N Engl J Med
EASL 2026: First meaningful hep B functional cure in phase 3
Clinical takeaway: Bepirovirsen could offer an alternative to lifelong therapy for a subset of patients with chronic hep B, with the strongest response in those with lower baseline surface antigen. It is under priority review by FDA with both Breakthrough and Fast Track Designations.
Chronic hepatitis B affects more than 240 million people worldwide and accounts for roughly 56% of liver cancer cases. Current standard of care relies on nucleos(t)ide analogues that suppress the virus but rarely clear it, leaving most patients on indefinite therapy with a functional cure rate under 1%. A finite regimen that delivers meaningful cure rates would change how the disease is managed.
In a pair of replicate phase 3 trials, 20% and 19% of patients treated with bepirovirsen achieved functional cure at week 72, compared with none of those on placebo. Functional cure was defined as undetectable hepatitis B surface antigen and HBV DNA below the limit of quantification for at least 24 weeks after stopping all therapy. This endpoint is endorsed by both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) for finite hep B regimens.
Response was concentrated in patients with lower baseline surface antigen. Among those enrolling with HBsAg ≤1000 IU/mL, functional cure rates reached 25% and 28% across the two trials. In the higher stratum (>1000 to ≤3000 IU/mL), rates fell to 10% and 5%. A sustained HBV DNA suppression endpoint alone after stopping nucleos(t)ide therapy was met in 23% of bepirovirsen recipients overall.
Bepirovirsen is an unconjugated antisense oligonucleotide that targets all HBV transcripts, reducing viral protein production and stimulating an immune response. These B-Well trials enrolled 1,834 adults across 29 countries with virologically suppressed, noncirrhotic chronic hep B and baseline HBsAg of 100 to 3000 IU/mL. Patients received 24 weeks of weekly subcutaneous bepirovirsen or placebo on top of stable nucleos(t)ide therapy, continued antiviral therapy through week 48, and discontinued all treatment at week 48 if eligible.
The safety profile was consistent with prior bepirovirsen studies. Adverse events occurred in 89% of bepirovirsen recipients during treatment versus 65% on placebo, most commonly injection-site reactions. Grade 3 or higher events were reported in 16% versus 3%, driven largely by transient ALT elevations that the authors note are recognized markers of therapeutic response. Decreases in platelet count and eGFR resolved after treatment.
Implementation will hinge on access to quantitative HBsAg testing, which is not yet routine in many settings and is required to identify the lower-HBsAg patients most likely to respond. Durability beyond week 72 is still being assessed in the ongoing B-Sure trial.
"Today's standard of care for CHB imposes a heavy burden on patients and healthcare systems, and rarely delivers a functional cure," said Jinlin Hou, MD, director of the Guangdong Institute of Hepatology and lead author. "Combined with improved testing and diagnosis, this innovation has the potential to improve the lives of millions living with CHB."
Source: Hou J. N Engl J Med. 2026 May 28. Phase 3 results of bepirovirsen treatment for chronic hepatitis B virus infection