A nontumorigenic variant of FGF19 treats cholestatic liver diseases

Abstract

Hepatic accumulation of bile acids is central to the pathogenesis of cholestatic liver diseases. Endocrine hormone fibroblast growth factor 19 (FGF19) may reduce hepatic bile acid levels through modulation of bile acid synthesis and prevent subsequent liver damage. However, FGF19 has also been implicated in hepatocellular carcinogenesis, and consequently, the potential risk from prolonged exposure to supraphysiological levels of the hormone represents a major hurdle for developing an FGF19-based therapy. We describe a nontumorigenic FGF19 variant, M70, which regulates bile acid metabolism and, through inhibition of bile acid synthesis and reduction of excess hepatic bile acid accumulation, protects mice from liver injury induced by either extrahepatic or intrahepatic cholestasis. Administration of M70 in healthy human volunteers potently reduces serum levels of 7α-hydroxy-4-cholesten-3-one, a surrogate marker for the hepatic activity of cholesterol 7α-hydroxylase (CYP7A1), the enzyme responsible for catalyzing the first and rate-limiting step in the classical bile acid synthetic pathway. This study provides direct evidence for the regulation of bile acid metabolism by FGF19 pathway in humans. On the basis of these results, the development of nontumorigenic FGF19 variants capable of modulating CYP7A1 expression represents an effective approach for the prevention and treatment of cholestatic liver diseases as well as potentially for other disorders associated with bile acid dysregulation.

Non-Alcoholic Steatohepatitis: From Pathophysiology to Novel Therapies

“…Based on these findings, a number of studies were performed to generate mutant FGF19 variants that should lack these pro-tumorigenic properties but retain the beneficial metabolic effects (for review see [54] ). In this regard, the variant M70 (or NGM282) has recently been described as a 'biased ligand' for FGFR4, which lacks tumor-promoting features, but is still able to suppress CYP7A1 activity in vitro and in vivo [63,64] . Clinical phase II trials are currently performed to investigate the potential of this drug to improve metabolic parameters in patients with T2D and NASH (NCT01943045 and NCT02443116).…”

Essential roles of bile acids and their nuclear receptors, FXR and PXR, in the cholestatic liver disease

“…As a potential therapeutic strategy for cholestatic liver disease, FGF15/19 has the disadvantage that it needs to be injected instead of oral treatment. However, FGF19 derivative NGM282 with UDCA has been tested for clinical trial phase II in PBC patients (Luo et al 2014). Given that FGF15/19 is a mitogenic peptide, the carcinogenic properties of FGF15/19 should be carefully considered for the clinical purpose.…”

Bile Acid Uptake Transporters as Targets for Therapy

“…This hormone, when released from the gut, binds to the tyrosine kinase receptor FGF receptor 4/β-Klotho on hepatocytes, which activates the jun N-terminal kinase 1/2 signaling pathway [53]. Intestinal FXR activation [54] and the FGF19 mimetic M70 [55,56] dampen cholestatic liver injury by strongly reducing hepatic bile acid synthesis and the circulating bile acid pool. So, mouse studies clearly show hepatoprotection through (gut-specific) FGF15/19 signaling, primarily by reducing bile acid pools, sharing its mode of action with ASBT-inhibition.…”