Preclinical development of capsid assembly modulators for the treatment of chronic hepatitis B virus infection

PROJECT SUMMARY Despite the availability of a safe and effective vaccine, there remains over 257 million people chronicallyinfected with hepatitis B virus (HBV) world-wide. Individuals with chronic HBV infections are at risk forcomplications due to liver disease and liver cancer. Chronic HBV is currently managed with nucleos(t)idereverse transcriptase inhibitors (NrtI) which partly suppress HBV DNA replication, normalize alanineaminotransferase levels (ALT) and slow disease progression. Front-line therapies, however, are not curativeand patients with chronic HBV exhibit poor off-treatment responses requiring life-long therapy. New antiviralsand immunomodulatory approaches are, therefore, needed to further suppress viral replication and provide theconditions that are required for immune control known as a “functional cure”. One of the most promisingclasses of compounds under investigation are the core protein allosteric modulators (CpAM) that block HBVreplication at multiple stages of the viral life-cycle. Here, we report on a best-in-class CpAM that exhibits potentpan-genotypic antiviral activity. In this project, we propose to advance our lead CpAM into definitive IND enabling studies to ready the compound for Phase 1 clinical trials in healthy volunteers and chronic HBVpatients. Combination regimens that include a CpAM, antivirals possessing distinct mechanisms of actionand/or novel immunomodulatory agents will be evaluated in a mouse model of HBV infection in preparation forPhase 2 development in chronic HBV patienst.