Antiviral profile of hepatitis B virus capsid assembly modulator ALG-001075, the parent of pevifoscorvir sodium.

Abstract

Chronic hepatitis B virus (HBV) infection remains an important unmet medical need with 240 million patients worldwide. The HBV capsid assembly process has emerged as a key target for more efficient antiviral intervention. Pevifoscorvir sodium (ALG-000184), an oral prodrug of the potent HBV capsid assembly modulator (CAM) ALG-001075 showed significant reductions in HBV DNA, HBV RNA and other viral antigens (HBsAg, HBcrAg and HBeAg) in Phase I clinical participants with chronic HBV infection. We aim to characterize the antiviral properties of ALG-001075. ALG-001075 is a highly potent CAM that inhibited HBV DNA production in cellular settings with EC50 values below 1 nM and an EC99.9 value of only 22 nM. ALG-001075 was shown to induce the formation of empty, but not aberrant viral particles as demonstrated by fluorescence quenching, electron microscopy, size-exclusion chromatography, immunofluorescent staining and NMR analysis, thereby classifying it as a CAM-E. Notably, solid-state NMR spectra of wild-type capsids in the presence of ALG-001075 revealed a characteristic CAM-E fingerprint at atomic resolution. ALG-001075 showed potent antiviral activity against HBV strains from genotypes A-J, nucleoside analogue-resistant virus strains and known CAM-resistance mutations, with the exception of T33N, T33P and V124G, which induced 6-to-28-fold loss in ALG-001075 activity. The in vivo efficacy of ALG-001075 was confirmed in adeno-associated virus-HBV mice, where ALG-001075 demonstrated up to 5 log10 reduction in circulating HBV DNA levels. Because of its robust antiviral potency and favorable preclinical resistance profile, ALG-001075 was selected for further clinical development under the form of its prodrug pevifoscorvir sodium.