Published May 28, 2026
N Engl J Med 2026;394:2395-2406
DOI: 10.1056/NEJMoa2515131
Abstract
Background
Treatment with bepirovirsen, an antisense oligonucleotide targeting hepatitis B virus (HBV) transcripts, has the potential to result in a functional cure, defined by at least 24 weeks of a sustained HBV DNA level below the lower limit of quantification (LLOQ) and hepatitis B surface antigen (HBsAg) loss after fixed-duration therapy.
Methods
In two replicate, double-blind trials (B-Well 1 and B-Well 2), we randomly assigned adults with noncirrhotic chronic HBV infection in a 2:1 ratio to receive subcutaneous bepirovirsen (at a weekly dose of 300 mg) or placebo for 24 weeks. All the patients were receiving stable nucleoside or nucleotide analogue (NA) therapy and had an HBsAg level of more than 100 to 3000 IU per milliliter. Eligible patients discontinued NA therapy at 48 weeks. The primary outcome was a functional cure at week 72.
Results
The percentage of patients with a functional cure at week 72 was significantly higher with bepirovirsen than with placebo both in the B-Well 1 trial (in 127 of 650 patients [20%] vs. none of 328 patients) and in the B-Well 2 trial (in 106 of 570 patients [19%] vs. none of 286 patients). In a pooled analysis at 72 weeks, adverse events were reported in 91% of the patients in the bepirovirsen groups and in 73% of those in the placebo groups; serious adverse events were reported in 7% and 4% of the patients, respectively. During the treatment period, adverse events of grade 3 or higher were reported in 16% of the patients who received bepirovirsen and in 3% of those who received placebo; increases in the alanine aminotransferase level were the most common grade 3 adverse events with bepirovirsen (in 6% of the patients).
Conclusions
In two phase 3 trials involving patients with chronic HBV infection, a functional cure after the discontinuation of NA therapy was reported in significantly more patients treated with bepirovirsen than in those who received placebo. (Funded by GSK; ClinicalTrials.gov numbers, NCT05630807 and NCT05630820.)
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Notes
This article was published on May 28, 2026, and updated on June 11, 2026, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by GSK.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the trial patients and their families, along with site staff members, for their support, time, and commitment to the trials; Emma Ilsley, Chelsea Macfarlane, Stuart Kendrick, Ruth Tarzi, and Fiona Campbell for their contributions to the trials, along with the members of the data and safety monitoring committee, the hepatic adjudication committee, the hepatitis B patient council, the B-Well study team, and other bepirovirsen project team members for their contributions; and Claire Barron of Fishawack Indicia, part of Avalere Health, for her medical-writing support.
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Copyright © 2026 Massachusetts Medical Society. All rights reserved.
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History
Published online: May 28, 2026
Published in issue: June 25, 2026
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- A Major Step toward a Cure for Hepatitis B Infection, New England Journal of Medicine, 394, 24, (2471-2472), (2026)./doi/full/10.1056/NEJMe2605575
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