Research Summary

Bepirovirsen Improved Functional Cure vs Placebo in Phase 3 Chronic Hepatitis B Trials

Anthony Calabro, MA

Key Highlights

  • Bepirovirsen 300 mg weekly for 24 weeks achieved a functional cure at week 72 in 20% of patients in B-Well 1 and 19% in B-Well 2, compared with 0% in both placebo groups.
  • Among patients with baseline HBsAg ≤1000 IU/mL, functional cure occurred in 25% and 28% of bepirovirsen-treated patients in B-Well 1 and B-Well 2, respectively.
  • Adverse events through week 72 were reported in 91% of patients receiving bepirovirsen and 73% receiving placebo.
  • In an accompanying editorial, Anna S. Lok, MD, wrote that the B-Well trials “represent a major step toward a functional cure for HBV infection.”

Bepirovirsen was associated with significantly higher functional cure rates than placebo in adults with noncirrhotic chronic hepatitis B virus (HBV) infection receiving stable nucleoside or nucleotide analog (NA) therapy, according to results from 2 phase 3 trials published in The New England Journal of Medicine.1

The replicate B-Well 1 and B-Well 2 trials evaluated bepirovirsen, an antisense oligonucleotide targeting HBV transcripts, as a finite therapy for patients with virologically suppressed chronic HBV infection. Functional cure was defined as HBV DNA below the lower limit of quantification (LLOQ) and HBsAg loss for at least 24 weeks after fixed-duration therapy.1

Researchers conducted 2 replicate, double-blind, placebo-controlled trials in 29 countries across Europe, the Asia-Pacific region, and the Americas. Adults with documented chronic HBV infection were randomly assigned in a 2:1 ratio to receive subcutaneous bepirovirsen 300 mg weekly or placebo for 24 weeks while receiving background NA therapy; eligible patients discontinued NA therapy at week 48.1

The primary outcome was functional cure at week 72. Eligible participants had received stable NA therapy for at least 6 months before screening and had HBsAg levels >100 to 3,000 IU/mL, HBV DNA <90 IU/mL, and alanine aminotransferase (ALT) levels no more than 2 times the upper limit of normal. Patients with suspected or confirmed cirrhosis, selected coinfections, recent interferon-containing therapy, or certain autoimmune or vascular conditions were excluded.1

Study Findings

In B-Well 1, functional cure at week 72 occurred in 127 of 650 patients (20%) receiving bepirovirsen and in none of the 328 patients receiving placebo. In B-Well 2, functional cure occurred in 106 of 570 patients (19%) receiving bepirovirsen and in none of the 286 patients receiving placebo. The common risk difference was 17.5 percentage points in B-Well 1 and 13.3 percentage points in B-Well 2, with P < .001 for both comparisons.1

Among patients with baseline HBsAg ≤1000 IU/mL, functional cure occurred in 25% of bepirovirsen-treated patients in B-Well 1 and 28% in B-Well 2, compared with 0% in both placebo groups. In the higher HBsAg stratum, functional cure occurred in 10% and 5% of bepirovirsen-treated patients in B-Well 1 and B-Well 2, respectively. At week 48, NA therapy was discontinued in 24% of bepirovirsen-treated patients in each trial and in none of the placebo-treated patients.

Safety findings were generally consistent across the 2 trials. Through week 72, adverse events were reported in 91% of patients in the bepirovirsen groups and 73% in the placebo groups; serious adverse events occurred in 7% and 4%, respectively. During the 24-week treatment period, grade 3 or higher adverse events occurred in 16% of patients receiving bepirovirsen and 3% receiving placebo, with ALT increases being the most common grade 3 event in the bepirovirsen group.1

Clinical Implications

According to the study authors, the findings support the efficacy of bepirovirsen as a finite 24-week therapy to achieve functional cure and demonstrate added benefit over continued NA therapy as standard care in these patients. The authors also stated that broader implementation of quantitative HBsAg testing will be essential for identifying eligible patients in clinical practice.

In an accompanying editorial, Anna S. Lok MD wrote that the B-Well trials “represent a major step toward a functional cure for HBV infection,” while noting that bepirovirsen is an attractive option for selected patients.2 Dr Lok also cautioned that the durability of HBsAg loss requires longer follow-up and that alternative therapies are needed for patients not represented in the trials, including those with cirrhosis or baseline HBsAg levels >3000 IU/mL.2

The authors noted limitations, including relatively small subgroup sizes and small numbers of patients in certain racial and ethnic groups, which may limit generalizability for some groups. They also noted that central stratification during randomization may have resulted in differing average baseline HBsAg levels across countries.1

Expert Commentary

“(T)he results of the two B-Well trials with duplicate design now presented by Hou and colleagues in the Journal are remarkable,” Dr. Lok wrote in her editorial.2 “Not only did these phase 3 trials aim at a cure for HBV infection, but they also had encouraging results that involved adding only one investigational agent—bepirovirsen, an antisense oligonucleotide—to NA therapy.
 

References

  1. Hou J, Lim SG, Buti M, et al; B-Well Study Group. Phase 3 results of bepirovirsen treatment for chronic hepatitis B virus infection. N Engl J Med. 2026;394:2395-2406. doi:10.1056/NEJMoa2515131I
  2. Lok AS. A major step toward a cure for hepatitis B infection. N Engl J Med. 2026;394:2471-2472. doi:10.1056/NEJMe2605575