Drug Discovery

The therapeutic area

NASH

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), which is caused by the accumulation of excess fat in the liver. NASH is associated with chronic liver inflammation and liver cell injury, and it can lead to fibrosis, cirrhosis and eventually liver cancer or liver failure. Global rates of NAFLD and NASH are, in tandem with the rates of obesity, increasing rapidly. It is estimated that about 20 % of the Western adult population can be diagnosed with NAFLD. Of those patients, an estimated 25 percent will develop NASH, with thus a severe chance for further disease progression to eventual liver failure and an ultimate need for transplant. NASH will overtake Hepatitis C as the leading cause of liver transplants in the US. There is currently no approved medication for the treatment of NASH.

InorbitTX’s differentiating chemistry

The pharmaceutical industry has over the last decades been confronted with an increased failure rate of (candidate) drugs in late development stages and even after approval and commercialization. Part of this undesirable outcome is clearly linked to the physical chemical properties of the new drugs, which are applied to optimize their target potency. However, this tack seems to be a kiss of death, as just these applied properties increase the risk for Drug-Induced Liver Injury (DILI), and thus the risk for failure of the new drug. Inorbit has developed a unique, groundbreaking chemistry platform to change these properties by replacing the often used sensitive groups and to reduce lipophilicity, but still maintaining potency at the target, thus increasing chances for successful development and commercialisation.

InorbitTX Projects

InorbitTX focusses its efforts on 2 projects aimed for the treatment of fatty liver diseases (NAFLD / NASH); FXR and KHK.

Farnesoid X Receptor (FXR) Agonists

The Farnesoid X Receptor, or abbreviated the FXR, is a nuclear receptor, which is abundantly  expressed in the liver and small intestine. Bile acids (BA) are natural ligands of FXR. Their interaction with the FXR is critical to the regulation of cellular pathways that modulate BA synthesis, lipid metabolism, inflammation and fibrosis. FXR agonism and activation is believed to have high potential as a new treatment modality for NAFLD and NASH.

Current Status

InOrbitTX’s lead FXR agonist IOT022 shows:

• • Excellent in vitro potency.
  • Excellent in vitro ADME characteristics.
  • No acyl-glucuronidation, mitigating the risk for Drug Induced Liver Injury.
  • Potent in vitro gene up-regulation in human hepatocytes.
  • Excellent in vivo pharmacokinetic properties.
  • Potent efficacy in high fat – high cholesterol fed mice.
  • Excellent efficacy in STAM model for NASH.
  • Important differentiation from competitor FXR agonists, mitigating the pruritus risk, giving it best in class potential.

The company is to complete IND enabling studies and to start Phase I studies with IOT022 in Q1-2024.

KetoHexoKinase inhibitors

Fructose, about half the amount of sugar that is consumed, is predominantly metabolised to fat in the liver.  Overconsumption of sugar, and thus fructose, is therefore seen as one of the major causes for fatty liver.  The enzyme KetoHexoKinase (KHK) facilitates the first step of the conversion of fructose to fat.  Inhibition of this enzyme KHK will thus prevent the formation of this new fat and may thus prevent the fattening of the liver, ultimately leading to NASH.

InOrbitTX’s KetoHexoKinase inhibitor project shows

• • Excellent in vitro potency.
  • Excellent in vitro ADME characteristics.
  • Excellent efficacy in acute in vivo tests

The company is to confirm Candidate Drug status and start IND enabling studies for the lead compound IOT038  in Q3-2022.