The therapeutic area
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. It is projected that by 2020 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.
The InorbitTX Approach
- Selective scouting and targeting efficacious drugs, which carry the sensitive group of interest, have high lipophilicity, and thus are at high risk for DILI.
- Replacement of the sensitive group to reduce the lipophilicity and glucuronidation potential of molecules.
- Establishment of strong initial assurance of safety and efficacy, optimizing the chances for successful drug development and commercialization.
- A virtual, flexible way of working, using an extensive, reliable, high quality and cost effective network of collaborators, predominantly in India.
The Inorbit Advantage:
- Patentable distinct designed compounds based on molecules with proven efficacy in patients.
- Highly efficient way to identify and characterize lead compounds and candidate drugs.
- Significantly shortened drug discovery timeline at reduced cost.
InorbitTX’s lead discovery efforts include 3 projects aimed for the treatment of fatty liver diseases (NAFLD / NASH); FXR, KHK, and DGAT2). InorbitTX has identified numerous targets in other highly interesting therapeutic areas to which its specific chemistry can be applied as well.
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.
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 vitrogene up-regulation in human hepatocytes.
- Excellent in vivo pharmacokinetic properties.
- Potent efficacy in High fat-high cholesterol fed mice.
- Important differentiation from competitor FXR agonists, giving it best in class potential.
The company start IND enabling studies with IOT022 in Q2-2019.