Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)?

ABSTRACT

Introduction: Fibroblast growth factor (FGF) 21 is a member of the FGF19 sub-family of signaling molecules. They have been found to act at the localized paracrine/autocrine and systemic endocrine levels because of their extracellular matrix and co-receptor protein binding characteristics. While the molecule circulates systemically, it has specificity conferred by a co-factor binding protein β-Klotho which is preferentially expressed in hepatic and adipose tissues. This protein, in conjunction with the FGF receptor (FGFR), propagates the downstream effects of the growth factor signaling cascade, which has been linked to fat and glucose metabolism. FGF21 has been recognized as a possible pathway for the treatment of nonalcoholic fatty liver disease (NAFLD). Targeting of the FGF21/FGFR/β-Klotho pathway may halt or reverse hepatic fat infiltration, inflammation, and fibrosis.

Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of two FGF21 agonist therapies in development.

Expert opinion: Preclinical and clinical data justify further investigation of FGF21 agonist therapies for the treatment of NAFLD. However, issues including injection site reactions and possible effects on bone homeostasis mean that safety must be evaluated carefully.

KEYWORDS:

• Nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis
• fibroblast growth factor 21
• pegbelfermin
• BMS-986036
• AKR-001

Declaration of interest

N Alkhouri receives research funding from Akero (the maker of AKR-001) and BMS (the maker of pegbelfermin). M Noureddin receives research funding from BMS (the maker of pegbelfermin). T Rolph is an employee of Akero Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One referee is an employee and stockholder of Bristol-Myers Squibb, which is developing pegbelfermin (PEG-FGF21) for NASH. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.