Two replicate phase 3 randomized controlled trials involving patients with chronic hepatitis B virus (HBV) infection demonstrate a functional cure after the discontinuation of conventional long-term antiviral therapy in about 20% of patients given the drug bepirovirsen.

For the double-blind trials, published today in the New England Journal of Medicine, researchers from the international B-Well Study Group, including scientists from drug co-developer GSK, randomly assigned 1,838 adults with noncirrhotic chronic HBV infection to receive subcutaneous bepirovirsen (300-milligrams [mL] weekly injections) or a placebo for 24 weeks. 

Recruitment took place from December 2022 to May 2025 in 29 countries in Europe, the Asia-Pacific region, and the Americas.

A ‘functional cure’

All patients were receiving long-term nucleoside or nucleotide analogue (NA) oral therapy and had a low hepatitis B surface antigen (HBsAg) concentration. Patients who had undetectable HBsAg and unmeasurable HBV DNA from 24 to 46 weeks stopped NA treatment in week 48. 

Currently, chronic HBV is treated with NA therapy and pegylated interferon injections, which both suppress HBV replication and lower the risk of cirrhosis and liver cancer but rarely offer a cure or eliminate the risk of liver cancer. Interferon is also tied to multiple adverse effects.

In contrast, bepirovirsen can achieve a functional cure—when the virus becomes undetectable without continuous therapy—by breaking down HBV RNA, inhibiting viral replication, and priming the immune system, the study authors noted.

“Chronic hepatitis B virus (HBV) infection is a serious global health issue affecting 240 million people worldwide and causing over a million deaths annually,” they wrote. “Persons with chronic HBV infection often have a reduced quality of life and face stigma and discrimination.” 

16% of drug recipients had severe adverse events

The proportion of patients with a functional cure at week 72 was significantly higher in the bepirovirsen group than among placebo recipients in both in the B-Well 1 trial (127 of 650 patients [20%] vs 0 of 328) and the B-Well 2 trial (106 of 570 patients [19%] vs 0 of 286).

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

The percentage of bepirovirsen recipients who achieved a functional cure was higher among those with a lower HBsAg level (1,000 international units per mL [IU/mL] or less at baseline (with cures in 25% in B-Well 1 and 28% in B-Well 2) than among those with an HBsAg concentration of 1,000 to 3,000 IU/mL (with cures in 10% and 5%, respectively). 

In both trials, 24% of patients in each bepirovirsen group met the criteria for stopping NA therapy at week 48, compared with no placebo recipients. Of the 62 patients who stopped NA therapy but did not achieve a functional cure, five had quantifiable HBV DNA at week 72, but none relapsed clinically. 

In a pooled analysis at 72 weeks, adverse events were reported in 91% of bepirovirsen recipients and 73% of the placebo groups, and serious adverse events (SAEs) in 7% and 4%, respectively. 

In total, 16% of bepirovirsen recipients had adverse events of grade 3 or higher (severe or medically significant, but not immediately life-threatening), compared with 3% of the placebo group. The most common grade 3 adverse event was an increase in alanine aminotransferase (ALT), indicating liver impairment, with bepirovirsen (6% of patients). Adverse events led to the discontinuation of treatment in 3% of the bepirovirsen group.

“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,” the researchers wrote. 

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

‘An attractive option for selected patients’ 

In an editorial in the same journal, Anna Lok, MD, of the University of Michigan at Ann Arbor, said the trials’ results are “impressive but cannot be generalized to patient groups that were not included in the trials—those with cirrhosis, coinfection with human immunodeficiency virus [HIV], or an HBsAg level of more than 3000 IU per milliliter.