ARB-1740, a RNA Interference Therapeutic for Chronic Hepatitis B Infection

Abstract

Current approved nucleoside analogue treatments for chronic hepatitis B virus (HBV) infection are effective at controlling viral titer but are not curative and have minimal impact on the production of viral proteins such as surface antigen (HBsAg), the HBV envelope protein believed to play a role in maintaining the immune tolerant state required for viral persistence. Novel agents are needed to effect HBV cure, and reduction of HBV antigenemia may potentiate activation of effective and long-lasting host immune control. ARB-1740 is a clinical stage RNA interference agent composed of three siRNAs delivered using lipid nanoparticle technology. In a number of cell and animal models of HBV, ARB-1740 caused HBV RNA reduction, leading to inhibition of multiple elements of the viral life cycle including HBsAg, HBeAg, and HBcAg viral proteins as well as replication marker HBV DNA. ARB-1740 demonstrated pan-genotypic activity in vitro and in vivo, targeting three distinct highly conserved regions of the HBV genome, and effectively inhibited replication of nucleoside analogue-resistant HBV variants. Combination of ARB-1740 with a capsid inhibitor and pegylated interferon-alpha led to greater liver HBsAg reduction which correlated with more robust induction of innate immune responses in a human chimeric mouse model of HBV. The preclinical profile of ARB-1740 demonstrates the promise of RNA interference and HBV antigen reduction in treatment strategies driving toward a cure for HBV.

The role of long noncoding RNAs in hepatocellular carcinoma

“…It is worth noted that the current pipeline of HCC-targeted ASOs and RNAi is broad, for both of which have been already applied in the treatment of HBV. Briefly, ASOs and siRNAs are modified by chemical conjugates (such as N-acetylgalactosamine, GalNAc) [166] or formulated in delivery vehicles (such as lipid nanoparticles) [167], thereby achieving an optimized pharmacokinetic profile. These commercial experiences in HBV treatment using ASOs and RNAi provide a substantial basis for lncRNA interference and HCC therapy.…”

Therapeutic shutdown of HBV transcripts promotes reappearance of the SMC5/6 complex and silencing of the viral genome in vivo

“…18 19 Thus, interventions silencing and reducing the HBV minichromosome appear essential to cure chronic HBV infection. Small interfering RNAs (siRNAs) targeting the overlapping pregenomic and subgenomic viral RNAs represent a promising therapeutic approach currently under investigation for anti-HBV therapy [20][21][22][23][24] because it bears the potential to reduce both viraemia and antigen levels. Interferon-α (IFNα) has immunomodulatory and direct antiviral effects, [25][26][27] including the ability to repress and destabilise the cccDNA.…”

Therapeutic siRNA: state of the art

“…As a result, tumor reduction was achieved, but some serious AEs (SAEs) were also observed. 150 Moreover, several other RNAi therapeutics also employ liposomes as delivery materials, e.g., ALN-VSP, 151 ALN-PCS, 152 MRX34, 183 Atu027, 175,184 ARB-1467, 185 ARB-1740, 186,187 etc. The clinical studies of all these therapeutics are currently discontinued.…”

“…ARB-1740 is a clinically investigated and liposome-formulated RNAi agent that contains three siRNAs targeting different regions of the HBV genome. 186,187 However, the study of ARB-1740 has been suspended because Arbutus transferred their liver-targeted delivery system from liposomes to GalNAc-siRNA conjugates.…”