Liver X Receptor (LXR) /
LXR / NASH
Phenex has more than 20 years of experience in drug discovery with nuclear receptors. As transcriptions factors, the ability of individual nuclear receptors to regulate multiple genetic networks has marked them as attractive pharmaceutical targets for a broad spectrum of diseases. The nuclear receptors FXR and LXR, two key functional players in the control of metabolism and liver integrity, provide a powerful option to treat liver related diseases that are caused by metabolic dysregulation.
What is NASH?
Representing the progressive manifestation of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) is a chronic liver disease recognized as a major healthcare concern. The progression is further aggravated by features and complications of the metabolic syndrome such as obesity and type 2 diabetes promoting the development of liver cell stress, subsequent inflammation and fibrosis, cirrhosis, and end-stage liver disease. Albeit several drugs are in clinical development, there is no approved dedicated therapy available as of today.
FXR (Farnesoid X receptor) is a bile acid receptor found mainly in the gastrointestinal tract and the liver. FXR agonists such as the bile acid-based drug Obeticholic Acid (OCA) have demonstrated huge medical benefit in clinical trials with NASH patients and in Primary Biliary Cirrhosis (PBC). Several other FXR agonists have followed into clinical development including Cilofexor, a differentiated FXR agonist that we have sold to Gilead Sciences for further development.
LXR inverse agonist PX016 for the treatment of NASH
LXR (Liver X Receptor) represents the direct functional counterplayer to FXR. The two LXR isoforms LXR alpha and beta share pivotal roles in controlling de novo lipogenesis (DNL), intestinal lipid uptake, cholesterol fluxes and insulin.
Just like FXR, LXR is at the crossroads of the major metabolic pathways that control the development of NAFLD and the progression towards NASH. High LXR expression levels are also directly correlated with disease progression. When LXR is activated by its natural ligands, cholesterol derivatives, it induces liver fat production and deposition. The pharmacological inhibition of this function removes the breeding ground for NASH development and progression.
What makes PX016 superior to other NASH treatments?
In order to efficiently silence LXR-driven gene expression, we have designed a potent LXR inverse agonist, PX016. These characteristics distinguish our clinical candidate:
- PX016 is strongly hepatotropic, minimizing unwanted effects on reverse cholesterol flux in the periphery
- Very potent reduction in liver steatosis and in plasma triglycerides
- Reduction in toxic lipid mediators (ceramides and diacylglycerols) to improve peripheral and hepatic insulin sensitivity
- Reduction in body weight by reducing intestinal lipid uptake
- And an, most likely indirect but potent antifibrotic effect that comes through the combined improvement in the aforementioned parameters
PX016 does not have the liabilities of FXR drugs such as pruritus or HDL-c lowering or LDL-c increases. It can also be combined with other anti-NASH drugs such as ACC inhibitors. In fact, PX016 was shown to revert the increase in plasma TG seen with an ACC inhibitor into plasma TG lowering (Publications & Posters).
Ahn SB, Jang K, Jun DW, Lee BH, Shin KJ. Expression of liver X receptor correlates with intrahepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Dig Dis Sci. 59(12):2975-82. (2014).
Albhaisi S, Sanyal A. Recent advances in understanding and managing non-alcoholic fatty liver disease. F1000Research 7. (2018).
Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 13(4):213-24. (2012).
Chen G, Liang G, Ou J, Goldstein JL, Brown MS. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci U S A. 101(31):11245-50. (2004).
Estes, C. et al. Modeling NAFLD Disease Burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J. Hepatol. 69(4):896-904. (2018).
Friedman SL, Neuschwander-Tetri BA, Rinella, M, Sanyal, AJ. Mechanisms of NAFLD development and therapeutic strategies. Med. 24(7):908-922. (2018).
Kalaany NY, Mangelsdorf D J. LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Rev. Physiol. 68:159-91. (2006).
Musso G, Cassader M, Gambino R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Rev. Drug Discov. 15(4):249-74. (2016).