / Medical treatment / Medicine / Metabolic disorders / Metabolism / Monkeys / Monkeys & apes / Mutation / Pharmacology / Pichia pastoris / Primates / Rodents / Therapy / Type 2 diabetes / Weight Loss - drug effects