A 24-week course of bepirovirsen enabled about one in five patients with chronic hepatitis B virus (HBV) infection to achieve a sustained functional cure after stopping long-term antiviral therapy, according to two identical phase 3 trials. No patients in the placebo group met the primary endpoint, providing phase 3 evidence that a finite treatment course can produce durable hepatitis B surface antigen (HBsAg) loss in some patients.
The findings, published in the New England Journal of Medicine, came from the global B-Well 1 and B-Well 2 trials, which evaluated bepirovirsen, an antisense oligonucleotide designed to block HBV messenger RNA. By reducing viral transcripts and HBsAg, the drug aims to achieve a functional cure, defined as sustained loss of HBsAg and HBV DNA levels below the lower limit of quantification for at least 24 weeks after all treatment has stopped.
Current nucleoside or nucleotide analogue therapy effectively suppresses HBV replication but rarely leads to loss of hepatitis B surface antigen, leaving most patients on lifelong treatment. A finite therapy that achieves durable viral control could offer some patients the opportunity to stop chronic antiviral therapy.
The investigators conducted two identical, randomized, double-blind, placebo-controlled trials at centers in 29 countries between December 2022 and May 2024. The studies enrolled 1,838 adults with chronic HBV infection without cirrhosis who had been taking stable nucleoside or nucleotide analogue therapy for at least six months. Eligible patients had hepatitis B surface antigen levels of 100 to 3,000 IU/mL, suppressed HBV DNA, and alanine aminotransferase (ALT) levels no more than twice the upper limit of normal. Most were hepatitis B e antigen (HBeAg)-negative at baseline.
Patients were randomly assigned in a 2:1 ratio to receive weekly subcutaneous injections of bepirovirsen 300 mg or placebo for 24 weeks while continuing their background antiviral therapy. Those who maintained HBsAg loss and undetectable HBV DNA through week 46 stopped antiviral therapy at week 48 and were evaluated 24 weeks later for the primary endpoint at week 72.
The primary endpoint was met in both trials. In B-Well 1, 20% of patients treated with bepirovirsen achieved a functional cure, compared with none of those who received placebo. Results were nearly identical in B-Well 2, where 19% of patients in the bepirovirsen group achieved a functional cure, while none in the placebo group did.
About one-quarter of patients treated with bepirovirsen met the criteria to stop background antiviral therapy at week 48, while none in the placebo group did. Among those who discontinued treatment, most maintained viral suppression through week 72. Overall, 23% of patients treated with bepirovirsen maintained HBV DNA levels below the lower limit of quantification after stopping antiviral therapy in both trials, compared with none who received placebo. Only 2% experienced low-level HBV DNA recurrence after treatment was discontinued, and none developed virologic or clinical relapse during follow-up.
Treatment responses were greatest among patients with lower baseline HBsAg levels. Among those with baseline HBsAg levels of 1,000 IU/mL or less, 25% in B-Well 1 and 28% in B-Well 2 achieved a functional cure. By comparison, functional cure rates were 10% and 5%, respectively, among patients with baseline HBsAg levels above 1,000 IU/mL. Treatment effects were otherwise generally consistent across prespecified subgroups.
Exploratory analyses also suggested recovery of immune function. Among patients who achieved a functional cure and did not have hepatitis B surface antibodies at baseline, about two-thirds developed protective antibody responses by week 72. Among the small subgroup of HBeAg-positive patients, about one-quarter lost HBeAg after treatment, although functional cure remained less common in this group.
Safety findings were similar across the two trials. During the 72-week study period, adverse events occurred in 91% of patients treated with bepirovirsen and 73% of those who received placebo, while serious adverse events occurred in 7% and 4%, respectively. During the 24-week treatment period, injection-site reactions were the most common adverse event, affecting 53% of patients receiving bepirovirsen vs 14% of those receiving placebo. Most reactions were mild and occurred during the first month of treatment.
During the treatment period, grade 3 or higher adverse events occurred in 16% of patients treated with bepirovirsen, compared with 3% of those who received placebo. ALT elevations were the most common severe adverse event, occurring in 6% of treated patients. Investigators noted that these temporary ALT increases occurred alongside declines in HBsAg and have previously been linked to treatment activity. Platelet counts and estimated glomerular filtration rate decreased during treatment but returned toward baseline after therapy ended. Permanent discontinuation of bepirovirsen occurred in 3% of treated patients. No patients met criteria for drug-induced liver injury, and no treatment-related deaths were reported.
The investigators acknowledged several limitations. Some subgroup analyses included few patients, particularly racial and ethnic minority groups and patients who were HBeAg-positive, limiting the precision of those findings. In addition, because enrollment was limited to patients with HBsAg levels of 3,000 IU/mL or less, the results may not apply to all patients with chronic HBV infection. The authors also noted that wider use of quantitative HBsAg testing will be needed to identify patients most likely to benefit from bepirovirsen in routine clinical practice.
For practicing hepatologists and gastroenterologists, the findings suggest that a 24-week course of bepirovirsen could offer selected patients with well-controlled chronic hepatitis B an opportunity to stop lifelong antiviral therapy while maintaining viral suppression. “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.
The study was funded by GSK, which designed, monitored, and analyzed the trials and provided medical writing support. Multiple authors are GSK employees, and additional author disclosures are available with the published article.
Expert Insight
GI & Hepatology News asked Tatyana Kushner, MD, MSCE, associate professor of medicine and director of outcomes clinical research in the division of gastroenterology & hepatology at Weill Cornell Medicine, New York, to comment on the findings.
What do you see as the main takeaway from this study?
Dr. Kushner: This is a landmark study for the hepatitis B field. Current treatments are highly effective at suppressing viral replication, but they rarely achieve loss of HBsAg, which is considered a functional cure. This is the first Phase 3 trial to demonstrate positive results in achieving functional cure in people living with chronic hepatitis B. These findings represent an important step toward a future where treatments can do more than control the virus — they may ultimately offer the possibility of curing hepatitis B.
How might the findings influence clinical practice?
Dr. Kushner: These results demonstrate that a functional cure is achievable for a subset of people living with chronic hepatitis B. If these findings lead to the approval of bepirovirsen, we could, for the first time, have a finite treatment for hepatitis B that offers the potential for functional cure, allowing some patients to discontinue lifelong antiviral therapy.
What are the next steps for this research?
Dr. Kushner: Although the Phase III B-Well trial demonstrated that functional cure is achievable in approximately 19% of patients with HBsAg levels ≤3,000 IU/mL and 28% of those with HBsAg levels ≤1,000 IU/mL, several important questions remain. First, we need a better understanding of which patients are most likely to respond to treatment and, conversely, which patients are unlikely to benefit so that therapy can be appropriately individualized and unnecessary treatment avoided. Second, longer-term follow-up is needed to determine whether functional cure is durable beyond the 96-week study period. Safety will also be an important consideration. In the trial, approximately 89% of participants experienced an adverse event, with 16% experiencing severe adverse events. The most commonly reported adverse events included elevations in liver enzymes, thrombocytopenia, and renal dysfunction. If approved for clinical use, we will need to better understand how these safety findings translate into real-world practice and what type of monitoring will be required. Finally, additional research is needed to develop effective treatment strategies for patients with baseline HBsAg levels ≥3,000 IU/mL, who were less likely to achieve functional cure with this regimen.
What message would you like to leave readers with about this work?
Dr. Kushner: This represents a very exciting advance in the treatment of chronic hepatitis B. With the anticipated approval of bepirovirsen, clinicians should begin discussing this potential future treatment option with appropriate patients. An important next step will be incorporating quantitative HBsAg testing into routine clinical practice, as this has not traditionally been performed for most patients but will likely play a key role in identifying those most likely to benefit from therapy.
Dr. Kushner disclosed that she has received research support from Gilead and Mirum and that she has served as an advisor to Gilead, Mirum, GSK and VIR.