The US Food and Drug Administration (FDA) has approved bepirovirsen (Hibsago) for adults with chronic hepatitis B virus (HBV) infection. Developed by GSK, the antisense oligonucleotide (ASO) is a new treatment that could offer a finite course of therapy capable of sustained viral control without continued antiviral medication in some patients.
The FDA accepted the application with Priority Review and granted Breakthrough Therapy designation in April 2026. The approval is supported by the phase 3 B-Well 1 and B-Well 2 trials. All participants were also receiving background nucleoside or nucleotide analogue treatment.
Patient Eligibility Criteria
Not all patients with chronic hepatitis B can receive bepirovirsen. The FDA approval is specific to adults who meet several criteria. They must have no cirrhosis. Patients must have a history of at least six months of prior nucleos(t)ide analog reverse transcriptase inhibitor (NrtI) therapy. Their HBV DNA levels must be suppressed, and their HBV surface antigen (HBsAg) levels must be at or below 3,000 IU/mL, as measured by an FDA-authorized test.
The drug is administered via subcutaneous injection. The dosing schedule involves 300 mg twice a week for the first two weeks, followed by 300 mg once a week through week 24. Each 300-mg dose requires two separate 150-mg injections.
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How Does Bepirovirsen Work?
Bepirovirsen is designed to reduce HBV activity by targeting viral messenger RNA (mRNA). It works by binding to a specific genetic sequence found in various types of HBV RNA. This action activates a naturally occurring enzyme called RNase H1, which then breaks down the targeted viral RNA. The result is less viral DNA and fewer viral proteins, including HBsAg, being produced.
Importantly, bepirovirsen can target viral RNA from two sources. It can act on RNA produced from HBV DNA that persists within infected liver cells, known as cccDNA. It can also target RNA from HBV DNA that has become integrated into the patient’s own DNA.
Functional Cure Defined
Functional cure is a key goal in hepatitis B treatment. It is defined as sustained control of HBV without the need for medication, rather than the complete elimination of the virus from the body. This is a significant advancement, as current standard antiviral therapies like tenofovir and entecavir effectively suppress viral replication but rarely eliminate HBsAg.
The B-Well 1 and B-Well 2 trials were randomized, double-blind, and placebo-controlled. They enrolled 1,838 adults with non-cirrhotic chronic HBV who were on stable nucleos(t)ide analogue therapy. Eligible patients had baseline HBsAg levels above 100 IU/mL but at or below 3,000 IU/mL, along with HBV DNA below 90 IU/mL and normal liver enzyme levels. The patients were randomized 2:1 to receive either subcutaneous bepirovirsen or a placebo for 24 weeks while continuing their background NA treatment.
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After the initial treatment period, all participants stopped their antiviral therapy at week 48. The primary goal was to achieve functional cure at week 72, defined as sustained HBsAg loss and undetectable HBV DNA for at least 24 weeks after all treatments had ceased. Both trials successfully met this primary endpoint.
The results showed a clear difference between the treatment and placebo groups. In B-Well 1, 127 of the 650 patients (20%) receiving bepirovirsen achieved functional cure. In B-Well 2, 106 of the 570 patients (19%) in the bepirovirsen group reached the same goal. Not a single patient in the placebo groups achieved a functional cure.
Among those with levels of 1,000 IU/mL or less, functional cure rates rose to approximately 25% in B-Well 1 and 28% in B-Well 2.
At week 48, about 24% of the bepirovirsen-treated patients in both trials met laboratory-based criteria for discontinuing their NA therapy. This rate was zero for the placebo groups. Discontinuation rates were even higher in patients with lower baseline HBsAg, reaching 31% and 33% in the two trials, respectively.
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Safety and Side Effects
Across the pooled B-Well trials, adverse events were reported in 91% of patients receiving bepirovirsen, compared to 73% of those receiving a placebo. Serious adverse events occurred in 7% of the bepirovirsen group versus 4% of the placebo group. Injection-site reactions were common, affecting 53% of treated patients, but were typically mild.
One of the most notable laboratory findings was an elevation in alanine aminotransferase (ALT). Grade 3 ALT elevations were reported in about 6% of patients on bepirovirsen. Investigators also observed decreased platelet counts and declining renal function, which could require treatment interruption or discontinuation. No cases of drug-induced liver injury were reported, and there were no treatment-related deaths.
The approved FDA labeling includes boxed warnings for on-treatment hepatic flares and thrombocytopenia, including a potentially life-threatening risk of bleeding. It also warns about worsening renal function and serious inflammatory reactions. The labeling specifies minimum monitoring requirements, including weekly checks for platelets, ALT, and bilirubin through week 12, and regular monitoring of estimated glomerular filtration rate (eGFR).
Early durability data from the trials are encouraging. Among the patients who achieved a functional cure at week 72, 91% maintained their response without any additional treatment through week 96. Longer-term follow-up is still needed to confirm if these responses remain stable over many years and to determine if the treatment reduces the risk of serious long-term complications like cirrhosis and liver cancer.
