The antisense oligonucleotide bepirovirsen, which targets hepatitis B virus (HBV) transcripts, achieved significantly higher rates of functional cure than placebo in two replicate phase 3 trials involving patients with chronic HBV infection receiving stable nucleos(t)ide analogue (NA) therapy.

Published in The New England Journal of Medicine and funded by GSK, the study comprised two replicate, double-blind, placebo-controlled phase 3 trials called B-Well 1 and B-Well 2.

The trials enrolled 1,834 participants across 29 countries who had non-cirrhotic chronic HBV infection and were receiving stable nucleoside or NA therapy – the standard treatment for HBV. They also had HBV DNA levels below 90 IU/ml and hepatitis B surface antigen (HBsAg) levels between 100 and 3,000 IU/ml at baseline.

Participants were randomised 2:1 to receive either a weekly dose of subcutaneous bepirovirsen 300 mg or placebo, alongside their standard NA therapy, for 24 weeks. Eligible patients discontinued NA therapy at week 48 and were assessed for outcomes at week 72.

The primary endpoint was functional cure, defined as sustained HBV DNA below the lower limit of quantification and HBsAg loss without rescue therapy.

Efficacy and safety of bepirovirsen

At week 72, functional cure was achieved in 20% (127/650) of bepirovirsen-treated patients versus 0% (0/328) of placebo recipients in B-Well 1, and in 19% (106/570) versus 0% (0/286), respectively, in B-Well 2 (both P<0.001).

Responses were more common among patients with baseline HBsAg levels of 1000 IU/ml or less. In this subgroup, functional cure rates reached 25% in B-Well 1 and 28% in B-Well 2 with bepirovirsen, compared with 0% in placebo groups.

Sustained HBV DNA suppression after NA discontinuation was reported in 23% of bepirovirsen-treated patients in both studies, which was a key secondary outcome, and this rose to 29% and 33% in the lower HBsAg subgroup.

Safety findings were broadly consistent across both trials. By week 72, adverse events were reported in 91% of patients receiving bepirovirsen and 73% receiving placebo, while serious adverse events occurred in 7% and 4%, respectively. These reactions mostly occurred during the first four weeks of treatment and the majority were classed as mild.

During treatment, grade 3 or higher adverse events occurred in 16% of the bepirovirsen groups versus 3% of the placebo groups, with alanine aminotransferase elevations being the most common severe event. Injection-site reactions were also frequent, at 53% of the bepirovirsen groups and 14% of the placebo groups.

Adverse events that led to permanent treatment discontinuation occurred in 3% of the patients in the bepirovirsen groups.

Future priorities and transformational treatment

The authors noted several study limitations, including relatively small subgroup populations and limited representation of some racial and ethnic groups, which may affect generalisability. Central stratification during randomisation may also have contributed to differences in baseline HBsAg levels between countries.

Assessment of long-term durability remains ongoing and will continue in the B-Sure follow-up study, they added.

They also suggested that sequential or combination approaches incorporating bepirovirsen with other HBV-targeted therapies, including small interfering RNA agents, PAPD5/PAPD7 inhibitors, immunotherapies or pegylated interferon, may further improve functional cure rates.

Broader implementation of quantitative HBsAg testing was highlighted as important for identifying suitable candidates in clinical practice.

Vanessa Hebditch, director of communications and policy at the British Liver Trust, said the findings were an ‘encouraging step’ towards therapies that could fundamentally change the course of the disease.

She added: ‘Patients with hepatitis B have been waiting decades for treatments that do more than keep the virus under control.

‘With more than 268,000 people in the UK estimated to be living with hepatitis B, continued investment in better treatments, alongside improved testing and diagnosis, remains vital.’

In January, when the preliminary results of these phase 3 trials were first announced, Tony Wood, chief scientific officer at GSK, said: ‘Bepirovirsen has the potential to transform treatment goals for people living with chronic hepatitis B by achieving significant functional cure rates – a first for the disease.’

He added that chronic hepatitis B affects more than 240 million people and leads to approximately 56% of liver cancer cases worldwide. A 2025 study found that HBsAg loss is associated with an 89% reduction in risk of liver cancer and a 62% reduction in risk of all-cause mortality.

Earlier this year, data from the UK Health Security Agency revealed significant progress is being made towards eliminating hepatitis C as cases of chronic hepatitis C have fallen 61% in the last decade.

Reference
Hou J et al. Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection. N Engl J Med 2026; May 28: doi: 10.1056/NEJMoa2515131.