FASN is a key enzyme of lipid (fat) synthesis and is the only enzyme in the human body capable of converting metabolized sugar into a fatty acid, palmitate. This saturated fatty acid building block is used to make longer chain, polyunsaturated fatty acids used by the cell for energy production, and itself is an important component of cellular signal transduction pathways.
In diseases such as NASH and in certain tumors, this pathway does not function properly and overproduces lipids—causing unfavorable metabolic and inflammatory problems to occur. In individuals living with NASH, this promotes excess accumulation of fat in the liver, which can damage the liver and stimulate inflammation and fibrotic scarring— ultimately contributing to the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
Fatty acid synthase (FASN) has also been shown to play a role in inflammation and fibrosis, providing the opportunity to simultaneously tackle several components of disease.
Our preclinical programs have shown the therapeutic benefit of FASN inhibition in diet-induced mouse models of NASH. Mice fed a “Western diet” containing high amounts of fat and sugar develop liver damage characterized by excessive fat, inflammation and eventually fibrosis. Our inhibitors reduce the build-up of damaging liver fat as well as reduce inflammation and fibrosis, even while the animals continue to eat an unhealthy high fat, high sugar diet.
In a separate mouse NASH model that progresses to develop hepatocellular carcinoma (HCC), treatment with a FASN inhibitor not only reversed fibrosis but also reduced the number of liver tumors observed. Several animals were tumor-free. This study was conducted by our collaborator Dr. Scott Friedman at the Mt. Sinai Hospital in New York.
In cancer models, our FASN inhibitors have demonstrated significant anti-tumor effects, especially in tumor cells that are dependent on FASN for their survival. Breast, ovarian, and a special subset of non-small cell lung cancer cells (those with a mutation in the K-Ras gene) are particularly susceptible to FASN inhibition.
We have created a platform of proprietary, selective FASN inhibitors, including our lead product candidate TVB-2640, which is oral, highly potent, selective and reversible, and first-in-class. TVB-2640 is rapidly absorbed in the human body with well-behaved pharmacokinetics.