Bepirovirsen Acts as a Functional Cure in Phase 3 Trials

A 24-week course of bepirovirsen achieved functional cure rates in chronic hepatitis B (CHB) of approximately 20% across 2 replicate phase 3 trials at rates that dwarfed placebo and that no currently approved therapy routinely delivers. The full dataset is now published in the New England Journal of Medicine as multiple regulatory agencies, including the FDA, review the data.^1,2

The results of the B-Well 1 (NCT05630807) and B-Well 2 (NCT05630820) trials were simultaneously presented at the European Association for the Study of the Liver (EASL) Congress.³

What the Full Phase 3 Dataset Reveals

The B-Well 1 and B-Well 2 trials enrolled 1834 adults with noncirrhotic chronic hepatitis B infection who were receiving stable nucleoside or nucleotide analogue (NA) therapy and had a hepatitis B surface antigen (HBsAg) level between 100 and 3000 IU/mL. Patients were randomly assigned in a 2:1 fashion to receive subcutaneous bepirovirsen at 300 mg weekly or placebo for 24 weeks. Eligible patients discontinued NA therapy at week 48.¹

A functional cure for hepatitis B is defined as virus DNA below the lower limit of quantification (LLOQ) and undetectable HBsAg for at least 24 weeks after stopping all treatment, and it was achieved in 20% of patients treated with bepirovirsen in B-Well 1 (127 of 650) and 19% in B-Well 2 (106 of 570), compared with zero patients in either placebo group (P < .001 for both). In patients with a lower baseline HBsAg of 1000 IU/mL or less—a subgroup representing roughly 45% of diagnosed CHB cases globally—functional cure rates rose to 25% and 28%, respectively.^1,2

Among patients who were eligible for and discontinued NA therapy, a sustained hepatitis B virus DNA level below the LLOQ at week 72 was observed in 23% of bepirovirsen recipients in each trial compared with none in the placebo groups.¹ This end point signals durable viral control off treatment without requiring the more stringent HBsAg clearance that defines a functional cure. In addition, at 1 year after the end of treatment, 49% of bepirovirsen recipients achieved a quantitative HBsAg of 100 IU/mL or less.

Why HBsAg Loss Matters Beyond Virology

The clinical significance of achieving a functional cure extends well beyond viral suppression. HBsAg loss has been associated with an 89% reduction in the risk of hepatocellular carcinoma and a 62% reduction in all-cause mortality.⁴

Current standard-of-care NA therapy effectively suppresses viral replication but rarely clears HBsAg. The functional cure rates are typically below 1%, meaning most patients require indefinite treatment with associated costs, adherence challenges, and the persistent risk of virologic breakthrough.¹

Safety Profile and Clinical Monitoring Implications

The full publication provides a more granular look at tolerability than prior reports. Adverse events (AEs) of any grade were reported in 91% of bepirovirsen recipients by week 72, compared with 73% of placebo recipients, and serious AEs occurred in 7% and 4%, respectively. During the 24-week treatment period, injection-site reactions were the most common AE of special interest, affecting 53% of bepirovirsen patients versus 14% in the placebo group; the majority were mild, and none were classified as serious.

Grade 3 or higher AEs occurred in 16% of bepirovirsen recipients during the treatment period versus 3% of placebo recipients, with elevations in alanine aminotransferase (ALT) being the most common, occurring in 6% of patients. However, transient ALT elevations, which occurred primarily between weeks 5 and 10 in parallel with HBsAg declines, appear to reflect an immune-mediated therapeutic response rather than drug-induced liver injury, according to the researchers. No patients met formal criteria for drug-induced liver injury.

Decreases in platelet count and estimated glomerular filtration rate (eGFR) were observed during treatment, but both measures returned to near-baseline levels by week 72 in most patients. Few events resulted in permanent discontinuation of treatment, and the authors recommended utilizing regular monitoring for laboratory abnormalities or temporarily pausing treatment to mitigate the development of AEs.

“The adoption of recommended monitoring and dose-modification criteria in clinical practice will be paramount to supporting the patient in receiving optimal benefit of treatment and ensuring that the development of serious clinical consequences is kept to a minimum,” they wrote.¹

Regulatory Timeline and Global Access Landscape

Bepirovirsen is currently under priority review by the FDA with both Breakthrough Therapy and Fast Track designations.⁵ Regulatory reviews are also underway in Europe, Japan (with SENKU designation), and China (with Breakthrough Therapy and Priority Review designation). GSK anticipates the first regulatory decisions in the third quarter of 2026.²

The authors acknowledged limitations that are relevant to the drug's eventual real-world reach. Subgroup analyses were constrained by relatively small numbers of Black and Hispanic or Latino patients, which may limit generalizability for those populations. The investigators also noted that broader implementation of quantitative HBsAg testing will be essential for identifying eligible patients in clinical practice. Assessment of long-term response durability is ongoing in the B-Sure trial (NCT04954859).

“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 authors concluded in the study.

References

1. Hou J, Lim SG, Buti M, et al. Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection. N Engl J Med. Published online May 28, 2026. doi:10.1056/NEJMoa2515131
2. GSK. Bepirovirsen achieves unprecedented functional cure rates with potential to redefine treatment for chronic hepatitis B. Press release. May 28, 2026. Accessed May 29, 2026. https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/
3. Steinzor P. Bepirovirsen achieves clinically meaningful functional cure rates in chronic hepatitis B. AJMC^®. May 28, 2026. Accessed May 28, 2026. https://www.ajmc.com/view/bepirovirsen-achieves-clinically-meaningful-functional-cure-rates-in-chronic-hepatitis-b
4. Drysdale M, Chang R, Song R, et al. Association of hepatitis B surface antigen loss with clinical outcomes among patients with chronic hepatitis B infection: a retrospective cohort study in the United States. Z Gastroenterol. 2025;63(08):e48. doi:10.1055/s-0045-1810830
5. Joszt L. Bepirovirsen for chronic hepatitis B receives breakthrough therapy designation, priority review. AJMC. May 5, 2026. Accessed May 28, 2026. https://www.ajmc.com/view/bepirovirsen-for-chronic-hepatitis-b-receives-breakthrough-therapy-designation-priority-review