Bepirovirsen: The first antisense oligonucleotide approved to achieve a functional cure for chronic hepatitis B

Abstract

Chronic hepatitis B (CHB) remains a major global health burden despite the availability of potent nucleos(t)ide analogue (NA) therapy. Although NAs effectively suppress hepatitis B virus (HBV) DNA replication and reduce the risks of cirrhosis and hepatocellular carcinoma, they have limited effects on covalently closed circular DNA and hepatitis B surface antigen (HBsAg) production, and most patients require prolonged treatment. Bepirovirsen is an antisense oligonucleotide that targets conserved HBV RNA sequences, promotes RNase H1-mediated RNA degradation, and reduces viral antigen expression and replication. In August 2026, Japan approved bepirovirsen (Hibsago) for selected adults with chronic HBV infection receiving NA therapy, representing its first global regulatory approval. Approval was supported by the phase III B-Well 1 and B-Well 2 trials, in which a functional cure after treatment withdrawal was achieved in 20% and 19% of bepirovirsen-treated patients, respectively, versus 0% with a placebo. Response rates were higher among patients with lower baseline HBsAg levels. The overall safety profile was acceptable; however, elevated alanine aminotransferase levels were observed in 6% of bepirovirsen-treated participants. Ongoing studies will further define long-term durability, broader applicability, and optimal treatment strategies.