Hope on the horizon: Emerging therapies for hepatitis D

Abstract

Current treatment options for hepatitis D are limited, with pegylated interferon-alpha (PEG-IFNα) being the only therapy available in the Asia-Pacific region. However, PEG-IFNα has limited efficacy and significant side effects. Pegylated interferon lambda acts on interferon-lambda (Type III) receptors predominantly expressed in hepatocytes. In 2023, bulevirtide was approved in the European Union and Russia for treating chronic hepatitis D. This drug works by binding to and inhibiting the sodium taurocholate co-transporting polypeptide receptor on liver cells, which is the primary entry point for the virus. Recently, several new drugs have entered various stages of development, offering hope for improved hepatitis D virus (HDV) management. Two more viral entry inhibitors are HH003 and tobevibart. Other agents include nucleic acid polymers (REP 2139-Mg), prenylation inhibitors (lonafarnib), and RNA interference-based therapies (elebsiran). Emerging trials are now considering combination therapies, such as SOLSTICE, a Phase 2 clinical trial evaluating tobevibart alone or combined with elebsiran. The combination dosed monthly achieved > 50% virologic and biochemical response at 24 weeks of therapy. The efficacy and safety of these drugs will further be evaluated in ECLIPSE 1, 2, and 3 trials. With these new treatments on the horizon, the prospects for improved HDV patient outcomes are promising.

Keywords: Bulevirtide; Elebsiran; Hepatitis B; Hepatitis D; Lonafarnib; Nucleic acid polymers; Pegylated interferon; Tobevibart; Treatment.

Figure 1

Hepatitis D virus life cycle and therapeutic strategies. Hepatitis D virus (HDV) (and hepatitis B virus) entry is facilitated by the Sodium taurocholate co-transporting polypeptide (NTCP), which binds HBV surface antigen (HBsAg). Entry inhibitors, including Bulevirtide and monoclonal antibodies, can act to prevent viral entry. Replication of the HDV genome (HDV G) and the hepatitis B virus genome is nuclear, and one proposed mechanism of action of nucleic acid polymers is inhibition of this phase. HDV mRNA is used to make hepatitis D large antigen (HDAg-L). The HDAg-L is prenylated (which can be inhibited by prenylation inhibitors) and, along with HDV G, is used to assemble the HDV ribonucleoprotein (RNP). The HDV RNP is enveloped in the Golgi apparatus by HBsAg. Nucleic acid polymers can prevent the release of the HBsAg, while siRNA strategies can help reduce the amount of HBsAg made. The signaling pathways employed by interferons are given in the insets, and these mediate broader antiviral activity. (Created in BioRender (2025) https://BioRender.com/hrg3zi7). IFNα: Interferon-alpha.