TOPLINE

Bepirovirsen, an antisense oligonucleotide targeting hepatitis B virus (HBV) transcripts, led to functional cure in a significantly higher proportion of patients with chronic HBV infection than placebo over 24 weeks after the discontinuation of nucleoside or nucleotide analog (NA) therapy.

METHODOLOGY

• Researchers conducted two identical phase 3 randomized trials (B-Well 1 and B-Well 2) across 29 countries to evaluate the efficacy and safety of bepirovirsen vs placebo in patients with chronic HBV infection receiving NA therapy.
• Eligible patients had been receiving NA therapy for at least 6 months, had hepatitis B surface antigen (HBsAg) levels of 100-3000 IU/mL, HBV DNA levels < 90 IU/mL, and alanine aminotransferase levels up to two times the upper limit of the normal range.
• A total of 1834 patients received weekly subcutaneous injections of bepirovirsen 300 mg (with loading doses on days 4 and 11) or placebo for 24 weeks, alongside background NA therapy. The mean age ranged from 48.7 to 50.2 years, and men comprised 69%-73% of participants across both trials.
• Patients continued background NA therapy through week 48; those meeting the discontinuation criteria (HBV DNA level below the lower limit of quantification [LLOQ] and undetectable HBsAg from week 24 to week 46) stopped all HBV treatment at week 48.
• The primary outcome was functional cure — defined as an HBV DNA level below the LLOQ (< 20 IU/mL or not detected), undetectable HBsAg, and no receipt of rescue therapy — at 72 weeks.

TAKEAWAY

• At week 72, a significantly higher proportion of patients receiving bepirovirsen than those receiving placebo achieved functional cure ; the common risk differences were 17.5 percentage points in B-Well 1 and 13.3 percentage points in B-Well 2 (P < .001 for both).
• A sustained HBV DNA level below the LLOQ at week 72 after treatment discontinuation was observed in 23% of patients treated with bepirovirsen vs 0% of those treated with placebo in each trial (P < .001 for both trials).
• Among patients in the lower HBsAg stratum (baseline HBsAg level ≤ 1000 IU/mL ), the risk difference for functional cure was 24.6 percentage points in B-Well 1 and 27.8 percentage points in B-Well 2 (P < .001 for both).
• In the pooled safety analysis during the 24-week treatment period , serious adverse events were infrequent (4% with bepirovirsen vs 1% with placebo). Grade ≥ 3 adverse events occurred in 16% of participants treated with bepirovirsen vs 3% of those treated with placebo; the most common event in the bepirovirsen group was an increase in the alanine aminotransferase level (6% of patients).

IN PRACTICE

“These findings support the efficacy of bepirovirsen as a 24-week finite therapy to achieve functional cure and show added benefit over continued therapy as standard care in these patients,” the authors wrote.

SOURCE

This study was led by Jinlin Hou, MD, Southern Medical University, Guangzhou, China. It was published online on May 28, 2026, in The New England Journal of Medicine.

LIMITATIONS

The relatively small number of patients in the subgroup analyses, along with underrepresentation of some racial and ethnic groups, may have limited generalizability. In addition, central stratification during randomization may have led to differences in average baseline HBsAg levels across countries.

DISCLOSURES

The trial was supported by GSK. Seven authors reported being employees of GSK and six of them disclosed holding stock or stock options in the company. Several authors reported serving as consultants; receiving travel support, grants, contracts, or research funding; participating in data and safety monitoring boards and scientific advisory boards; receiving lecture fees; and other ties with various companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.