Can Hepatitis B Finally Be Cured?

How an antisense drug moved from an experimental molecule to successful Phase 3 trials.

⏱ In 30 Seconds

✓ Bepirovirsen is an antisense oligonucleotide designed to target hepatitis B virus (HBV) RNA.
✓ In two Phase 3 trials, functional cure was achieved in 20% and 19% of treated participants, compared with 0% in placebo groups.
✓ Bepirovirsen is now under regulatory review, although questions remain about how many patients will benefit and its safety profile.

Chronic hepatitis B can be effectively controlled with antiviral drugs such as tenofovir and entecavir, which suppress HBV replication and substantially reduce the risk of liver disease. However, these treatments rarely produce a functional cure, and many patients require long-term therapy.

Bepirovirsen is an antisense oligonucleotide that targets HBV RNA, with the aim of reducing both viral replication and the production of viral proteins.

In 2026, two large Phase 3 trials reported functional cure in 20% and 19% of participants treated with bepirovirsen, compared with 0% in the placebo groups.

These results caught my attention because functional cure has remained difficult to achieve in chronic hepatitis B. At the same time, a response in around one in five patients leaves an equally important question: why do some patients respond while most do not?

Why Chronic Hepatitis B Is Difficult to Cure

According to the World Health Organization, around 240 million people were living with chronic HBV infection in 2024, with approximately 1.1 million deaths, mostly from cirrhosis and liver cancer.

Although hepatitis B can be prevented with an effective vaccine, treatment is much more difficult once chronic infection has been established.

Current antiviral drugs can suppress HBV DNA extremely well, but persistent viral templates remain inside infected liver cells. Viral proteins can therefore continue to be produced.

One of the most important is hepatitis B surface antigen, or HBsAg.

Sustained disappearance of HBsAg is uncommon with conventional treatment — and that is one reason chronic hepatitis B has been so difficult to functionally cure.

Targeting HBV RNA with Bepirovirsen

Bepirovirsen is an antisense oligonucleotide (ASO) — a short piece of synthetic nucleic acid designed to recognize a specific RNA sequence.

It binds HBV RNA and recruits RNase H to degrade it.

The Basic Idea

HBV DNA
↓
HBV RNA
↓
Viral proteins

Bepirovirsen interrupts the pathway at the RNA stage

Degradation of HBV RNA can reduce viral replication and the production of viral proteins such as HBsAg.

The drug may also have an immunological effect through TLR8 stimulation, although how much this contributes to its clinical activity remains under investigation.

The Development of Bepirovirsen

During development, the molecule was known by several names:

ISIS 505358 → IONIS-HBVRx → GSK3228836 → bepirovirsen

The molecule emerged from the antisense programme at Ionis Pharmaceuticals and was subsequently developed with GSK.

How Bepirovirsen Reached Phase 3

Clinical trials usually progress through several phases, with each stage answering a different question about a new treatment.

Phase 1 · First testing in people
Phase 1 studies are usually small and focus mainly on safety, dosage and how the drug behaves in the body. Bepirovirsen, then known as ISIS 505358, entered first-in-human testing at this stage.

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Phase 2 · Does the treatment show an effect?
Phase 2 studies test the drug in people with the disease and begin to examine whether the treatment has the intended biological or clinical effect. In an early study of 31 people with chronic hepatitis B, HBsAg levels fell rapidly and the effect increased with higher doses.

↓

Phase 2b · The B-Clear trial
Phase 2b studies generally examine effectiveness and treatment regimens in a larger group of patients. B-Clear was the Phase 2b trial of bepirovirsen in people with chronic hepatitis B. With the 24-week treatment, around 9–10% achieved sustained loss of HBsAg and HBV DNA after treatment ended.

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Phase 3 · Two large trials: B-Well 1 and B-Well 2
Phase 3 trials test a treatment in a much larger group of patients to confirm its benefits and assess its safety. B-Well 1 and B-Well 2 were two separate Phase 3 trials involving more than 1,800 adults with chronic hepatitis B.

Functional cure was achieved in 20% of participants in B-Well 1 and 19% in B-Well 2, compared with 0% in the placebo groups.

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Regulatory review · What happens after Phase 3?
After Phase 3, trial data can be submitted to regulatory authorities, which evaluate the treatment's benefits, risks and manufacturing information before deciding whether it can be approved. Bepirovirsen is now at this stage.

What “Functional Cure” Means in Hepatitis B

The word functional is important. It does not mean that every trace of HBV has been eliminated from the liver.

What is a functional cure?
In chronic hepatitis B, a functional cure means sustained loss of hepatitis B surface antigen (HBsAg) together with continued control of the virus after treatment has ended. HBV may still remain in some liver cells, so this is different from completely eliminating the virus from the body.

In the B-Well trials, functional cure required sustained HBsAg loss together with HBV DNA below the lower limit of quantification after fixed-duration treatment.

Interpreting the Phase 3 Results

The Phase 3 results are significant and certainly promising. But from my perspective, there is still a long way to go. A functional cure rate of around 20% means that only about one in five patients achieved sustained control after treatment ended.

There are also some questions about safety. More severe adverse events were reported more often in participants receiving bepirovirsen than in those receiving placebo, including increases in ALT.

What is ALT?
ALT (alanine aminotransferase) is an enzyme found mainly in the liver. An increase in blood ALT can be a sign of liver-cell injury or inflammation, although the result needs to be interpreted in its clinical context.

For now, I think the results are encouraging, but I would like to see more data before becoming too optimistic about what bepirovirsen could mean for patients with chronic hepatitis B.

HBV, HPV and Cancer Prevention

HBV and HPV illustrate two different strategies for reducing virus-associated cancer risk.

The story of how Jian Zhou helped make the HPV vaccine possible shows how persistent HPV infection can be prevented before it becomes established.

With HBV, millions of people are already living with chronic infection, which can eventually lead to cirrhosis and hepatocellular carcinoma. HBV is one of several viruses known to cause human cancers.

The two approaches can be summarized as:

HPV → prevent persistent infection → prevent cancer
HBV → treat established persistent infection → pursue functional cure

Whether bepirovirsen ultimately reduces liver cancer risk will require long-term follow-up. The Phase 3 trials demonstrated functional cure, not cancer prevention.

What Comes Next for Bepirovirsen

Bepirovirsen is being developed as a fixed-duration treatment intended to produce sustained control after therapy stops.

The Phase 3 results show that this is possible for a proportion of patients, although most participants did not achieve functional cure and important safety and long-term questions remain.

Bepirovirsen is currently under regulatory review.

Phase 3 Clinical Trial

Hou J, Lim SG, Buti M, et al.
Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.
New England Journal of Medicine. 2026;394:2395–2406.

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This article is intended for general educational purposes. Readers seeking a more technical account should consult the original publications and specialist literature linked above.

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