- In two phase 3 clinical trials, roughly one in five adults with chronic hepatitis B achieved sustained loss of hepatitis B surface antigen (HBsAg) and undetectable hepatitis B viral DNA after completing a finite course of bepirovirsen treatment.
- Bepirovirsen reduces HBsAg production, aiming to restore the immune system’s ability to control the infection rather than simply suppressing viral replication.
- Participants with lower baseline HBsAg levels experienced higher functional cure rates, suggesting patient selection may play an important role in treatment success.
- While the results represent promising steps toward a functional cure for chronic hepatitis B, further research is necessary to improve response rates, evaluate long-term durability, and determine how the therapy performs in broader patient populations.
Current first-line treatment will typically involve antiviral therapy to suppress viral replication. However, these drugs rarely eliminate hepatitis B surface antigen (HBsAg), which is a key marker of persistent infection. Thus, many individuals
As a result, researchers have increasingly focused on therapies capable of achieving a functional cure, defined as sustained loss of HBsAg and undetectable HBV DNA after treatment has ended.
Now, results from two large phase 3 clinical trials indicate that the investigational drug bepirovirsen could mark a significant step toward a functional cure for chronic hepatitis B, offering hope beyond lifelong antiviral treatment for some patients.
The findings, published in the New England Journal of Medicine, showed that approximately 20% of eligible patients achieved a sustained functional cure after completing a finite course of treatment, an outcome not observed in those receiving a placebo.
The phase 3 B-Well 1 and B-Well 2 studies enrolled more than 1,800 adults with non-cirrhotic chronic hepatitis B across 29 countries, who had been receiving nucleotide analogue (NA) treatment for at least 6 months between 2022 and 2025.
Participants were randomly assigned 2:1 to receive either 300 milligrams (mg) subcutaneous injections of bepirovirsen or a placebo weekly for 24 weeks, in addition to background NA therapy, followed by an additional 24 weeks of NA treatment.
All participants had an HBsAg level of more than 100 to 3000 international units per milliliter (IU/ml). Eligible individuals discontinued NA therapy at 48 weeks. The primary outcome was a functional cure at week 72, defined as maintaining undetectable hepatitis B viral DNA and loss of HBsAg for at least 24 weeks after stopping treatment.
After 72 weeks of follow-up, researchers found that:
- around 20% of patients receiving bepirovirsen achieved a functional cure
- no patients receiving placebo met the functional cure endpoint
- patients with lower baseline HBsAg levels appeared even more likely to respond, with functional cure rates reaching approximately 26% in some subgroups.
Speaking to Medical News Today, study author Seng-Gee Lim, MD, Director of Hepatology at the National University Health System, Singapore, emphasized the importance of the trial findings:
“Functional cure rate of 19% in Hepatitis B patients with HBsAg level [under] 3,000 IU/ml and 26% in those with HBsAg [under] 1,000 IU/ml. This finding provides meaningful cure rates for the first time for hepatitis B patients”
“These findings are encouraging because they show researchers are making real progress towards treatments that go beyond simply controlling hepatitis B,” Opel Baker, MBChB, DipOccMed, MRCGP, general practitioner at the Mayfield Clinic Brighton and Hove, in the United Kinhdom, who was not involved in the study, explained to MNT.
“While the treatment won’t work for everyone, every successful clinical trial helps us understand the disease better and brings us closer to more effective, personalised therapies. It’s an exciting step forward in a field that has seen relatively little therapeutic innovation for many years,” said Baker.
Bepirovirsen belongs to a class of medicines called antisense oligonucleotides (ASOs). Unlike existing antiviral therapies, which primarily block viral replication, antisense therapies target the virus’ messenger RNA.
This reduces production of viral proteins, including HBsAg, which researchers believe may play an important role in suppressing the body’s immune response against the hepatitis B virus.
Lowering HBsAg levels may allow the immune system to regain some of its ability to recognize and control infected liver cells.
Earlier clinical studies demonstrated that bepirovirsen could substantially reduce HBsAg levels, although durable functional cures remained relatively uncommon.
Experts have long considered a functional cure one of the most important goals in hepatitis B research. Researchers hoped larger phase 3 studies would determine whether these responses could be achieved more consistently.
While current treatments can suppress viral replication, they rarely clear HBsAg. This means that people remain at risk of viral reactivation if treatment is stopped. These findings suggest that a finite treatment course could allow some individuals to discontinue therapy while maintaining viral control.
“A functional cure would be a major breakthrough for people living with chronic hepatitis B,” Baker highlighted to MNT.
“Although current antiviral treatments are very effective at suppressing the virus, they rarely remove the need for long-term monitoring or treatment. A functional cure could reduce the risk of serious complications such as cirrhosis and liver cancer, lessen the psychological burden of living with a chronic infection and improve patients’ quality of life.”
– Opel Baker, MBChB, DipOccMed, MRCGP
Similarly, Lim also highlighted the importance of achieving a functional cure on liver and psychological health.
“Clinical studies and meta analyses show that loss of HBsAg as seen in functional cure is associated with even more benefits than just viral control with suppressing the virus — more significant reductions in liver cancer, liver failure and mortality,” the researcher told us.
“Moreover, compliance with long term antiviral therapy is suboptimal, while functional cure means patients are off all therapy. Functional cure has also important patient related benefits such as loss of stigmatisation and improvement in psychological health,” he added.
While encouraging, the results do not represent a functional cure for all people living with chronic hepatitis B.
The trials enrolled a specific group of patients, including those without cirrhosis and with relatively low HBsAg levels. As such, it remains unclear whether similar outcomes would be achieved in broader populations.
Additionally, roughly four out of five participants did not achieve a functional cure, highlighting the continued need for improved therapies and combination treatment approaches. Bepirovirsen was also associated with more adverse events than placebo, although many were mild to moderate.
Longer-term follow-up will also be necessary to determine how durable these responses remain over many years and whether a functional cure translates into lower rates of liver cancer and other complications.
The researchers plan further investigations to determine whether combining bepirovirsen with immune-based treatments, including therapeutic vaccines and other novel agents, could further improve cure rates.
Although additional research and regulatory review remain ahead, the latest results suggest a functional cure for chronic hepatitis B may be moving closer to routine clinical practice.
“It’s important to remember that research is moving fast, and there is a genuine reason for optimism,” Baker noted.
“Although these treatments are still being evaluated, advances like this offer hope that future therapies may provide better long-term outcomes. In the meantime, patients should continue taking any prescribed medication, attend regular monitoring appointments and speak to their healthcare team before making any changes to their treatment,” he added
According to Lim, “bepirovirsen is the first step towards functional cure, and this is hope for those living with hepatitis B but better therapies will lead to higher cure rates in the future.”
