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Phase 3 Results of Bepirovirsen HBV
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A functional cure, defined as an HBV DNA level below the lower limit of quantification (LLOQ) and hepatitis B surface antigen (HBsAg) loss (i.e., a level of <0.05 IU per milliliter) for at least 24 weeks after finite (fixed-duration) therapy - with or without a positive test for hepatitis B surface antibody - is the treatment goal for patients with chronic HBV infection and the recommended end point for new finite HBV therapies.4,5 HBsAg loss is associated with better clinical outcomes than HBV DNA suppression alone, but it is rarely achieved with currently approved therapies, which include nucleoside and nucleotide analogues (NAs) and pegylated interferon.4-8 In addition to showing the benefits of HBsAg loss, a functional cure ends the need for further NA treatment, therefore removing the risk of virologic breakthrough from resistance or nonadherence, along with the costs and side effects of long-term NA therapy.5,9-11
Editorial
A Major Step toward a Cure for Hepatitis B Infection
Author: Anna S. Lok, M.D.
Published May 28, 2026
Download the PDF here
For these historical reasons, the results of the two B-Well trials with duplicate design now presented by Hou and colleagues in the Journal9 are remarkable. Not only did these phase 3 trials aim at a cure for HBV infection, but they also had encouraging results that involved adding only one investigational agent - bepirovirsen, an antisense oligonucleotide - to NA therapy.
The B-Well trials represent a major step toward a functional cure for HBV infection, and bepirovirsen is an attractive option for selected patients. The durability of HBsAg loss has to be confirmed with longer follow-up, and alternative therapies are needed for other patients, such as those with cirrhosis or a baseline HBsAg level above 3000 IU per milliliter. Ultimately, curative therapies must be simple, safe, accessible, and affordable to benefit the 240 million persons worldwide who are living with chronic HBV infection.10
The B-Well trials enrolled patients with noncirrhotic chronic hepatitis B with suppressed HBV DNA during receipt of NA therapy and a low HBsAg level (≤
3000 IU per milliliter). A total of 1838 patients were randomly assigned in a 2:1 ratio to receive bepirovirsen or placebo administered as a weekly subcutaneous injection for 24 weeks. The patients who had undetectable HBsAg and unquantifiable HBV DNA from week 24 to week 46 were eligible to discontinue NA therapy at week 48. The primary outcome of a functional cure was assessed at week 72.
Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection
NEJM Published May 28, 2026
Download the PDF here
Download the PDF here
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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