The mainstays of antiviral therapy for chronic HBV infection in Japan primarily comprise interferons (IFNs) and nucleos(t)ide analogs (NAs). These therapies effectively suppress viral replication and induce hepatitis quiescence. However, such therapies often fail to eliminate viral antigens, thus not fully mitigating the risk of liver cancer progression. NAs are the current standard first-line treatment for chronic hepatitis B. They suppress HBV-DNA effectively and are orally administered with minimal side effects. However, their limited impact on HBsAg makes attainment of a functional cure challenging. This limitation has highlighted the urgent need for an innovative therapeutic approach, leading to the global development of various therapeutic drug candidates beyond IFNs and NAs [1, 2]. Herein, current trends in the development of therapeutics for hepatitis B are appraised.

The main categories of antiviral drugs targeting HBV infection and replication include drugs that inhibit the sodium taurocholate co-transporting polypeptide (NTCP), which was identified as the functional receptor for HBV entry into human hepatocytes. Targeting NTCP presents a promising novel therapeutic option as it may prevent the de novo infection of regenerating hepatocytes [3]. HBV capsid assembly modulators disrupt the HBV life cycle by interfering with the formation of the viral capsid, an essential component for viral replication. This prevents the virus from effectively producing new infectious particles [4,5,6]. Nucleic acid polymers have both entry and post-entry antiviral activities in HBV-infected hepatocytes [7]. A combination with immune therapy has been investigated [8].

HBV-RNA inhibitors are novel drugs under development for HBV. These are a class of direct-acting antiviral agents specifically targeting HBV-RNAs showing good results in suppressing HBsAg. HBV-RNAs, including the 3.5 kb messenger RNA (mRNA) that also functions as pregenomic RNA (pgRNA), the 2.4 kb and 2.1 kb mRNAs encoding HBsAg, and the 0.7 kb mRNA encoding the HBx protein, are transcribed from the HBV genome and present as cccDNA in hepatocyte nuclei. There are three subcategories of HBV-RNA inhibitors: small interfering RNA (siRNA), antisense oligonucleotide (ASO), and destabilizing HBV RNA. These agents, which are aimed at all RNAs transcribed from cccDNA, exert a significant effect by targeting both HBV-DNA and HBsAg, with several studies already progressing to clinical trials [9]. In this journal issue, Watanabe et al. report on the discovery of the HBV replication inhibitor SAG-524, which was optimized from a massive library screening and has been shown to reduce the levels of HBsAg and HBV-DNA by destabilizing HBV-RNA through a PAPD5-mediated mechanism [10]. This suggests a new class of HBV-RNA inhibitors targeting proteins that interact with HBV-RNA. Their study evaluated the antiviral properties and selectivity of SAG-524 against HBV using an HBV infection model in vitro and a chimeric mouse model with humanized liver in vivo. SAG-524 significantly reduced the levels of HBsAg and HBV-DNA, suggesting its potential contribution to functional therapy against HBV. Although SAG-524 has a mechanism of action against HBV that is similar to RG7834, it is an entirely different molecule. RG7834 and its derivative GS-8873 induced neurotoxicity, particularly peripheral neuropathy in rats and monkeys [11, 12]. On the other hand, SAG-524 did not cause death or severe adverse events (treatment-related pathological changes) in monkeys; it did not affect the liver, heart, kidney, or sciatic nerve up to a dose of 1,000 mg/kg/day. Interestingly, the neurotoxicity caused by other HBV RNA destabilizers was not observed in SAG-524.

During HBV infection, PAPD5/7, which is one of the non-canonical RNA poly(A) polymerases, plays a crucial role in stabilizing HBV-RNA, a key process for HBV’s life cycle by maintaining the viral RNA essential for producing new virus particles. Targeting these enzymes presents a novel strategy for HBV treatment, potentially disrupting HBV’s replication and persistence in infected cells. RG-7834, an oral HBV therapeutic belonging to the dihydroquinolidinone compound family, functions as an RNA destabilizer by inhibiting PAPD5/7, leading to HBV RNA degradation [13]. AB-452 acts as an RNA destabilizer targeting PAPD5/7, exhibiting superior HBsAg-lowering properties in vitro [14]. In preclinical studies using an HBV-infected mouse model facilitated by AAVHBV, GSK3965193 and bepirovirsen were evaluated as standalone treatments and in tandem. Oral administration of GSK3965193 alone led to a maximum 1 log reduction in HBsAg levels. Subcutaneous bepirovirsen achieved up to 2 log reduction in HBsAg levels. These agents achieved a 3 log reduction in HBsAg levels in combination therapies, surpassing the efficacy of either agent as a monotherapy [15].

These results suggest that SAG-524 has potent anti-HBV effects and good tolerability when used in combination with ETV, a similar oral drug, and as a monotherapy. SAG-524 is highly promising as it can be administered orally, unlike siRNA and ASO which are injectable formulations, offering a significant advantage for patient adherence. Further preclinical studies of SAG-524 are necessary before proceeding to clinical trials.