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HBV RNA Interference
RNA Interference: An Investigational Strategy for HBV Reported at EASL 2023

Released: August 16, 2023

Activity Information

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Key Takeaways
  • RNA interference may provide a new therapeutic strategy for people with chronic HBV infection.
  • At EASL 2023, promising phase II data from 2 strategies were presented: those for the antisense oligonucleotide bepirovirsen and those for the investigational siRNA VIR-2218 combined with the investigational human monoclonal antibody VIR-3434.

Current treatments for chronic hepatitis B virus (HBV) infection efficiently control virus replication and improve prognosis, but unlike those for hepatitis C virus infection, they do not lead to complete viral clearance. Thus, lifelong treatment usually is required for patients with HBV infection. Hepatitis B surface antigen (HBsAg) loss has been associated with a favorable prognosis and is the ideal goal for therapy.

Many novel approaches (most in phase I) to achieve HBsAg loss were covered at EASL 2023—including gene editing, ARCUS-POL nuclease, capsid assembly modulators, core protein inhibitors, and TLR8 agonists. One interesting approach with phase II data is RNA interference.

RNA Interference as an HBV Therapeutic Strategy
RNA interference by small-interfering RNAs (siRNAs) and antisense oligonucleotides has been evaluated in phase I/II trials for patients with chronic HBV infection. RNA interference targets posttranscriptional messenger RNAs and pregenomic RNAs to reduce HBV antigen production and viral replication.

This family of drugs has 2 activities: a direct-acting antiviral effect (by reducing viral antigens) and an immune restoration role (reducing HBsAg production limits overwhelming of the host immune response against HBV). Phase I/II trials of siRNAs have shown them to be safe and well-tolerated, although data are limited.

Reports at EASL 2023 on this strategy included the investigational antisense oligonucleotide bepirovirsen and the combination of the investigational siRNA VIR-2218 combined with the investigational human monoclonal antibody VIR-3434. Both showed early promise.

Bepirovirsen
Interim results from the large (N = 457) randomized phase IIb B-Clear study demonstrated bepirovirsen to be a potent antiviral. Early data on long-term durability of response were evaluated in a small subset of patients in the first report of the B-Sure study and presented at EASL 2023.

This smaller B-Sure study enrolled 25 complete responders from the B-Clear study: 12 who responded to a finite course of bepirovirsen without receiving nucleos(t)ide analogue (NA) therapy and 13 who responded to a finite course of bepirovirsen with NA therapy. The study examined maintenance of response in those who had either ceased receiving NA therapy per study protocol or had never received NA therapy.

As shown in the table, of those with complete data with ≥9 months of follow-up, 100% maintained response (3/3 who had originally received bepirovirsen without NA therapy and 4/4 who had originally received bepirovirsen with NA therapy). No patients restarted NA therapy.

Table. B-Sure: Durability of Response Among B-Clear Bepirovirsen Complete Responders

These data, although including only small numbers, provide early evidence on the durability of response with bepirovirsen. Obviously, there is a need for data with more patients and longer follow-up.

VIR-2218 Plus VIR-3434
Data from posttreatment follow-up of the phase II MARCH trial on the combination of VIR-2218 and VIR-3434 in patients with chronic HBV infection who were virologically suppressed also were reported at EASL 2023. VIR-2218 is an investigational siRNA targeting the HBx region of the HBV genome. VIR-3434 is an investigational Fc-engineered human monoclonal antibody targeting the conserved antigenic loop of HBsAg.

This part 1 report included 40 patients. After 8-20 weeks of treatment, mean HBsAg reductions were approximately 3 log10 IU/mL; 90% of participants achieved HBsAg <10 IU/mL. HBsAg gradually rebounded after end of treatment but remained almost 1 log10 IU/mL below baseline on average in all cohorts at 48 weeks after end of treatment. No participants achieved HBsAg loss or functional cure. Adverse events were generally mild or moderate.

The authors concluded that the on-treatment data from part 1 of the MARCH study established initial proof of concept that combination treatment with VIR-2218 plus VIR-3434 is well tolerated and results in additive antiviral activity.

The rebound after cessation means that this treatment would need either a longer duration or be associated with other drugs with other modes of action. Longer durations of treatment with VIR-2218 plus VIR-3434 currently are under investigation, as are combinations of VIR-2218 with other agents, including pegIFN-α. The ideal duration and/or combinations remain to be identified.

Your Thoughts?
What do you think of these data? Does RNA interference seem a likely prospect for new HBV therapy? Share your opinion in the comment box below.