Keywords
Hepatitis B Virus; Capsid Assembly Modulator; GST-HG141; cccDNA
Abstract
HBV Capsid Assembly Modulators (CAMs) had emerged as promising oral agents for Anti-Hepatitis B Virus (HBV) drug development, with a potential for Chronic Hepatitis B (CHB) functional cure. Here we report the discovery and preclinical characterization of GST-HG141, a novel HBV CAM, currently under phase II clinical evaluation in CHB patients. In vitro, GST-HG141 induced HBV core protein assembly and the formation of intact capsids without affecting capsid morphology. GST-HG141 potently inhibited HBV DNA secretion in HepG2 2.15 cells, and was additive with nucleos(t)ide analogs, but with no shift from T = 4 towards T = 3 capsid formation in contrast to other CAM-Es. Furthermore, GST-HG141 retained potent antiviral activity against HBV genotypes A-D, and against nucleos(t)ide- and CAM-resistant mutants, but with significantly different resistance profile from other CAMs. In the HBV-infected Primary Human Hepatocytes (PHH), GST-HG141 inhibited de novo synthesis of the HBV cccDNA, but had no effect on the established cccDNA pools. Finally, in an AAV/HBV mouse model in vivo, GST-HG141 robustly and dose-dependently reduced serum (~3.0 log10) and liver (0.9 log10) HBV DNA with no significant effect on body weight. Our data demonstrate that GST-HG141 acts on different steps of the HBV life cycle, consistent with the CAM-E MOA, but its exact MOA and resistance profile appears to be distinct from other CAM-Es and CAM-As reported in the literature. GST-HG141 has since completed Ph1a clinical study in healthy subjects (NCT04386915) (9), and demonstrated robust antiviral efficacy in a 28-day Ph1b study in CHB patients (NCT04868981) (data will be reported elsewhere). Further clinical evaluation of GST-HG141 is ongoing.
Citation
Zhang G, He H, Zhang D, Wu W, Mao J, et al. (2024) Preclinical Characterization of GST-HG141, a Novel Hepatitis B Virus Capsid Assembly Modulator. SM J Infect Dis 7: 11.