Preclinical Antiviral and Safety Profiling of the HBV RNA Destabilizer AB-161

• Published in: Viruses Vol. 16; no. 3; p. 323
• Main Authors: Lam, Angela M, Dugyala, Ravi R, Sheraz, Muhammed, Liu, Fei, Thi, Emily P, Graves, Ingrid E, Cuconati, Andrea, Steuer, Holly Micolochick, Ardzinski, Andrzej, Overholt, Nathan, Mason, Jeremy D, Gotchev, Dimitar, Cole, Andrew G, Harasym, Troy O, Sofia, Michael J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.02.2024; MDPI
• Subjects: Animals; Antiviral activity; Antiviral agents; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Cell culture; Chemical properties; Collagen; Coordination Complexes; DNA, Circular; DNA, Viral - genetics; Dogs; Drug therapy; Genomes; Genotype & phenotype; Genotypes; HBV RNA; HBV RNA destabilizer; Hepatitis B; Hepatitis B surface antigen; Hepatitis B Surface Antigens - genetics; Hepatitis B virus - physiology; Hepatitis B, Chronic - drug therapy; Infections; Liver; Liver cancer; Male; Medical research; Mice; Naphthalenesulfonates; Nerve conduction; Neurotoxicity; Nucleoside analogs; PAPD5; PAPD7; Physiological aspects; Rats; Ribonucleic acid; RNA; RNA polymerase; RNA, Messenger; RNA, Viral; Sensory neurons; Testing; Viruses; United States; United States > US; Japan; Germany; HBV RNA destabilizer; PAPD7; HBV RNA; PAPD5
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v16030323

HBV RNA destabilizers are a class of small-molecule compounds that target the noncanonical poly(A) RNA polymerases PAPD5 and PAPD7, resulting in HBV RNA degradation and the suppression of viral proteins including the hepatitis B surface antigen (HBsAg). AB-161 is a next-generation HBV RNA destabilizer with potent antiviral activity, inhibiting HBsAg expressed from cccDNA and integrated HBV DNA in HBV cell-based models. AB-161 exhibits broad HBV genotype coverage, maintains activity against variants resistant to nucleoside analogs, and shows additive effects on HBV replication when combined with other classes of HBV inhibitors. In AAV-HBV-transduced mice, the dose-dependent reduction of HBsAg correlated with concentrations of AB-161 in the liver reaching above its effective concentration mediating 90% inhibition (EC ), compared to concentrations in plasma which were substantially below its EC , indicating that high liver exposure drives antiviral activities. In preclinical 13-week safety studies, minor non-adverse delays in sensory nerve conductance velocity were noted in the high-dose groups in rats and dogs. However, all nerve conduction metrics remained within physiologically normal ranges, with no neurobehavioral or histopathological findings. Despite the improved neurotoxicity profile, microscopic findings associated with male reproductive toxicity were detected in dogs, which subsequently led to the discontinuation of AB-161's clinical development.