Neurotrophic Tyrosine Receptor Kinase Inhibitors as Novel Therapeutics for Liver Fibrosis

Background

Liver fibrosis involves the replacement of healthy liver tissue with scar tissue and is a leading cause of liver failure and liver-related mortality. In the United States, liver fibrosis is highly prevalent due to high rates of obesity and type II diabetes. The typical disease progression of non-alcoholic fatty liver disease starts with accumulation of fat in hepatocytes, which can lead to a condition called non-alcoholic steatohepatitis (NASH) that is characterized by inflammation and fibrosis of the liver. NASH affects up to 12% of adults in the United States and fibrosis associated with NASH, potentially triggered by liver injury and inflammation, is currently the strongest predictor of patient mortality.

There is no FDA-approved therapy for NASH or for liver fibrosis. The current standard of care involves treating the underlying causes of disease, such as obesity or inflammation. These methods typically fail to reverse fibrosis and associated liver damage, creating a great unmet need for novel treatments. In recent years, there have been several attempts to develop new drugs, but so far, the clinical efficacy of these compounds has been limited and disappointing, especially in advanced fibrosis where NTRK3 signaling is more active.

Technology Overview

Investigators at Mount Sinai performed a cutting-edge single-cell RNA sequencing study aligning gene expression changes in both NASH patients and a mouse model of NASH with fibrosis. This experiment led to the discovery of an autocrine signaling loop between hepatic stellate cells, the cellular driver of fibrosis, that emerges in late-stage disease. Analysis of this autocrine signaling pathway led to the identification of Neurotrophic Tyrosine Receptor Kinase 3 (TrkC or NTRK3) as a potential druggable target that is strongly implicated in advanced fibrosis or cirrhosis. Promisingly, it was observed that only four weeks of treatment with the Trk inhibitor LOXO-195 at a modest dosage was sufficient to reverse fibrosis in a mouse model of advanced NASH.

While most drugs that are in the clinical development pipeline for treatment of NASH attempt to treat the disorder by reducing inflammation in the liver or fat accumulation in hepatocytes, LOXO-195 directly targets fibrosis via hepatic stellate cells. Because of this, LOXO-195, and other TrkC inhibitors, are likely to be effective anti-fibrotic agents regardless of the underlying cause of liver fibrosis, and could be effective in fibrosis of other organs as well.

Further Details:

• Wang et al. “An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis.” Sci. Transl. Med. (15) January 2023.

Stage of Development

• TrkC (also called NTRK3) identified as a potential druggable target for advanced liver fibrosis whose expression is restricted to fibrogenic cells (hepatic stellate cells/myofibroblasts) in liver
• LOXO-195 validated as an anti-fibrotic agent in a mouse model of NASH with advanced fibrosis and in cultured human hepatic stellate cells/myofibroblasts, the primary cellular source of fibrosis in NASH and other common liver diseases
• Testing of other Trk inhibitors is underway

Benefits

• Robust reduction/reversal of fibrosis in mouse model of NASH with advanced fibrosis
• Potential to treat liver fibrosis regardless of underlying causes
• Favorable safety profile (some Trk inhibitors already in clinical trials)
• New approach, targeting hepatic stellate cells

Applications

• Treatment and prevention of advanced liver fibrosis resulting from NASH
• Treatment and prevention of advanced liver fibrosis resulting from other causes, e.g., alcoholism or viral infection
• Potential to treat fibrotic disease in other organs