Phase 3 Bepirovirsen Trial Shows HBsAg Loss In Chronic Hepatitis B

Key Takeaways

• Week-72 functional cure occurred more often with bepirovirsen than with placebo in both trials.
• Response rates were higher among participants with lower baseline HBsAg concentrations.
• Adverse events, including grade 3 or higher events, were reported more often with bepirovirsen than with placebo.

At week 72, functional cure was observed in about one in five adults receiving bepirovirsen in the phase 3 B-Well trials, while no placebo recipients reached that outcome. The 24-week finite regimen was studied in selected noncirrhotic adults with chronic hepatitis B who were already maintained on long-term nucleos(t)ide analogue therapy. Across the two replicate trials, HBsAg loss and functional cure were seen with active treatment, whereas functional cure was not seen with placebo.

Two replicate phase 3, randomized, double-blind trials enrolled 1,838 adults with noncirrhotic chronic HBV infection across 29 countries. Recruitment ran from December 2022 to May 2025 in Europe, the Asia-Pacific region, and the Americas. All participants were receiving long-term nucleos(t)ide analogue therapy and had low baseline HBsAg concentrations before randomization to bepirovirsen 300 mg weekly by subcutaneous injection or placebo for 24 weeks. The main efficacy assessment was scheduled at week 72 after the finite treatment period.

Week-72 functional cure occurred in B-Well 1 in 127 of 650 patients, or 20%, with bepirovirsen and in 0 of 328 with placebo. In B-Well 2, the corresponding numbers were 106 of 570, or 19%, with bepirovirsen and 0 of 286 with placebo. Among participants with baseline HBsAg concentrations of 1,000 IU/mL or less, cure rates were 25% in B-Well 1 and 28% in B-Well 2. Among those with baseline HBsAg concentrations of 1,000 to 3,000 IU/mL, rates were 10% and 5%, consistent with higher response at lower baseline HBsAg concentrations.

The finite-treatment design included planned cessation of background nucleos(t)ide analogue therapy for some participants at week 48. In each bepirovirsen group, 24% met criteria to stop NA therapy at that point, whereas no placebo recipients did. Among 62 patients who stopped NA therapy without functional cure, five had quantifiable HBV DNA at week 72 and none had clinical relapse. Those post-NA observations were limited to the reported follow-up through week 72.

In the pooled 72-week safety analysis, adverse events occurred in 91% of bepirovirsen recipients and 73% of placebo recipients. Serious adverse events were reported in 7% versus 4%, and grade 3 or higher adverse events in 16% versus 3%. ALT increase was the most common grade 3 adverse event at 6%, and adverse events led to discontinuation in 3% of bepirovirsen recipients.