Vir combo of tobevibart + elebsiran for chronic HDV treatment

Vir has posted its second registrational trial, Phase 3 ECLIPSE-2 (EUCT: 2024-519282-22-00), evaluating tobevibart + elebsiran vs. bulevirtide switch (n=150) for chronic HDV. 

Vir has stated that two pivotal studies will be needed to support marketing applications in the US and Europe:  

• ECLIPSE-1 (n=120): Tobevibart + elebsiran vs deferred treatment, in regions where BLV is not available or its use is limited
• ECLIPSE-2 (n=150): Tobevibart + elebsiran vs BLV switch, in those who achieved incomplete viral suppression with BLV, in regions where BLV is approved and commercially available

The initiation of ECLIPSE-2 follows comments at EASL 2025, suggesting initiation in mid-2025.

• Inclusion criteria defines “incomplete viral suppression”, specifically, patients who are:
  • Receiving BLV 2 mg SC QD for ≥24 weeks at Day 1, with
  • HDV RNA ≥500 IU/mL at screening
• Part 1 (Day 1 – Wk 96): Testing effectiveness of tob + ele in HDV participants who have received BLV
  • Arm 1 (N=100): Tobevibart + elebsiran SC Q4W, administered in clinic
  • Arm 2 (N=50): Bulevirtide switch arm will receive BLV 2 mg SC QD administered at home for 24 weeks, at which time the primary endpoint will be assessed. They will then switch to tobevibart + elebsiran SC Q4W administered in clinic
  • Primary endpoint: HDV RNA <LLOQ, TND at Wk 24
• Part 2 (Wk 96-Wk 240): Testing effectiveness of tob + ele in keeping HDV levels undetectable (i.e. SVR) in patients who interrupt treatment
  • Participants in Arm 1 who achieved and maintained HDV RNA <LLOQ, TND between Wk 48 and Wk 96 will interrupt tob + ele starting at Wk 96
    • Other participants in Arm 1 and Arm 2 will continue to receive tob + ele as chronic therapy
  • Primary endpoint: HDV RNA <LLOQ, TND, 24 weeks after interruption (i.e. Wk 120)
• Trial Sites: France (n=47 planned), UK (n=18 planned), others TBD

• The ECLIPSE-2 protocol, available at the EU Clinical Trials site, provides informative details on study design, study rationale, and statistical considerations.
• Finite therapy: The introduction of Part 2 shows that Vir is clearly seeking to generate evidence to assess tob + ele as a finite therapy option.
• Importance of undetectable HDV RNA: Throughout the protocol, Vir continues to highlight the significance of deep virologic response, stating that “long-term suppression of HDV RNA is associated with more favorable clinical outcomes” and that “there continues to be an unmet need among patients who have been treated with bulevirtide in achieving undetectable HDV RNA.”
• ALT normalization: ALT will be monitored in ECLIPSE-2, but not as a primary endpoint as in ECLIPSE-1. Recall that in Ph 2 SOLSTICE, Vir’s combo achieved lower rates of ALT normalization compared to its mAb monotherapy. Whether long-term ALT improvements will materialize over time will likely continue to be an area of scrutiny for Vir’s combo regimen, considering that siRNA treatment in HDV has been shown to lead to ALT elevations
• Next steps: Assuming rapid enrollment and success in both ECLIPSE-1 and ECLIPSE-2, Vir could launch (base case) as early as 1H’28.