Combination therapeutics for hepatitis delta virus infection: implications of the tobevibart-elebsiran SOLSTICE phase 2 trial

The hepatitis D virus (HDV) is a hepatotropic pathogen reliant on co-infection with the hepatitis B virus (HBV) that can facilitate an accelerated and aggressive form of chronic liver disease. Though the global scale of HDV infection is only a fraction of the overall burden of HBV, individuals with HBV-HDV co-infection experience the highest risk for progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) (1). As such, effective therapies to control HDV viremia and mitigate HDV-related liver complications are critically needed. In this respect, results from the recently published phase II SOLSTICE trial represent an important step forward in the evolving therapeutic landscape (2).

This trial evaluated the combined effects of two complementary therapeutics, tobevibart and elebsiran, for treatment of chronic HDV. The pairing of these two novel medications sought to capitalize on the unique life cycle of HDV. As a satellite virus of the HBV, HDV is principally dependent on the HBV surface antigen (HBsAg) for entry into hepatocytes and viral particle assembly. As an engineered monoclonal antibody, tobevibart has an enhanced circulatory half-life and a receptor region that binds a highly conserved epitope of the HBsAg. This allows tobevibart to efficiently neutralize and clear circulating viral particles, as well as inhibit viral entry into hepatocytes (3). Elebsiran, conversely, is a small interfering RNA (siRNA) molecule that reduces intracellular production of HBsAg. Both therapeutics are delivered via subcutaneous (SC) injection at 2- or 4-week intervals. Pre-clinical and early phase trials demonstrated favorable outcomes with this combination approach (3-5).

The SOLSTICE trial was an open-label, randomized-control, phase II study that compared tobevibart plus elebsiran every 4 weeks or tobevibart monotherapy every 2 weeks for 48 weeks in adults with chronic HDV and compensated liver disease. The primary endpoint was achievement of a composite response defined as an HDV RNA level that was either undetectable or ≥2 log₁₀ international units per milliliter (IU/mL) lower from baseline, plus normalization in alanine aminotransferase (ALT) levels. This endpoint aligns with contemporary HDV trials that seek the dual objectives of virological and biochemical control, as this is associated with clinical outcome improvement (6). Key secondary and exploratory endpoints included assessment of the composite response, virologic response, and ALT response at 48 weeks, and changes in quantitative HBsAg titer.

All participants had well-controlled HBV on nucleoside/nucleotide analogue (NUC) therapy for a minimum of 12 weeks, where HBV DNA levels were near or below the limit of detection at time of enrollment. The study included those with compensated cirrhosis (51% of subjects), which was defined as Child-Pugh class A and either a liver stiffness measurement ≥12 kPa by elastography or biopsy-proven Metavir stage 4 fibrosis. Those with decompensated cirrhosis were excluded from the trial.

The results from the trial were highly encouraging. At week 24 of therapy, the primary composite endpoint was observed in 47% and 70% of participants who received tobevibart plus elebsiran versus tobevibart monotherapy, respectively. At week 48, the composite endpoint was achieved in 56% and 61% of these two respective treatment arms. Undetectable HDV RNA was observed in 66% of participants with tobevibart plus elebsiran by week 48, whereas 48% of those receiving tobevibart alone achieved this mark. Notably, 91% of participants who received combination therapy achieved quantitative HBsAg levels below 10 IU/mL at week 48. Virological and biochemical results were also similar between participants with and without compensated cirrhosis, suggesting that the presence of advanced fibrosis at baseline may not significantly attenuate antiviral and/or biochemical responses. Although adverse events were common, the most frequently described event were transient influenza-like symptoms that were predominantly mild or moderate in severity. No participants receiving tobevibart plus elebsiran required adverse effect-related treatment discontinuation.

Current treatment options for HDV are significantly limited by efficacy, applicability, or side effect profile. Nucleotide/nucleoside analogues (NUC) have marginal impact on HDV replication, despite exhibiting potent control on HBV. Off-label use of pegylated interferon (peg-IFN) has therefore served as the historical standard to treat HDV (7,8). While the immunomodulatory properties of peg-IFN for HDV contribute to a modest rate of sustained virological response (ranging from 23% to 57%) with a finite duration of 48 weeks, its use is limited by contraindications and poor safety and tolerability which is associated with poor patient acceptance and adherence (8). Furthermore, bulevirtide, a first-in-class therapeutic that inhibits HDV entry into hepatocytes by blocking the sodium taurocholate co-transporting polypeptide (NTCP), became the first fully approved medication for HDV in Europe by the European Medicines Agency (9). A new biologics licensing application was submitted to the US Food and Drug Administration (FDA) in late 2025 (10) and approved in May 2026 on the basis of two phase 3 clinical trials which demonstrated complete virological suppression at 48 weeks in 12–20% of those treated with bulevirtide 2 or 10 mg SC daily, respectively, and a sustained virologic response in up to 46% of patients treated with a finite duration regimen of peg-IFN for 48 weeks and bulevirtide for 96 weeks (11-13). Although bulevirtide is supported by excellent trial and real-world observational data and represents a critical advance in HDV therapeutics, relapse is common after discontinuation and combination with peg-IFN is limited by poor tolerability and acceptance (14,15).

In this light, the results from the phase II SOLSTICE trial provides hope for an additional step in advancing HDV treatment outcomes based on higher rates of virologic suppression than what has been historically reported with bulevirtide or peg-IFN. Although a composite endpoint of 2 log decline in HDV RNA plus ALT normalization has been commonly applied as a pragmatic endpoint for assessment of therapeutic response, HBsAg loss and/or suppression of HDV RNA to undetectable levels likely represent a more desirable endpoint (6) which has been associated with lower risk of disease progression (16,17). Although attainment of these more stringent endpoints appears to be feasible with tobebivart plus elebsiran based on the SOLSTICE trial findings, the high rate of HBsAg suppression to <10 IU/mL and undetectable HDV RNA strongly suggests enhanced potency and potential for higher rates of complete virologic response, and will be examined further in the phase 3 ECLIPSE program (18).

Important limitations must be carefully considered in the interpretation of the SOLSTICE trial results. This includes an open-label study design without randomization or placebo control, absence of formal hypothesis testing, a small sample size, preliminary results of short-term endpoints (trial to be continued to 192 weeks), predominantly white subject population (82%), and near absence of non-genotype 1 HDV genotypes (97%). Multiple questions regarding the tobevibart +/− elebsiran regimens remain unanswered, including the relationship between HBsAg titer decline and HDV RNA suppression, the influence of selected HDV RNA test based on divergent thresholds for lower limit of detection (LLOD) and lower limit of quantification (LLOQ) between Robogene (LLOQ 63 IU/mL, LLOD 14 IU/mL) and Victorian Infectious Diseases Reference Laboratory (VIDRL) assays (LLOQ 10 IU/mL, LLOD 5 IU/mL), and discordance between HDV suppression and ALT normalization which resulted in unexpectedly lower rates of composite endpoint (2 log decline HDV RNA plus ALT normalization) with tobevibart plus elebsiran versus tobevibart alone. Furthermore, the clinical significance of influenza-like symptoms (69–73%) and illness (25–30%) and a notable signal of neutropenia (neutrophil count <1,000/mm3) in 9–15% of subjects require further examination. Although declines in HDV RNA appear to be sustained beyond week 48 based on public reports of follow-up SOLSTICE data, including 88% (21/24) achieving HDV RNA target not detected at week 96 (19), evaluations of long-term outcomes including off-treatment virologic, biochemical, and clinical endpoints will be necessary to assess the feasibility of finite duration regimens.

Overall, the results of the phase 2 SOLSTICE trial signal an exciting and pivotal advance in the treatment of chronic HDV. These preliminary data confirm that deep virologic suppression can be achieved with tobevibart and elebsiran, including in patients with cirrhosis, and offers the promise of a transition to a higher bar of virologic response beyond the composite endpoint, based on undetectable HDV RNA with or without ALT normalization. Long-term results from the final analysis of SOLSTICE and the larger randomized-controlled phase 3 ECLIPSE trial should clarify the lasting on-treatment and post-treatment impact of tobevibart and elebsiran, as well as address important questions centered on safety and generalizability. Such data should also confirm the potential role of this combination approach in context of the expanding treatment landscape of HDV pharmacotherapy that may include bulevirtide, peg-IFN, brelovitug, lonafarnib, and other investigational agents in development.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0084/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0084/coif). J.K.L. has received research contracts (to Yale University) from Akero, Becton Dickinson, Bluejay, Gilead, Inventiva, and Novo Nordisk. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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