Globally, chronic hepatitis B (CHB) infection is one of the leading causes of liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Existing antiviral therapy can suppress viral replication but not fully eradicate the virus nor the risk of liver-related complications. Novel treatments targeting alternative steps of the viral cycle or to intensify/restore the host’s immunity are being developed. We discuss novel drugs that have already entered clinical phases of development. Agents that interfere with specific steps of HBV replication include RNA interference, core protein allosteric modulation, and inhibition of viral entry or viral protein excretion (NAPs and STOPS). Agents that target the host’s immunity include toll-like receptor agonists, therapeutic vaccines, immune checkpoint modulators, soluble T-cell receptors, and monoclonal antibodies. Most have demonstrated favorable results in suppression of viral proteins and genomic materials (i.e., HBV DNA and/or pre-genomic RNA), and/or evidence on host-immunity restoration including cytokine responses and T-cell activation. Given the abundant clinical experience and real-world safety data with the currently existing therapy, any novel agent for CHB should be accompanied by convincing safety data. Combination therapy of nucleos(t)ide analogue, a novel virus-directing agent, and/or an immunomodulatory agent will be the likely approach to optimize the chance of a functional cure in CHB.
|HBV DNA||HBsAg||Anti-HBs *||Anti-HBc||cccDNA||Integrated DNA|
|Main Mechanism||Remarks||Drug Names||Delivery||Phase||Clinical Trial Identifier|
|Inhibition of viral entry||NTCP binding||Myrcludex B/Bulevertide||SC||3||NCT03852719|
|RNA interference||siRNA||Dicerna GAIXc-HBVS (RG 6346)||SC||1/2||NCT03772249|
|JNJ 3989 (ARO-HBV 1 & ARO-HBV 2)||2||NCT04129554|
|ASO||GSK-836 (ISIS-358)-non GaINAc||SC||2||NCT04449029|
|Inhibition of capsid formation||CpAM||Class 1||GLS-4 (Morphothiadin)/ritonavir||Oral||2||NCT04147208|
|Class 2||ABI-HB0731 (Vebicorvir)||2||NCT03780543|
|Class 2||ALG-000184 (prodrug of ALG-001075)||1||NCT04536337|
|Class 1||RO7049389 (RG7907)||1||NCT02952924|
|Inhibition of HBsAg release||Nucleic acid polymer||REP 2139 or REP 2165||IV||2||NCT02565719|
|Interaction with host nuclear receptor||FXR agonist||EYP001||Oral||2||NCT04465916|
|Enhancement of innate/adaptive immunity||TLR agonist||RO7020531 (also known as RG-7854, TLR7)||Oral||1||NCT02956850|
|Vesatolimod (TLR7, GS-9620)||2||NCT02166047|
|Selgantolimod (TLR8, GS-9688)||2||NCT03491553|
|T cell||ASC22 (Anti-PDL1)||SC||2||NCT04465890|
|Nivolumab (Anti-PD1)||IV||1||ACTRN12615001133527 *|
|APG-1387 (apoptosis inducer)||IV||2||NCT04568265|
|IMC-I109V (soluble T-cell receptor, ImmTAV molecule)||IV||1/2||NCT03973333|
|Therapeutic vaccine||HeberNasvac (ABX-203)||Intranasal||3||NCT02249988|
With the efficacy and safety data of the individual novel agents mentioned above, the approach of combining two or more novel agents to reduce viral antigen load, inhibit viral replication, and stimulate immunity is being actively explored.
The triple combination of RNAi (monthly injections for three doses of JNJ-3989) + CpAM (daily oral doses of JNJ-6379 for 85 days) + NA (daily oral doses beyond the end of CpAM dosing) led to mean 1.7 logs reduction in HBsAg on day 113 in 12 CHB patients. In addition, other viral products including HBV DNA, HBV RNA, and HBcrAg were profoundly suppressed. This combination therapy was in general well-tolerated with no serious or severe adverse events reported. Mild ALT flares were observed in five patients and were attributed to therapeutic flares .
A few more combination therapies are currently being evaluated in a phase 2 study that evaluates the safety and efficacy of multiple combination therapies (ClinicalTrials.gov identifier: NCT04225715). One of them is a similar example as the above with triple combination with RNAi (RG6346) + CpAM (RO7049389) + NA. Other examples include: triple combination of RNAi (RG6346) + TLR7 agonist (RO7020531) + NA, triple combination with RNAi (RG6346) + PEG-IFN + NUC, and triple combination with CpAM (RO7049389) + TLR agonist (RO7020531) + NA. The approach of sequential use of therapeutic vaccines after antigen knockdown by RNAi has been explored in mice models that showed encouraging results in suppression of viral burden and stimulation in the number of functional HBV-specific T cells and production of HBV-neutralizing antibodies . Clinical studies using this approach are awaited.
Some agents will require combination with NAs, especially CpAMs, NAPs, and most immune modulatory agents, in contrast to RNAi. This is likely to be related to whether the antiviral effect of the individual agent leads to silencing of cccDNA transcriptional activity, which is the case for RNAi via post-transcriptional knockdown of HBV transcripts. Theoretically, sequential combinational therapy will result in rapid decline in HBsAg (by virus-directing agents) which is beneficial for subsequent immune stimulation therapy . In transgenic mice models, GaINac-conjugated siRNA followed by therapeutic vaccine showed significantly stronger immune stimulatory effect in terms of development of polyfunctional, HBV-specific CD8+ T cells compared to mice given control RNAs with NA, and therapeutic vaccine . Although many RNAi-based combination therapies are still tested in clinical trials in combination with NAs, it remains to be unveiled whether the viral suppressive effects of NA can be substituted by other virus-directing agents.
The currently preferred treatment endpoint for CHB is functional cure. Novel agents work on different steps of viral replication or the host’s immune system, in order to reduce viral burden, inhibit viral replication, and restore host immunity. The therapeutic effects of both virus-directed and host-immunity-directed agents are intercalated and are equally crucial for achieving a functional cure. Most agents currently in clinical phases of development demonstrated favorable results in suppression of viral proteins and genomic materials, with initially promising results of enhancing the functional cure of CHB. With an increasing number of novel agents entering clinical phases of development, it is expected that each agent should demonstrate favorable safety data, and long-term follow-up data in the subjects that participated in these trials will be an important consideration. Most trials aimed to achieve broad eligibility by recruiting CHB patients with variable duration of infection and viral activity. However, it is likely that specific subgroups of patients will benefit most from selected agents so that a finite duration of therapy (partial cure or functional cure if HBsAg seroclearance can be achieved) instead of lifelong NA treatment can become feasible. For all trials mentioned, no cirrhotic patients were included and this will need to be addressed when more safety data are available. Combination therapy with two or more novel agents theoretically leads to synergistic therapeutic effects. NA and/or PEG-IFN are still the backbone of these combination regimens. The best cocktail of therapies is being sought, and different regimens are likely to be needed for different patient populations with various viral factors (e.g., HBsAg levels, previous treatment exposure), and host factors (e.g., HLA allele, gender).