Elafibranor Scientific Facts
Elafibranor (GFT505) is a new dual PPAR α/δ pluripotent product
PPARα and PPARδ are nuclear receptors controlling gene expression, with multiple beneficial activities for the treatment of NASH
- Increase of fatty acid oxidation (FAO), resulting in a decrease of liver fat.
- Improvement of lipid profile (increase of HDL-c and decrease of LDL-c & triglycerides).
- Increase of insulin sensitivity.
- Anti-inflammatory activities.
- Anti-fibrotic activities.
- Increase of energy expenditure.
Elafibranor treatment has a beneficial effect on NASH in preclinical models:
- Prevents the onset of NASH.
- Reverses established NASH.
- Stops progression of established fibrosis, with anti-fibrotic potential.
- Prevents activation and proliferation of human stellate cells (cells involved in the fibrotic process).
Clean safety profile: preclinical, phases 1 & 2
- No in vivo PPARγ activity thus no PPARγ related side effect issues.
Other potential applications in liver diseases (antifibrotic properties).
Efficacy on histological NASH parameters in disease models (fibrosis, steatosis, …)
In various relevant disease models, Elafibranor reverses liver steatosis and fibrosis, and increases liver regeneration.
In a recognized model of liver steatosis induced in C57Bl/6J or diabetic db/db mice by 6 weeks of methionine and choline-deficient (MCD) diet,
- the macroscopic and microscopic examination of the liver showed that Elafibranor oral administration prevented the development of steatosis and liver inflammation
- Elafibranor also potently reduced the plasma concentration of ALT, a marker of liver dysfunction.
- Furthermore, the MCD diet-induced upregulation of pro-inflammatory and pro-fibrotic genes was totally blocked by Elafibranor .
- When administered orally to db/db mice with established MCD diet-induced steatosis, Elafibranor potently reversed the pathology by eliminating liver steatosis and hepatic inflammation, resulting in normalized liver enzyme levels.
The liver-protective effects of Elafibranor have also been demonstrated in a rat model of CCl4-induced hepatic fibrosis.
- As determined through histological and transcriptomic analyses, Elafibranor totally prevented the development of liver fibrosis when administered concomitantly with CCl4.
- Elafibranor stopped the progression of established CCl4-induced liver fibrosis, and normalized liver enzyme levels.
- Elafibranor also reversed established CCl4-induced liver fibrosis, and favored the regeneration of the liver.
B. Staels et al., Hepatology 2013
Recent preclinical data in the foz/foz mice model that closely mimics the natural evolution of human NASH with hepatic fibrosis have confirmed that Elafibranor can reverse NASH as well as fibrosis.
- Treatment with Elafibranor results in a total reversion of hepatic fibrosis that was established due to high fat diet administration. Also,
- Elafibranor reverses steatosis, ballooning and inflammation
- Elafibranor induces significant weight loss, improves diabetes parameters and plasma lipids
The antifibrotic activities of Elafibranor are supported by effects on primary human stellate cells.
Elafibranor demonstrates :
- Dose dependent inhibition of TGFβ induced stellate cell activation
- Dose dependent inhibition of PDGF induced stellate cell proliferation
Elafibranor antifibrotic properties are associated with the inhibition of structurally related RTKs by Elafibranor
- The RTKs repressed by Elafibranor belong to a group involved in the fibrotic process
Last update: September 2015