NASH (nonalcoholic steatohepatitis) is a form of non-alcoholic fatty liver disease (NAFLD) that affects one in four individuals worldwide, making it one of the most common chronic liver diseases in man. NAFLD is associated with metabolic conditions such as obesity, diabetes, and high cholesterol. NAFLD is diagnosed by liver biopsy and is typically characterized as either fatty liver or steatohepatitis. Fatty liver is generally non-progressive or progresses slowly compared to steatohepatitis. NASH, which is steatohepatitis not caused by alcohol, is characterized by inflammation of the liver, which progresses to fibrotic remodeling (scarring) in 30-50% of individuals, increasing the risk for cirrhosis, liver decompensation, and hepatocellular carcinoma (HCC, liver cancer). NASH is currently the second leading cause of liver transplantation overall, and the leading cause in women. Pharmacologic therapy is not yet available, but NASH is increasingly a focus of drug development efforts. Learn more
Our bodies are constantly exposed to stresses such as bacterial or viral infections, inflammatory mediators; and potentially damaging oxidizing agents like free radicals. ASK1 (apoptosis signal-regulating kinase 1) is one of the many proteins that help the body cope with these stresses and limit injury in the involved organ; however, when the strength or duration of the stresses are too great, ASK1 turns from friend to foe and causes or worsens certain diseases. Notably, blocking ASK1 has been shown to be protective in several animal models of disease inspiring ongoing research efforts to develop an ASK1 inhibitor for clinical use.
ASK1 inhibitors in NASH
ASK1 is an important mediator of NASH that is central to the disease process. Studies in multiple animal models of NASH have shown that blocking the activity of ASK1 protects against NASH, and studies in NASH patients have shown that the more fibrosis is present in the liver, the more activated the ASK1 pathway is.
Utilizing extensive expertise and experience in the discovery and development of kinase inhibitors and drugs to treat NASH, Seal Rock is developing novel small molecules with high affinity, potency and selectivity for ASK1. Seal Rock’s lead product is the clinical-stage ASK1 inhibitor SRT-015. Its unique trimodal mechanism of action provides direct anti-fibrotic, anti-inflammatory, and liver cell protective activities, which should be ideal for complex diseases such as NASH. SRT-015 was highly efficacious in a high-fat diet NASH model, with significant positive effects on metabolic parameters and liver specific pathology, including fibrosis. We believe SRT-015’s high affinity, potency, and selectivity for ASK1 lead to an enhanced safety and efficacy profile in NASH patients. Notably, SRT-015 overcomes major liabilities associated with competitor kinase inhibitors and is now first in class. This data was presented at the American Association for the Study of Liver Disease 2020 meeting, click here to view the data. Further, by being liver-selective, very little SRT-015 is found outside the liver. This may further decrease the risk of unwanted effects. Consequently, we anticipate that SRT-015 will be able to be administered in high enough doses to achieve maximal efficacy in NASH patients.