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

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

doi:10.1371/journal.pone.0065763

Andrew C Adams, Jennifer A Martin + Show 9 more

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https://doi.org/10.1371/journal.pone.0065763

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Journal: PloS one	Publication Date: Jun 18, 2013
Citations: 171	License type: CC BY 4.0

Affiliation: University of South Florida

Abstract

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.

Highlights

The conventional approach to discover novel drugs for diabetes mellitus is traditionally centered on agents able to lower blood glucose with little to no attention paid to other measures of metabolic health
In this report we show that LY administration led to dramatic and rapid improvements in metabolic parameters including lowering of circulating glucose/insulin, ameliorated plasma lipid profiles and reduced body weight
Pharmacokinetics of LY in Diabetic Rhesus Monkeys Exposures to LY following its chronic subcutaneous administration to diabetic rhesus monkeys were evaluated by sandwich enzyme-linked immunosorbent assay (ELISA)

Summary

Introduction

The conventional approach to discover novel drugs for diabetes mellitus is traditionally centered on agents able to lower blood glucose with little to no attention paid to other measures of metabolic health. Long term clinical outcomes with the molecules developed via this methodology have been mixed at best This has led to a steady though guarded rise in attention towards novel so-called ‘‘glucose plus’’ targets that act via multifaceted mechanisms offering additional metabolic benefits beyond improvements in glycemic control [1,2]. One example of this new class of molecules is fibroblast growth factor 21 (FGF21) [3,4], which recently emerged as a promising agent able to simultaneously correct many if not all abnormalities in metabolically compromised animals [5,6,7]. The attractiveness of FGF21 based preclinical pharmacology as a superior ‘‘glucose plus’’ agent has already inspired initial efforts to optimize and evaluate re-engineered FGF21 analogues in animal models of metabolic disease [12,13,14]

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