Inventing new medicines: The FGF21 story

Abstract

Since the discovery of insulin in 1921, protein therapeutics have become vital tools in the treatment of diabetes mellitus. This heritage has been extended with the comparatively recent introduction of recombinant and re-engineered insulins, in addition to the advent of GLP1 agonists. FGF21 represents an example of a novel experimental protein therapy which is able to induce favorable metabolic effects in various species ranging from rodents to man. The aim of this review is to communicate the story of the FGF21 drug discovery path from identification in a functional in vitro screen, to the eventual evaluation of its utility in patients. Given that the development of FGF21 advanced hand-in-hand with rapidly evolving scientific research around this target, we have also attempted to describe our view of recent developments regarding the mechanistic understanding of FGF21 biology.

Keywords: Drug discovery; FGF21; LY2405319; Metabolism.

Figure 1

Schematic representation of the identification and evaluation of FGF21 therapeutic utility through the drug discovery process. (A) The functional screening assay involved the assessment of FGF21's effects on glucose uptake in combination with insulin utilizing in an adipocyte model. (B) Following the initial activity hit the glucose uptake screening system was refined to more accurately capture the magnitude of FGF21 action in a longer term treatment paradigm. (C) Subsequent work focused on demonstrating translatability of this in vitro effect into metabolic efficacy in rodent models of insulin resistance and hyperglycemia such as ob/ob mice, where FGF21 demonstrated glucose lowering comparable to that observed with insulin (A, B and C are adapted from [8]). (D) The next study confirmed that FGF21 is bioactive in diabetic non-human primates, a model of metabolic disease which closely resembles the human condition (adapted from [40]). (E) Finally, LY2405319, an FGF21 analog, was shown to be efficacious in humans, suggesting that FGF21-based therapies may indeed represent a novel therapeutic option .