Highlights
- Elebsiran, a novel small interfering RNA (siRNA) targeting HBV transcripts, significantly enhances hepatitis B surface antigen (HBsAg) loss when combined with pegylated interferon alfa (PEG-IFNα) in chronic HBV patients.
- Randomized phase 2 trials show HBsAg loss rates up to 33.3% with elebsiran plus PEG-IFNα, substantially higher than PEG-IFNα monotherapy alone.
- The HBV therapeutic vaccine BRII-179 demonstrates potential for immunological profiling, identifying anti-HBs responders who achieve higher functional cure rates with combination therapy.
- Safety profiles for elebsiran plus PEG-IFNα are favorable, with mostly mild to moderate adverse events and manageable alanine aminotransferase elevations.
Background
Chronic hepatitis B virus (HBV) infection remains a major global health burden, affecting approximately 296 million individuals worldwide, and is a leading cause of cirrhosis and hepatocellular carcinoma. The ultimate therapeutic goal is achieving a functional cure characterized by sustained loss of hepatitis B surface antigen (HBsAg), with or without seroconversion to anti-HBs antibodies. Currently approved nucleos(t)ide analogues and pegylated interferon alfa (PEG-IFNα) therapies infrequently achieve this endpoint, typically under 10% after finite treatment courses. Consequently, novel therapeutic approaches, including RNA interference mechanisms and therapeutic vaccines, are under investigation to enhance clearance rates and durability of response.
Key Content
Development and Mechanism of Elebsiran (VIR-2218)
Elebsiran (VIR-2218) is a chemically stabilized, liver-targeted small interfering RNA designed to degrade HBV transcripts, including those encoding HBsAg. By reducing viral antigen load, elebsiran may restore HBV-specific immune responses, complementing the immunomodulatory effects of PEG-IFNα. This dual mechanism holds promise for synergistic antiviral efficacy and improved rates of functional cure.
Clinical Trials Evaluating Elebsiran and PEG-IFNα
Two key phase 2 clinical trials, published in 2024 and 2025, have evaluated the efficacy and safety of elebsiran in combination with PEG-IFNα compared to PEG-IFNα alone in adults with chronic HBV infection.
- Wong et al. (2025), Nat Med: This partially randomized, open-label, phase 2 trial enrolled virally suppressed patients naive to the therapeutic vaccine BRII-179. Participants were randomized to receive 48 weekly doses of PEG-IFNα monotherapy or combination therapy with 13 doses of elebsiran (100 mg or 200 mg) administered every 4 weeks. Additionally, participants previously treated with both elebsiran and BRII-179 were stratified by anti-HBs response and treated with combination therapy.
- Key findings included 24 weeks post-treatment HBsAg loss rates of 33.3% for elebsiran 100 mg plus PEG-IFNα, 21.1% for elebsiran 200 mg plus PEG-IFNα, and only 5.6% for PEG-IFNα monotherapy.
- Patients identified as anti-HBs responders to BRII-179 had higher HBsAg loss rates (42.1%) compared with nonresponders (8.3%).
- The combination therapy was generally safe with tolerable adverse events.
- Yuen et al. (2024), Lancet Gastroenterol Hepatol: This multi-national, open-label phase 2 study assessed six cohorts receiving varying durations of elebsiran and pegylated interferon-alfa-2a (180 μg weekly). All participants were on background nucleos(t)ide analog therapy with low HBV DNA and HBsAg >50 IU/mL.
- Mean maximum HBsAg reduction ranged between -1.7 to -3.0 log10 IU/mL depending on dosing schedule.
- HBsAg seroclearance at any timepoint was observed in 11 participants receiving combination therapy, with 6 sustaining clearance 24 weeks post-treatment.
- A notable proportion (42%) of initially HBeAg-positive patients achieved HBeAg seroclearance or anti-HBe seroconversion.
- Treatment-emergent adverse events were mostly grade 1-2, with transient alanine aminotransferase elevations observed, especially during combination therapy phases.
Role of HBV Therapeutic Vaccine BRII-179 in Immunological Profiling
The inclusion of BRII-179 in Wong et al.’s study provided insight into the immunological responsiveness of chronic HBV patients. Patients with anti-HBs antibody titers ≥10 IU/L after prior vaccination exhibited significantly higher rates of HBsAg loss following combination therapy. This suggests that immunoprofiling with BRII-179 may help identify patients most likely to benefit from RNA interference and PEG-IFNα regimens, optimizing personalized functional cure strategies.
Safety and Tolerability
Across both studies, the combination of elebsiran and PEG-IFNα was associated with an acceptable safety profile. Most adverse events were mild to moderate, including flu-like symptoms related to interferon. Elevated liver enzymes, particularly alanine aminotransferase, were common but reversible. No new safety signals were observed, supporting further clinical development.
Expert Commentary
The accumulating evidence highlights elebsiran as a potent RNA interference agent capable of markedly reducing HBsAg levels when combined with PEG-IFNα therapy. The increased HBsAg loss rates—up to one-third of treated patients—represent a substantial improvement over conventional monotherapies. This advance addresses a key unmet need in chronic HBV management: achieving sustained functional cure.
Mechanistically, elebsiran’s targeted silencing of viral transcripts decreases antigen-induced immune exhaustion, while PEG-IFNα enhances antiviral immunity and modulates host responses. The synergistic antiviral activity is thus biologically plausible and corroborated by clinical data.
The immunologic stratification leveraging BRII-179 responders is a significant translational step. It provides a precision medicine approach by selecting patients with preexisting or induced immune competence to optimize therapeutic outcomes. Nonetheless, further research is needed to validate this biomarker strategy in larger cohorts.
Limitations of these studies include relatively small sample sizes and short follow-up durations. Long-term durability of HBsAg loss, clinical outcomes such as fibrosis regression, and real-world applicability remain to be established. Ongoing trials incorporating monoclonal antibodies targeting HBsAg and combination regimens are eagerly awaited to refine curative treatment paradigms.
Conclusion
Phase 2 clinical trials affirm that elebsiran combined with PEG-IFNα delivers a meaningful advance in chronic HBV therapy by significantly improving HBsAg loss rates, the surrogate marker for functional cure. The safety profile is manageable, and incorporation of immunologic profiling via the BRII-179 vaccine platform offers a promising strategy for patient selection.
These findings warrant progression to larger phase 3 studies and integration into clinical guidelines pending confirmatory data. The era of RNA interference treatment against HBV ushers new hope for patients worldwide, aligning therapeutic innovation with the longstanding goal of durable cure in chronic hepatitis B.
References
- Wong GL, Yuen MF, Lin B, et al. Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial. Nat Med. 2025 Nov 7. doi: 10.1038/s41591-025-04049-z. PMID: 41203919.
- Yuen MF, Lim YS, Yoon KT, et al. VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study. Lancet Gastroenterol Hepatol. 2024 Dec;9(12):1121-1132. doi: 10.1016/S2468-1253(24)00237-1. PMID: 39389081.
