There are over 250 million individuals chronically infected with hepatitis B virus (HBV) world-wide that are at risk from complications due to liver disease and liver cancer. Chronic HBV infection is currently managed with nucleos(t)ide reverse transcriptase inhibitors (NrtIs) or pegylated-interferons that suppress HBV DNA replication and normalize alanine aminotransferase (ALT) levels leading to reductions in morbidity and mortality. Unfortunately, however, these agents are not curative and patients generally exhibit poor off-treatment responses that require indefinite therapy.
Currently, only a small fraction of patients on front-line monotherapies achieve undetectable levels of circulating HBV DNA and experience a concomitant loss of surface antigen (HBsAg) expression. This status, termed a functional cure, leads to a reduction in the risk of progression to liver disease and cancer and is an ideal endpoint for therapy. The goal of future HBV therapy, therefore, is to improve the rate of functional cure within a finite treatment duration. It is widely believed that combinations of direct acting antivirals and other complementary agents will be required to deliver more durable antiviral responses and promote the conditions for the development of strong anti-HBV immune control.
One of the most promising strategies under investigation are the core protein allosteric modulators (CpAMs) that block HBV replication at multiple steps in the viral lifecycle. At Venatorx, we are actively pursuing the development of next generation CpAMs that have the potential to be included in future combination regimens for the treatment of chronic HBV infections. Using a structure-based drug design approach, we have identified a series of CpAMs that exhibit best-in-class antiviral activity and possess excellent DMPK and safety properties.
Venatorx has nominated VNRX-9945 as a Development Candidate and advanced into IND-enabling preclinical toxicology studies to ready the compound for first-in-human testing in healthy volunteers and HBV infected patients.