CRV431

ContraVir is developing CRV431 for treating hepatitis B and is currently preparing to enter IND-enabling studies based on strong preclinical data. CRV431 belongs to a known drug class of cyclophilin inhibitors derived from cyclosporine A, and was designed specifically to optimize potency and selectivity against HBV.

CRV431 works by disrupting certain host mechanisms that are “hijacked” by HBV as it replicates within liver cells. It is expected to be effective against all HBV genotypes due to the fact that it interrupts more than one point in the viral life cycle that are common in all HBV sub-types.

Potential Advantages of CRV431
  • Best-in-class potency and selective index against HBV
  • Interrupts HBV at multiple points, limiting replication and potential resistance
  • Blocks HBV entry into liver cells and suppresses HBsAg and HBeAg in vitro
  • Reduces HBV DNA without toxicity; prevents liver fibrosis in vivo

Hepatitis B

Hepatitis B, an infectious disease caused by the hepatitis B virus (“HBV”), affects the liver and occurs in both acute and chronic modalities. Patients who test positive for HBsAg, an HBV surface protein antigen, for more than six months are said to be chronic and are at risk of developing liver disease. The virus is transmitted by exposure to infectious blood or bodily fluid but is preventable by vaccination.

Currently there are about 350 million chronic HBV patients worldwide and 786,000 reported HBV-related deaths in 2010. The United States is the largest individual market with the highest absolute growth rate of HBV patients at around 15.4% through 2033 and around 9% growth in much of Europe.

Individuals with chronic hepatitis B are significantly more prone to developing cirrhosis of the liver and liver cancer. 20%-30% of all chronic hepatitis B patients develop these complications, and individuals with chronic hepatitis B are 100 times more likely to develop liver cancer than non-infected individuals. The limited efficacy of treatments for liver cancer and low survival rate (15%) mean that any treatment targeted at suppressing HBV replication before these complications arise is important to increase longevity. Learn more about chronic hepatitis B >>

Hepatitis B Virus

Opportunity

The safety and antiviral activity of CRV431 is built on a robust set of clinical data from chemically-related cyclophilin inhibitors. Naturally occurring cyclosporine A has been used for more than 30 years in the field of organ transplant due to its immunosuppressive properties, and cyclophilin inhibitors such as alisporovir (developed by DebioPharm and acquired by Novartis) achieved clinical safety and efficacy against hepatitis C virus. CRV431 has undergone extensive medicinal chemistry to shed its immunosuppressive activity and optimize its potency and target selectivity, which dramatically increases its therapeutic window for treating hepatitis B.

CRV431 inhibits HBV replication by simultaneously blocking several specific interactions of HBV proteins with host cell cyclophilins, which the virus uses to propagate infection and avoid detection by the cell’s natural antiviral mechanisms. There is also evidence that it blocks the entry of HBV into cells, stimulates an interferon-mediated antiviral immune response, and directly reduces inflammation and fibrosis, a major contributor to cirrhosis and development of liver cancer in chronic hepatitis B patients.

CRV431 has a clearly distinct and complementary mechanism of action, as compared to ContraVir’s clinical stage HBV drug TXL™, which the company believes can act as a cornerstone molecule for a future combination HBV curative treatment.

U.S. Sales of Approved HBV Drugs (2014)

Preclinical Study Data

In vitro and in vivo studies showed that CRV431 has good oral bioavailability and a significant first pass effect, which concentrates the drug in the liver. It was shown to effectively inhibit entry of HBV into liver cells via direct interaction with the NTCP receptor (cyclophilin-independent), which may represent another mechanism by which CRV431 may reduce chronic infection. Within cells, it significantly reduced or eliminated the production/secretion of hepatitis B surface antigen (HbsAg) and envelope antigen (HbeAg) as well as HBV DNA and cccDNA. CRV431 also reduced liver HBV DNA in a transgenic mouse model of viral replication without significant toxicity. Further animal studies confirmed a strong safety profile for CRV431, and highlighted the ability of CRV431 to reduce liver damage, preventing the development of fibrosis by ~55% in a mouse model of NASH (nonalcoholic steatohepatitis). This result is important considering that long-term liver damage resulting from chronic HBV infection is what ultimately drives mortality for many patients.

Liver HBV DNA in Mouse Model of Viral Replication