Liver fibrosis is excessive accumulation of scar tissue in the liver. It can be the result of almost any type of chronic liver disease, or it can be congenital. It is generally progressive and, in advanced cases, can be life threatening, causing cirrhosis and liver failure and requiring a liver transplant. Liver fibrosis is also a risk factor for liver cancer. Definitive evaluation of liver fibrosis and determination of its cause requires an intrusive biopsy with severe pain in many cases and major complications in some. Current therapies are aimed at treating the underlying disease process, which may stop progression but usually does not reverse the fibrosis. These researchers are developing a treatment for liver fibrosis that works by opposing the genes that produce the scar tissue. This drug candidate also has the potential to reduce existing build-up and improve liver function.
Hepatic fibrosis affects millions of patients worldwide and remains an unresolved challenge for clinicians. Characterized by excessive accumulation of extracellular matrix proteins, including collagen, fibrosis is the common end-stage outcome in most chronic liver diseases. Left untreated, liver fibrosis progresses to cirrhosis and hepatic failure, a life-threatening condition necessitating liver transplantation. Currently approved therapies are aimed only at the underlying disease, with reversal of fibrosis occurring in a subset of patients over several years; for many other patients, there are simply no treatment options. Given the morbidity/mortality associated with this disease, there is an urgent need for translation of emerging antifibrotic modalities into effective therapies. Scatter factor/hepatocyte growth factor (SF/HGF) is a hepatotrophic factor that exerts antifibrotic effects by opposing TGFβ1 activity. Unfortunately, clinical feasibility of SF/HGF gene/protein therapy is compounded by numerous logistical and financial challenges. Together with Angion Biomedica Corp., we have developed Refanalin, a small molecule mimetic of SF/HGF, for treatment of liver fibrosis. Data from in vitro assays indicate that Refanalin opposes the hepatic fibrogenic gene program. In preclinical models of liver fibrosis, Refanalin is therapeutic, attenuating profibrotic gene and protein expression, accelerating collagen catabolism, and improving hepatic function. Refanalin has oral bioavailability and oral efficacy, and data from pharmacokinetic/acute safety studies indicate that it is safe and has properties consistent with a drug-like compound.
In a chronic disease state requiring prolonged therapy, an orally efficacious drug is desirable. This is especially true in the liver, where first-pass metabolism optimizes hepatic delivery, minimizing extrahepatic effects. This application, designed to complete preclinical development of Refanalin, requests support from the program for GMP bulk synthesis, oral formulation and long-term toxicology studies. Together with the preclinical studies we conducted, the proposed studies are necessary and sufficient to support clinical trials of oral Refanalin administration in liver fibrosis.
Icahn School of Medicine at Mount Sinai, New York
, New York
Scott L. Friedman, M.D.
Efsevia Albanis, M.D.
Public Health Impact
Currently, no agents are approved as antifibrotic therapeutics in patients with chronic liver disease. At least 4 million Americans are infected with hepatitis C virus and up to 10 million may have obesity-related fatty liver associated with fibrosis (“non-alcoholic steatohepatitis,” or NASH); hundreds of millions worldwide are affected by these diseases.
Work on this project is complete. The investigators successfully filed an Investigational New Drug (IND) application using BrIDGs data and initiated clinical testing.
- Synthesis of Good Manufacturing Practice (GMP) material
- Development of an oral formulation
- Bridging study connecting previous and future toxicology studies
- Oral toxicology study with correlative pharmacology and histopathology