Bepirovirsen Phase 3 Results Offer Potential Cure for Chronic Hepatitis B

The investigational agent, bepirovirsen, evidenced potential to shift treatment of chronic hepatitis B virus (HBV) infection from suppressing the virus to eradicating it, in two phase 3 trials¹ in which 20 percent of patients attained functional cure.

The agent is an antisense oligonucleotide that disrupts production of HBV antigen and proteins by binding with, and degrading the virus RNA. The two trials (B-Well 1 and 2) are designated as pivotal for the FDA assessment of bepirovirsen under the granted Fast Track² and Breakthrough Designation.³The sponsor, GSK, has also submitted applications to agencies in Europe, Japan and China, and is anticipating the first regulatory decision in the third quarter of 2026.⁴

The criteria for functional cure in the two trials was an HBV DNA level below the lower limit of quantification (LLOQ) at <20 IU/ml or not detected, and hepatitis B surface antigen (HBsAg), below LLOQ at <0.05 IU/ml or not detected, for at least 24 weeks after completing treatment.

In the B-Well 1 and 2 trials, functional cure was achieved in 127 of 650 patients (20%) and in 196 of 570 patients (19%), respectively, at week 72, after 24 weeks of weekly treatment with bepirovirsen, compared to none in the placebo groups. There were higher functional cure rates among subgroups with lower baseline HBsAg levels (<1000 IU/ml), attained in 25% and 28%, in B-Well 1 and 2 trials, respectively.Patients with no detectable virus at week 48, an alanine aminotransferase (ALT) level of no more than twice the upper limit of normal, and negative for HBAg at week 46 were eligible to discontinue their nucleoside or nucleotide analog (NA) treatment.

Lead author Jinlin Hou, MD, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China, and colleagues note that the functional cure not only reflects an absence of detectable virus, but also "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."

In an editorial⁵ accompanying the report of the two trials, Anna Lok, MD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, characterizes the results of the trials as "remarkable;" She suggests that the approach could, for some patients, supplant NA treatment; which, she notes, suppresses the virus rather than eliminates it or the risk of hepatocellular carcinoma.

"The B-Well trials represent a major step toward a functional cure for HBV infection, and bepirovirsen is an attractive option for selected patients," Lok remarked.

The phase 3 B-Well 1 and 2 trials were conducted in 29 countries across Europe, the Asia-Pacific region, and the Americas and were identical in their double-blind, placebo-controlled design. Patients were recruited between December 2022 to May 2025 from among adults with documented chronic HBV infection who had been receiving stable NA therapy for at least 6 months.

All patients had an HbsAG level ranging form 100 to 3000 IU/ml, and HBV DNA level of less than 90 IU/ml, and ALT of no more than twice the upper-limit of normal. Patients were excluded on several criteria, including receipt of interferon-containing therapy within 12 months, and a history of, or suspected cirrhosis.

Patients were randomized on 2:1 ratio to add bepirovirsen (n=1,224) or placebo (n=614) to their NA treatment.Bepirovrsen 300mg was administered in two injections weekly for 24 weeks, after loading doses on days 4 and 11.Treatment response was assessed at week 72, 24 weeks after discontinuing all other HBV treatments in eligible patients.The investigators plan to assess durability of response at week 96, and to publish those results in a subsequent report.

"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," Hou and colleagues declare.

While Lok agrees that the overall results are "impressive," she also points out that the results cannot be generalized to patient groups not included in the trials, such as those with cirrhosis, co-infection with human immunodeficiency virus, or an HbsAg level of more than 3000 IU/ml.She looks forward to the planned longer follow-up, and is hopeful that therapies will be applicable for the broader population with chronic HBV.

"Ultimately, curative therapies must be simple, safe, accessible, and affordable to benefit the 240 million persons worldwide who are living with chronic HBV infection," Lok remarked.

References

1. Hou J, Lim S-G, Buti M, et al. Phase 3 results of bepirovirsen treatment for chronic hepatitis B virus infection. N Engl J Med. 2026, online May 28. doi:10.1056/NEJM0oa2515131.

2. GSK press release. GSK receives US FDA Fast Track designation for bepirovirsen in chronic hepatitis B. 2024, February 12. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-us-fda-fast-track-designation-for-bepirovirsen-in-chronic-hepatitis-b.

3. GSK press release. Bepirovirsen accepted for regulatory review and granted Breakthrough Therapy Designation by the US FDA. 2026, April 27. https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-accepted-for-priority-review-and-granted-breakthrough-therapy-designation-by-the-us-fda/.

4. GSK press release.Bepirovirsen achieves unprecedented functional cure rates with potential to redefine treatment for chronic hepatitis B. 2026, May 28. https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/.

5. Lok AS. A major step toward a cure for hepatitis B infection. N Engl J Med. 2026, online May 28. doi:10.1056/NEJMe2605575.