Dual HBsAg Knockdown Hits 44% in Phase 3 But Faces Precedent Void

Vir's Hepatitis D Combination Succeeds in First Pivotal Phase 3 Study

Vir Biotechnology's experimental two-drug combination, elebsiran and tobevibart, successfully met its primary objective in the first of three Phase 3 trials for chronic hepatitis D. The regimen eliminated detectable signs of the virus and normalized liver enzyme levels in 44% of treated participants after 48 weeks, compared to none in a delayed treatment cohort. It also achieved a key secondary endpoint, with 79% of patients showing a drop in viral levels. Two more Phase 3 trials are ongoing, with data expected early next year, potentially supporting a regulatory submission in 2027. Analysts predict this combination could become the preferred and dominant front-line treatment for hepatitis D.

• The elebsiran and tobevibart combination demonstrated significant efficacy in its first pivotal Phase 3 trial. After 48 weeks, 44% of treated patients achieved undetectable virus and normalized liver enzymes, meeting the main objective. Additionally, 79% of patients met a key secondary endpoint by achieving a reduction in viral levels, highlighting the drug's robust therapeutic potential for chronic hepatitis D.
• Despite the evolving treatment landscape for hepatitis D, including recent approvals and ongoing trials for rival therapies like Gilead's Hepcludex and Mirum's acquired drug, analysts like Cory Kasimov of Evercore ISI anticipate Vir's combination to emerge as the "preferred" and "dominant front-line product." This projection is based on the favorable comparative results, suggesting a strong competitive position upon market entry.
• Vir Biotechnology has a clear development pathway, with two additional Phase 3 trials currently underway, expected to produce data early next year. Positive outcomes from these studies would support a regulatory submission in 2027. This structured approach underscores Vir's commitment to bringing this critical treatment to market for chronic hepatitis D patients.

Elebsiran and Tobevibart: Phase 3 Design and Initial Efficacy

In this ongoing, phase 2, open-label trial, participants were randomly assigned to receive tobevibart plus elebsiran every 4 weeks or tobevibart monotherapy every 2 weeks. Both tobevibart (a monoclonal antibody) and elebsiran (a small interfering RNA) target hepatitis B virus surface antigen (HBsAg), and their efficacy and safety in the treatment of chronic hepatitis D virus (HDV) infection were unknown. The SOLSTICE Phase 2 clinical trial program similarly evaluated tobevibart alone or combined with elebsiran, with the combination dosed monthly.

The primary end point was a combined response, defined by an HDV RNA level below the limit of detection or a decrease in the HDV RNA level of at least 2 log IU per milliliter from baseline (virologic response) and normalization of the alanine aminotransferase (ALT) level, at week 24. At week 24, a combined response was observed in 47% of participants (15 of 32) who received tobevibart plus elebsiran and in 70% of participants (23 of 33) who received tobevibart, with a virologic response in 100% (32 of 32) and 82% (27 of 33), respectively, and normalization of the ALT level in 47% (15 of 32) and 76% (25 of 33). The combination dosed monthly achieved > 50% virologic and biochemical response at 24 weeks of therapy.

Through extended follow-up to week 48, a combined response was observed in 56% of participants (18 of 32) with tobevibart plus elebsiran and 61% of participants (20 of 33) with tobevibart; undetectable HDV RNA (also known as target not detected, or TND; no amplification during reverse-transcriptase-polymerase-chain-reaction assay) in 66% (21 of 32) and 48% (16 of 33), respectively; normalization of the ALT level in 56% (18 of 32) and 61% (20 of 33); and an HBsAg level below 10 IU per milliliter in 91% (29 of 32) and 21% (7 of 33). No ALT flares were observed in participants starting tobevibart and elebsiran simultaneously or receiving tobevibart monotherapy. The efficacy and safety of these drugs will further be evaluated in ECLIPSE 1, 2, and 3 trials.

The Persistent Challenges in Treating Chronic Hepatitis D

Chronic hepatitis D remains the most severe form of viral hepatitis, carrying a greater risk of developing cirrhosis and its complications. For decades, pegylated interferon alpha has represented the only therapeutic option, with limited virological response rates and poor tolerability, while newer agents such as bulevirtide still face durability and functional cure limitations.

• Limited and non-durable efficacy of pegylated interferon alpha: Trials investigating pegylated interferon alpha showed HDV RNA negativity rates of 25-30% 24 weeks after therapy, with treatment response of 25-40% HDV RNA suppression after 1-2 years and sustained response in about one quarter of patients. Therapy is plagued by low rates of sustained virologic response and frequent relapses even if SVR is achieved, with nine of sixteen patients testing HDV RNA-positive at least once during long-term follow-up and seven patients being HDV RNA-positive at the most recent visit, leading to the conclusion that the term sustained virological response should be avoided in HDV infection.

• Poor tolerability and restricted use of interferon-based therapy: Pegylated interferon alpha therapy is limited by moderate effectiveness (around 20%) and its adverse effects, with frequent side-effects and descriptions of the limitations of pegylated interferon alpha in the treatment for chronic hepatitis D. Pegylated interferon lambda is associated with less IFN typical side effects but the PegIFN lambda study has been discontinued due to liver toxicity issues, and ribavirin provides no additional benefit when added to pegylated interferon monotherapy.

• Bulevirtide monotherapy does not clear HBsAg and requires undefined duration: Bulevirtide at 2 mg/day, approved in 2020 by the European Medicines Agency, proved to be safe and effective as a monotherapy for up to 144 weeks, with plasma viremia significantly declining and/or becoming undetectable in more than 75% of patients treated for >24 weeks. However, serum HBsAg concentrations remain unchanged, with no patient losing hepatitis B surface antigen in a 114-patient cohort, and the optimal treatment duration has not yet been determined with treatment to be continued if a clinical benefit is observed; BLV was stopped in two patients with >6 months HDV-RNA undetectability, but both became HDV-RNA positive again.

• Combination strategies improve on-therapy response but not off-therapy cure: The combination of BLV 2 mg with PegIFN-α increased the HDV RNA undetectability rates on-therapy but not off-therapy, compared with PegIFN monotherapy, while combination therapy, but not BLV monotherapy, may induce hepatitis B surface antigen (HBsAg) loss in some patients. Adding PEG-IFN in eight patients induced an HDV-RNA decrease in all (1.29 ± 0.19 [SD] log within 12 weeks), and mathematical modelling predicted viral cure rates of 8.8% with bulevirtide compared with 18.8% with bulevirtide + Peg-IFN.

• Limited efficacy and toxicity of other investigational classes: Lonafarnib boosted with ritonavir showed limited off-therapy efficacy in a phase 3 study, is associated with dose-dependent gastrointestinal toxicity, and prevents hepatitis D virus assembly with better use with ritonavir which increases liver lonafarnib concentrations. Nucleic acid polymer-based therapy is promising but large studies are still lacking, and one year of entecavir treatment is ineffective in CHD with no significant decline in HDV RNA, ALT, or quantitative HBsAg levels observed.

Positioning Elebsiran/Tobevibart in the Evolving CHD Landscape

Chronic hepatitis D remains the most severe form of viral hepatitis, with pegylated interferon alpha historically offering limited sustained response and poor tolerability. Published randomized trials, network meta-analysis, and real-world cohorts indicate bulevirtide-based regimens, particularly bulevirtide plus peginterferon alfa-2a, achieve higher on-treatment virological and combined responses than interferon or nucleos(t)ide analogs alone, while nucleic acid polymer-based therapy shows promising HBsAg loss.