NASH Target Development Service for Fibroblast Growth Factor (FGF) Analogues

Non-alcoholic steatohepatitis (NASH) has emerged as one of the most common causes of chronic liver disease worldwide and is increasing as a cause of morbidity and mortality. Some members of the fibroblast growth factors (FGFs) are novel metabolic regulators with beneficial effects on the regulation of metabolism in animal models of NASH and therefore have great potential for the treatment of NASH.

Background of Fibroblast Growth Factor (FGF) Analogues

Fibroblast growth factor (FGF) is composed of 22 polypeptides that display diverse functions from embryonic development, tissue regeneration to the maintenance of metabolic homeostasis. FGFs act as autocrine, paracrine, and/or endocrine hormones by binding to FGF receptors (FGFRs). Currently, three members of FGFs family (FGF19, FGF21, and FGF23) act as endocrine proteins and play roles in bile acid, glucose and lipid metabolism, vitamin D modulation, phosphate homeostasis and metabolic adaptation during fasting, which are critical for maintaining whole-body homeostasis. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. Therefore, efforts are being made to develop fibroblast analogues without side effects and with good pharmacokinetic characteristics. Therefore, pharmaceutical efforts are in progress to develop FGF analogs without side effects and with a better pharmacokinetic profile. The most advanced analogs are based on FGF19 and FGF21, which have achieved good clinical results and are expected to be candidates for the treatment of metabolic disorders.

Fibroblast Growth Factor (FGF) Analogues for NASH

Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Both FGF19 and FGF21 show similar metabolic profile, such as lowering serum glucose, TG and cholesterol levels, as well as improving insulin sensitivity and reducing body weight in NASH disease models, indicating that they represent novel treatment for NASH and other metabolic disorders. Due to the short plasma half-life and poor drug-like properties of the native FGF21 molecule, some FGF21 analogs (LY2405319 and PF-05231023, BMS-986036) have been developed to improve the biophysical properties of FGF21 and show similar effects on metabolism to FGF21. The therapeutic potential of FGF19 is hampered by its hepatocarcinogenesis, and the FGF19 non-tumorigenic analogue (NGM282) has been developed. In the animal model of NASH, treatment with NGM282 resulted in significant improvements in all histological features associated with NASH, including hepatic steatosis, inflammation, ballooning degeneration, and fibrosis. Therefore, FGF19 and FGF21 analogues are potential therapeutic targets for NASH.

Fig.1 The role of FGF21 in the pathogenesis of NAFLD. (Liu, 2015)

The Features of Fibroblast Growth Factor (FGF) Analogues in Creative Biolabs

FGF19 and FGF21 are critical to regulate metabolism and may serve as biomarkers for chronic metabolic disorders. Additionally, they are also very important targets for the treatment of NASH and other metabolic disorders. At Creative Biolabs, we provide engineered FGF21, FGF19 and their analogues molecules with improved preclinical pharmacokinetics while preserving full therapeutic functionality. They have the following characteristics:

• High stability and bioactivity
• High solubility
• Long plasma half-life

Creative Biolabs has a "one-stop" drug target development service platform, which combines its own advantages to provide customers with a range of technical services including NASH target identification, validation, and design of corresponding treatment strategies. Our service platform is a cost-effective and effective option for you to accelerate the development of drug targets. If you want to know more about NASH, please feel free to contact us.

Reference

1. Liu, J.; et al. The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy. Metabolism. 2015, 64(3): 380-390.