Tobevibart Plus Elebsiran Shows Durable Viral Suppression in Chronic HDV at 96 Weeks

Chronic hepatitis D virus (HDV) infection remains one of the most severe and difficult-to-treat forms of viral hepatitis, frequently accelerating progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma.¹ Although therapeutic advances have emerged in recent years, treatment options remain limited, and durable viral suppression continues to represent a major unmet need.

New findings presented at the European Association for the Study of the Liver (EASL) Congress 2026 highlighted encouraging long-term efficacy and safety data for the investigational combination of tobevibart (VIR-3434) and elebsiran (VIR-2218) in patients with chronic HDV infection. Investigators from the ongoing phase 2 SOLSTICE (NCT05461170) trial reported that the combination regimen achieved increasing rates of HDV RNA target-not-detected (TND) responses through 96 weeks, alongside substantial hepatitis B surface antigen (HBsAg) reductions and generally favorable tolerability.

A separate subgroup analysis from the same study also suggested that elevated body mass index (BMI) may independently contribute to persistently elevated alanine aminotransferase (ALT) levels, even among patients achieving deep virologic suppression.²

Long-Term Viral Suppression Observed in SOLSTICE

The phase 2 study is evaluating the safety and antiviral activity of the monoclonal antibody tobevibart administered either alone or in combination with the small interfering RNA (siRNA) agent elebsiran in adults with chronic HDV infection. Participants included individuals with or without compensated cirrhosis who were receiving nucleos(t)ide reverse transcriptase inhibitor therapy.

In the 96-week analysis, investigators compared outcomes between participants receiving tobevibart 300 mg plus elebsiran 200 mg subcutaneously every 4 weeks and those receiving tobevibart monotherapy every 2 weeks.

The data demonstrated numerically greater antiviral activity with the combination regimen across multiple efficacy endpoints.

At week 72, HDV RNA TND—defined as no amplification on polymerase chain reaction testing—was achieved in 77% (24 of 31) of participants receiving combination therapy compared with 53% (17 of 32) among those receiving monotherapy. By week 96, response rates further increased to 88% (21 of 24) in the combination arm, while rates in the monotherapy cohort plateaued at 46% (11 of 24).

Investigators noted that the increasing TND rates over time with combination therapy may indicate continued antiviral benefit with prolonged treatment duration.

HBsAg Reductions May Signal Functional Cure Potential

Beyond HDV RNA suppression, investigators also reported substantial reductions in HBsAg levels among patients receiving combination therapy.

At week 72, 94% of participants treated with tobevibart plus elebsiran achieved HBsAg levels below 10 IU/mL compared with only 19% in the monotherapy arm. These rates remained largely consistent through week 96.

Because HDV depends on hepatitis B virus (HBV) surface antigen for viral assembly and propagation, reductions in HBsAg are considered an important therapeutic target in chronic HDV infection. Researchers have increasingly focused on therapies capable of simultaneously suppressing HDV replication and reducing HBsAg production.

The combination approach evaluated in SOLSTICE targets both pathways. Tobevibart is designed to block HBV and HDV entry into hepatocytes, while elebsiran suppresses HBV transcripts through RNA interference mechanisms. Investigators suggested the dual-targeted strategy may explain the deeper virologic responses observed with combination therapy compared with monoclonal antibody treatment alone.

ALT Normalization Influenced by Baseline BMI

Although viral suppression rates were high, a separate week 48 subgroup analysis suggested biochemical normalization may be affected by factors beyond HDV replication alone.² The subgroup analysis evaluated 32 participants receiving tobevibart plus elebsiran every 4 weeks and examined whether baseline participant characteristics influenced ALT normalization outcomes.

ALT normalization is commonly used as a marker of reduced hepatic inflammation during antiviral therapy. However, ALT elevations may also reflect metabolic dysfunction, steatosis, or obesity-related liver injury.

Overall, 97% (31 of 32) of participants achieved at least a 2-log₁₀ reduction in HDV RNA from baseline at week 48, while 66% (21 of 32) achieved HDV RNA TND. Despite these robust antiviral responses, ALT normalization occurred in only 56% (18 of 32) of participants.

Investigators observed a trend toward lower baseline BMI among participants who achieved ALT normalization. However, among the 21 participants who achieved HDV RNA TND at week 48, ALT normalization rates varied substantially by BMI subgroup. ALT normalization occurred in:

• 80% of participants with BMI below 25
• 64% of participants with BMI between 25 and 29.9
• 20% of participants with BMI of 30 or greater

Notably, participants in the highest BMI subgroup had lower baseline ALT values despite lower normalization rates, suggesting obesity-related liver inflammation may contribute independently to persistently abnormal ALT levels. The findings underscore the growing recognition that metabolic liver disease and viral hepatitis frequently coexist and may complicate treatment assessment.

Safety Profile Remained Favorable Through 96 Weeks

Across both analyses, investigators reported that treatment-emergent adverse events (AEs) were generally mild to moderate, transient, and manageable.^1,2

The most common AE was influenza-like syndrome occurring after the first dose, which typically resolved within 24 to 48 hours. No treatment-related serious AEs were reported in either treatment cohort. Investigators also noted that no new safety signals emerged through 96 weeks of follow-up.¹

These findings may be particularly important given the limited therapeutic landscape for HDV and concerns surrounding tolerability with existing interferon-based approaches.

Expanding HDV Treatment Landscape

The SOLSTICE data arrive amid growing momentum in HDV therapeutic development. Historically, pegylated interferon alfa has offered limited efficacy and poor tolerability in many patients with chronic HDV infection. More recently, the entry inhibitor bulevirtide became the first approved therapy specifically indicated for HDV in several regions outside the US.³

Emerging investigational strategies now include siRNA therapies, monoclonal antibodies, prenylation inhibitors, and combination regimens targeting multiple stages of the viral life cycle. The encouraging long-term viral suppression observed with tobevibart plus elebsiran may therefore represent an important step toward more durable and effective treatment paradigms. The regimen is currently being further evaluated in the phase 3 ECLIPSE clinical program for chronic HDV infection.¹

References

1. Asselah T, Chattergoon MA, Streinu-Cercel A, et al. Efficacy and safety of tobevibart (VIR-3434) alone or in combination with elebsiran (VIR-2218) in participants with chronic hepatitis delta virus infection: week 96 endpoint results from the phase 2 SOLSTICE trial. Presented at: EASL Congress; May 27-30, 2026; Barcelona, Spain.
2. Jucov A, Asselah T, Streinu-Cercel A, et al. SOLSTICE week 48 subgroup analysis: impact of BMI on ALT normalization after successful viral control in participants with chronic hepatitis delta virus infection treated with tobevibart plus elebsiran. Presented at: EASL Congress; May 27-30, 2026; Barcelona, Spain.
3. Koh C, Heller T, Glenn JS. Pathogenesis of and new therapies for hepatitis D. Gastroenterology. 2019;156(2):461-476.e1. doi: 10.1053/j.gastro.2018.09.058