The novel antisense oligonucleotide bepirovirsen has induced functional cure in one-fifth of patients with chronic hepatitis B virus (HBV) infection in the phase 3 B-Well 1 and B-Well 2 trials.
“In these two multicountry phase 3 trials involving patients with virologically suppressed chronic HBV infection during receipt of nucleoside or nucleotide analogue (NA) therapy, significantly more patients who were assigned to receive 24 weeks of bepirovirsen and then stopped all anti-HBV treatment had a functional cure than those who were assigned to receive placebo,” reported first author Dr Jinlin Hou from Nanfang Hospital in Guangzhou, China, and colleagues in their paper.
Functional cure at week 72 was observed in 20 percent of patients in the bepirovirsen arm vs none in the placebo arm in B-Well 1 (risk difference, 17.5 percentage points; p<0.001) and in 19 percent vs 0 percent in the respective treatment arms in B-Well 2 (risk difference, 13.3 percentage points; p<0.001). [N Engl J Med 2026;doi:10.1056/NEJMoa2515131]
When stratified according to the HBsAg levels at baseline, the percentage of patients who had a functional cure with bepirovirsen was 25 percent in B-Well 1 and 28 percent in B-Well 2 among those in the lower HBsAg stratum (≤1,000 IU/mL) and 10 percent and 5 percent, respectively, among those in the higher HBsAg stratum (>1,000 IU/mL).
Treatment goal
“A functional cure, defined as an HBV DNA level below the lower limit of quantification (LLOQ) and hepatitis B surface antigen (HBsAg) loss for at least 24 weeks after finite (fixed-duration) therapy—with or without a positive test for hepatitis B surface antibody—is the treatment goal for patients with chronic HBV infection and the recommended endpoint for new finite HBV therapies,” according to Hou and colleagues.
“In addition to showing the benefits of HBsAg loss, a functional cure 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,” they added.
In B-Well 1 and B-Well 2, 24 percent of bepirovirsen-treated patients discontinued NA therapy at week 48, whereas none of those who received placebo were able to discontinue NA therapy. Following NA therapy discontinuation, 23 percent of patients in the bepirovirsen arms and none in the placebo arms had a sustained HBV DNA level below LLOQ at week 72. HBV DNA replication (<2,000 IU/mL) occurred in 2 percent of bepirovirsen-treated patients, although none of them had virologic or clinical relapse.
“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 said.
Safety profile
In pooled safety analyses, adverse events (AEs) of grade ≥3 occurred in 16 percent of patients in the bepirovirsen arms and in 3 percent of those in the placebo arms during the treatment period (weeks 1–24). Alanine aminotransferase (ALT) elevation was the most common grade ≥3 AE in the bepirovirsen arms, reported in 6 percent of the patients.
“Decreases in mean values for both the platelet count and the estimated glomerular filtration rate (eGFR) were observed during bepirovirsen treatment, with levels returning to near baseline by week 72. No patients met the criteria for drug-induced liver injury,” the authors noted.
In the bepirovirsen arms, AEs required a dose interruption or delay in 16 percent of patients and led to permanent treatment discontinuation in 3 percent. Two bepirovirsen-treated patients died, and these deaths were assessed as being unrelated to treatment.
“The higher incidence of adverse events with bepirovirsen than with placebo was mostly linked to the known class effects of bepirovirsen and other antisense oligonucleotides,” the authors noted. “In most cases, ALT increases did not require treatment modification. Transient ALT increases after bepirovirsen initiation were associated with a reduction in HBsAg levels and are recognized as markers of a therapeutic response to bepirovirsen.”
Hou and colleagues emphasized the importance of adopting the recommended monitoring and dose-modification criteria in clinical practice to ensure that patients receive the optimal treatment benefit and that the development of serious clinical consequences is kept to a minimum.
Major step toward functional cure
“The B-Well trials represent a major step toward a functional cure for HBV infection,” wrote Dr Anna Lok from the University of Michigan, Ann Arbor, Michigan, US, in an accompanying editorial. [N Engl J Med 2026;doi:10.1056/NEJMe2605575]
Lok, however, noted that while the overall results were “impressive,” they could not be generalized to patient groups that were not included in the trials, such as those with cirrhosis, coinfection with human immunodeficiency virus, or an HBsAg level of >3,000 IU/mL. “Even among the patients with an HBsAg level of 1,000–3,000 IU/mL, the percentage who had a functional cure was substantially lower than that among those with the lower HBsAg level.”
Bepirovirsen, according to Lok, is an attractive option for selected patients, although the durability of HBsAg loss has to be confirmed with longer follow-up, and alternative therapies are needed for other patients.
“Ultimately, curative therapies must be simple, safe, accessible, and affordable to benefit the 240 million persons worldwide who are living with chronic HBV infection,” she concluded.
B-Well twin trials
The double-blind, placebo-controlled, phase III B-Well trials were identical in design and conducted in 29 countries across Europe, the Asia–Pacific region, and the Americas. The trials involved 1,838 patients (average age 50 years, 71 percent male, 68 percent Asian) with noncirrhotic chronic HBV infection who had been receiving stable NA therapy for at least 6 months before screening.
The patients were randomly assigned to receive bepirovirsen at a weekly dose of 300 mg (653 in B-Well 1 and 571 in B-Well 2) or placebo (328 in B-Well 1 and 286 in B-Well 2). Treatment was administered subcutaneously for 24 weeks.
At baseline, the patients had an HBsAg level ranging from 100 to 3,000 IU/mL (63 percent had ≤1,000 IU/mL), an HBV DNA level of <90 IU/mL, and an ALT level of no more than two times the upper limit of the normal range. The authors noted that the demographic characteristics were generally representative of chronic HBV-infected patients in clinical practice.
The results of the B-Well trials were presented by co-author Dr Seng-Gee Lim from the National University Health System, Singapore, at the annual EASL meeting. During his presentation, Lim asserted that the data from these trials could “change the landscape of hepatitis B treatment.”