Meeting report: 30th International Conference on Antiviral Research, in Atlanta, GA, USA

Vere Hodge, R Anthony

HBV replication is dependent on capsid assembly around pregenomic RNA (pgRNA) prior to synthesis of a partially double-stranded relaxed circular DNA genome and subsequent cccDNA synthesis. AB-423 inhibits HBV pgRNA encapsidation in a cell culture assay, maintains activity across genotypes A-D, against strains resistant to nucleoside/tide drugs and is highly selective for HBV versus other viruses. AB-423 also inhibits cccDNA synthesis, presumably by inhibiting the capsid uncoating process. There is at least additive activity in cell culture assays when combined with nucleoside/tide drugs and with ARB-1740 (see below). Similar results were obtained in a mouse model. ARB-1467 is a combination of three siRNAs packaged in lipid nanoparticles. By targeting all four viral RNA transcripts, ARB-1467 inhibits the production of all four HBV antigens. In a mouse model, ARB-1467 gives a rapid reduction of HBV virions and antigens in both liver and blood samples. ARB-1740 has improved in vivo potency and longer duration of activity relative to ARB-1467. ARB-1740 has modified oligonucleotide chemistry and changes in the HBV sites targeted. In a dose escalation Phase II trial, ARB-1467 doses increased from 0.2 mg/kg monthly to 0.4 mg/kg biweekly, with a possible extension up to a year based on the outcome after three months. In both HBeAg positive and negative patients, with the last dose (0.4 mg/kg) being on day 57, there was $0.5 log 10 reduction in HBsAg levels. Maybe, will ARB 1740 be more effective?