Harnessing the Action of Fibroblast Growth Factor21 as a Therapeutic Agent

Purpose of Review: Fibroblast growth factor (FGF) 21 has received considerable attention over the past decade. This protein belongs to the FGF-19 subfamily and functions primarily as an autocrine/paracrine hormone. FGF-21 requires a co-factor, βKlotho, for its activity; and interactions with tissue-specific fibroblast growth factor receptor (FGFR) subtypes result in a diverse set of signaling. The purpose of this review is to provide an overview of the current status of FGF-21 therapeutic development. Recent Findings: FGF-21 has the potential to treat obesity and accompanying comorbidities through its effects on various metabolic parameters. Strategies to improve the pharmacokinetics and pharmacodynamics of this protein include enchanced stability, PEGylation, use of fusion proteins, and antibody development. Several preclinical studies have evaluated these strategies, and strengths and weaknesses have been identified. To date, βKlotho-independent strategies have resulted in hypophosphatemia, hinting at the potential for skeletal toxicity. Two small human studies have evaluated FGF-21 variants. While the results were favorable including a reduction in body weight and improved lipid values, glucose concentrations were not significantly reduced. Summary: FGF-21 has significant potential as a therapeutic target. One of the challenges with harnessing the potential of FGF-21 as a therapeutic agent is the short half-life of its native form. In addition, FGFRs are widespread throughout the body, and significant off-target effects are possible; therefore, FGF-21 development should proceed with cautious enthusiasm.