Liver X Receptor (LXR) inverse agonist program for NASH

Aim & Indication

We are developing a unique and proprietary liver-targeted Liver X Receptor (LXR) inverse agonist (LXRias), named PX665, for the treatment of Non-Alcoholic steatohepatitis (NASH) and Type 2 Diabetes (T2D).

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease which develops on the basis of a fatty liver. Obesity, metabolic syndrome and type 2 diabetes, in particular, are key driving factors and the prevalence of NASH was estimated to range from 4–6% for most developed countries by 2016. Non-alcoholic fatty liver, the first manifestation of this metabolic liver disease which might progress to NASH, is even more prevalent but is not considered as dangerous as such. However, when sedentary lifestyle, excess caloric intake of unhealthy processed food and drinks persist for several years, the fatty liver might become inflamed. This causes the initiation of fibrotisation, i.e. excessive accumulation of extracellular matrix proteins and replacement of functional liver parenchyma finally leading to a loss of liver function.
NASH is recognized as a growing epidemic, it is the most rapidly growing cause of hepatocellular carcinoma (HCC) and is becoming a leading cause of cirrhosis, liver failure and of liver transplantation, thus causing enormous healthcare costs. Already today, there is a population in the hundreds of millions NASH patients worldwide which should be treated in order to prevent this fatal progression. But there is still no approved dedicated therapy available for NASH albeit several are in clinical development.

LXR inverse agonist PX665 for the treatment of NASH / Type 2 diabetes

Having gained deep experience in the field of NASH research by the development of two clinical stage FXR agonists, Px-102 and GS-9674, we have decided to focus on FXR's functional counterplayer, LXR (=liver x receptor) as a target for NASH. There are two LXRs in fact, LXRalpha and beta, and both share functions in controlling de novo lipogenesis (DNL), intestinal lipid uptake, cholesterol fluxes and insulin sensitivity as well as amplifying insulin's actions on lipid metabolism. Whereas FXR inhibits DNL upon activation, LXR stimulates it. LXR is actually the master switch for controlling fatty acid, triglyceride and VLDL synthesis. Thus, LXR is at the crossroads of all major metabolic pathways that control the development of NAFLD and the progression towards NASH. LXR's expression levels are directly correlated to the progression of the disease.

Thus, we aimed for inhibiting LXR's activities by having designed LXR inverse agonists. An inverse agonist, as opposed to an antagonist, does not only displace the endogenous ligand thereby nulling the transcriptional response. It is the even stronger principle since inverse agonists actively suppress LXR's transcriptional programs.

Our drug candidate PX665 is now advancing into preclinical development. PX665 has subnanomolar potency in in vitro assays, high selectivity over other nuclear receptors or other drug targets, and a good PK profile with high liver selectivity. PX665, as a potent LXR inverse agonist shows superior anti-NASH and antidiabetic effects:

  • PX665 shuts down liver DNL and inhibits intestinal lipid uptake resulting in prevention of liver steatosis PDF
  • PX665 improves NAS (NAFLD activity score) and fibrosis in the well-known STAM mouse model PDF
  • PX665 massively improves insulin sensitivity in a hyperinsulinemic euglygemic clamp mouse model (results will be shown at forthcoming EASL meeting, April 2019, in Vienna)
  • PX665 reduces body weight but still spares insulin and lowers fasting plasma glucose resulting in a massive lowering of HOMA index
  • PX665 is strongly hepatotropic thereby minimizing unwanted effects on reverse cholesterol flux in the periphery

PX665 is expected to enter phase I human testing by early 2020.

References

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