Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator Against the Hepatitis B Virus [Antiviral Agents]

NVR 3-778 is the first Capsid Assembly Modulator (CAM) that has demonstrated antiviral activity in HBV infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA containing virus particles with a mean antiviral EC₅₀ of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs in vitro resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pgRNA encapsidation, viral replication and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC₅₀ values of 0.81 µM against HBV DNA and between 3.7 to 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achievable in mice and thus enabling efficacy studies in vivo. The overall preclinical profile of NVR 3-778 predicted antiviral activity in vivo and supported further evaluation for safety, pharmacokinetics, and antiviral activity in HBV infected patients.

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