Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator against Hepatitis B Virus

• Published in: Antimicrobial agents and chemotherapy Vol. 63; no. 1
• Main Authors: Lam, Angela M., Espiritu, Christine, Vogel, Robert, Ren, Suping, Lau, Vincent, Kelly, Mollie, Kuduk, Scott D., Hartman, George D., Flores, Osvaldo A., Klumpp, Klaus
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.01.2019
• Subjects: Animals; Antigens, Viral - genetics; Antigens, Viral - metabolism; Antiviral Agents; Antiviral Agents - blood; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Benzamides; Benzamides - blood; Benzamides - chemistry; Benzamides - pharmacokinetics; Benzamides - pharmacology; Capsid; Capsid - chemistry; Capsid - drug effects; Capsid - metabolism; DNA, Viral; DNA, Viral - antagonists & inhibitors; DNA, Viral - genetics; DNA, Viral - metabolism; Drug Evaluation, Preclinical; Female; Hep G2 Cells; Hepatitis B; Hepatitis B - drug therapy; Hepatitis B - virology; Hepatitis B virus; Hepatitis B virus - drug effects; Hepatitis B virus - genetics; Hepatitis B virus - metabolism; Hepatocytes - drug effects; Hepatocytes - pathology; Hepatocytes - virology; Humans; Male; Mice; Microbial Sensitivity Tests; Piperidines; Piperidines - blood; Piperidines - chemistry; Piperidines - pharmacokinetics; Piperidines - pharmacology; Primary Cell Culture; RNA, Viral; RNA, Viral - antagonists & inhibitors; RNA, Viral - genetics; RNA, Viral - metabolism; Viral Core Proteins - antagonists & inhibitors; Viral Core Proteins - genetics; Viral Core Proteins - metabolism; Virus Replication - drug effects; chronic hepatitis B; HBV inhibitors; capsid assembly modulator; CHB
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.01734-18

NVR 3-778 is the first capsid assembly modulator (CAM) that has demonstrated antiviral activity in hepatitis B virus (HBV)-infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA-containing virus particles with a mean antiviral 50% effective concentration (EC 50 ) of 0.40 µM in HepG2.2.15 cells. NVR 3-778 is the first capsid assembly modulator (CAM) that has demonstrated antiviral activity in hepatitis B virus (HBV)-infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA-containing virus particles with a mean antiviral 50% effective concentration (EC 50 ) of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and a 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 pregenomic RNA 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 EC 50 values of 0.81 µM against HBV DNA and between 3.7 and 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 achieved in mice and, thus, enabling efficacy studies in vivo . The overall preclinical profile of NVR 3-778 predicts antiviral activity in vivo and supports its further evaluation for safety, pharmacokinetics, and antiviral activity in HBV-infected patients.