Imdusiran Shows Safety and Tolerability as Potential Functional Cure for Chronic Hepatitis B: NEJM
China: A phase 3 trial published in The New England Journal of Medicine found that bepirovirsen, an investigational antisense oligonucleotide therapy for chronic hepatitis B virus (HBV) infection, achieved significantly higher rates of functional cure compared to placebo after discontinuation of antiviral therapy. The findings highlight the potential of this novel treatment strategy to improve long-term outcomes in patients with chronic HBV infection.
Chronic hepatitis B remains a major global health challenge, affecting millions of people worldwide and increasing the risk of cirrhosis, liver failure, and hepatocellular carcinoma. Although current nucleoside or nucleotide analogue (NA) therapies can effectively suppress viral replication, they rarely achieve a functional cure, which is defined as sustained suppression of HBV DNA along with loss of hepatitis B surface antigen (HBsAg) after treatment completion. Researchers led by Jinlin Hou investigated whether bepirovirsen could help achieve this goal.
Bepirovirsen is an antisense oligonucleotide designed to target HBV transcripts and reduce viral protein production. To evaluate its efficacy and safety, the investigators conducted two replicate double-blind phase 3 studies, B-Well 1 and B-Well 2. Adults with noncirrhotic chronic HBV infection who were already receiving stable NA therapy were enrolled in the trials. Eligible participants had hepatitis B surface antigen levels ranging from more than 100 IU/mL to 3000 IU/mL.
Participants were randomly assigned in a 2:1 ratio to receive weekly subcutaneous injections of 300 mg bepirovirsen or placebo for 24 weeks. Antiviral NA therapy was discontinued at week 48 in eligible patients, and outcomes were assessed at week 72.
The researchers reported the following findings:
- In the B-Well 1 trial, 20% of patients treated with bepirovirsen achieved a functional cure at week 72, while no patients in the placebo group achieved this outcome.
- In the B-Well 2 trial, 19% of patients receiving bepirovirsen achieved a functional cure compared to none in the placebo group.
- Bepirovirsen treatment was associated with sustained viral suppression and hepatitis B surface antigen (HBsAg) loss even after discontinuation of conventional antiviral therapy.
- The findings support the potential of finite-duration treatment strategies for chronic hepatitis B infection.
- Adverse events were reported in 91% of patients treated with bepirovirsen compared with 73% of those receiving placebo.
- Serious adverse events occurred in 7% of patients in the bepirovirsen group and 4% in the placebo group.
- Grade 3 or higher adverse events during treatment were reported in 16% of patients receiving bepirovirsen versus 3% of patients receiving placebo.
- Elevated alanine aminotransferase levels were the most commonly reported severe adverse event associated with bepirovirsen therapy.
Despite these safety concerns, the researchers concluded that bepirovirsen significantly improved rates of functional cure in chronic HBV infection after discontinuation of NA therapy. The findings support continued development of antisense oligonucleotide-based approaches aimed at achieving long-term remission or cure in hepatitis B management.
Reference:
DOI: 10.1056/NEJMoa2515131
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