Dual Therapy Shows Antiviral Activity in Chronic Hepatitis D Patients: NEJM
Researchers have found in the phase II SOLSTICE trial that the investigational combination of tobevibart plus elebsiran demonstrated antiviral activity in patients with chronic hepatitis D virus (HDV) infection. At 24 weeks, 47% of patients on the dual therapy and 70% of those on tobevibart alone achieved both ALT normalization and a significant reduction or clearance of HDV RNA, suggesting promising efficacy for these new treatment approaches. The study was published in The New England Journal of Medicine by Tarik A. and colleagues.
Chronic infection with the hepatitis D virus, one of the most aggressive forms of viral hepatitis, is often characterized by a rapid progression of liver fibrosis to cirrhosis and liver failure. HDV depends on the presence of HBsAg for replication, which makes dual-targeted approaches important. The therapeutic options for HDV infection are limited, and the outcomes with conventional interferon-based therapy remain unsatisfactory. Given that tobevibart is a monoclonal antibody and elebsiran is a small interfering RNA, their action on HBsAg can reduce the HDV replication by interfering with the virus life cycle. This open-label, single-arm, phase 2 clinical trial was designed to assess the efficacy and safety of tobevibart alone and its combination with elebsiran in patients suffering from chronic HDV infection.
The trial randomly assigned participants to receive either:
Tobevibart plus elebsiran administered every 4 weeks, or
Tobevibart given as monotherapy every 2 weeks.
The primary endpoint was a combined response at week 24, defined as: virologic response, HDV RNA below the limit of detection or ≥2 log₁₀ IU/mL reduction from baseline, and normalization of alanine aminotransferase levels. Secondary endpoints included virologic response, ALT normalization, undetectable HDV RNA (target not detected), and HBsAg reduction at week 48.
Results
A total of 65 participants were included in the study: tobevibart plus elebsiran was given to 32, and tobevibart monotherapy to 33.
At week 24, a combined response was achieved by:
47% (15 of 32) in the tobevibart plus elebsiran group, and
70% (23 of 33) in the tobevibart monotherapy group.
Virologic response was achieved in:
100% (32 of 32) with the combination therapy, and
82% (27 of 33) with monotherapy.
ALT normalization occurred in:
47% (15 of 32) of combination-treated patients, and
76% (25 of 33) of those on monotherapy.
At week 48, the combined response rates were:
56% (18 of 32) in the combination group, and
61% (20 of 33) in the monotherapy group.
TND of HDV RNA was achieved by:
66% (21 of 32) in the combination group, and
48% (16 of 33) in the monotherapy group.
ALT normalization at week 48 was seen in 56% (18 of 32) and 61% (20 of 33), respectively.
91% (29 of 32) of patients receiving combination therapy had HBsAg levels below 10 IU/mL versus 21% (7 of 33) receiving tobevibart alone.
In the present phase 2 clinical trial, both tobevibart monotherapy and tobevibart plus elebsiran combination therapy significantly decreased HDV RNA and ALT levels up to 48 weeks. These results represent a major step toward targeted, combination-based antiviral therapy for chronic hepatitis D, offering new hope for patients with this difficult infection.
Reference:
Asselah, T., Chattergoon, M. A., Jucov, A., Streinu-Cercel, A., Lampertico, P., Wedemeyer, H., Kennedy, P. T., Gane, E. J., Bullard, B. L., Chow, S., Santos, D., Camus, G., Lu, Y., Pilowa, C., Hwang, C., Correll, T., Agarwal, K., & SOLSTICE Trial Investigators. (2025). A phase 2 trial of tobevibart plus elebsiran in hepatitis D. The New England Journal of Medicine, NEJMoa2508827. https://doi.org/10.1056/NEJMoa2508827
