Patients with chronic hepatitis B virus (HBV) infection show sustained hepatitis B surface antigen (HBsAg) and HBV DNA loss after 24 weeks of bepirovirsen therapy, according to study findings published in The New England Journal of Medicine.
Researchers conducted a phase 2b, randomized, parallel-cohort trial of participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Patients (N=457) with chronic HBV infection for more than 6 months were recruited for the B-Clear trial conducted between 2020 and 2022 at 123 sites in 22 countries.
Participants were randomly assigned in a 3:3:3:1 ratio to receive either weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks (n=138; group 1), bepirovirsen 300 mg for 12 weeks followed by 150 mg bepirovirsen for 12 weeks (n=136; group 2), bepirovirsen 300 mg for 12 weeks followed by placebo for 12 weeks (n=136; group 3), or placebo for 12 weeks followed by 300 mg bepirovirsen for 12 weeks (n=47; group 4). The primary outcomes of this trial were HBsAg levels under 0.05 IU/mL and HBV DNA of less than 20 IU/mL at week 55.
The mean age range of the study participants was 40.7 to 49.8 years, 46% to 75% were men, 50% to 65% were Asian, HBsAg levels ranged from 3.26 to 3.76 log10 IU/mL, HBV DNA levels ranged from 0.39 to 5.57 log10 IU/mL, and 62% to 91% had alanine aminotransferase (ALT) levels below the upper limit of the normal. Approximately half of the cohort were receiving nucleoside or NA therapy at baseline. Participants who received NA therapy tended to be older, were more likely to be men, and had HBV DNA levels lower than the cohort not receiving NA therapy.
The primary outcomes of low HBsAg and HBV DNA levels were achieved by 9% of the NA therapy recipients and 10% of the non-recipients in group 1, 9% and 6% in group 2; 3% and 1% in group 3; and 0% and 0% in group 4, respectively.
Using data from group 1, the researchers found that an HBsAg level of approximately 3000 IU/mL best predicted response to treatment.
During the first 12 weeks of treatment, 76% to 90% of bepirovirsen recipients and 43% to 54% of placebo recipients experienced an adverse event. The most common events among bepirovirsen recipients included injection site reactions, pyrexia, fatigue, and increased ALT levels. A total of 8 bepirovirsen recipients experienced a severe adverse event during the first 12 weeks. Adverse events of grades 3 or 4 occurred among 0% to 16% of NA recipients and 17% to 23% of nonrecipients.
In a pooled analysis, 17% of patients receiving NA therapy and 41% of those not receiving NA therapy at baseline had a transient increase in ALT levels to 3 or more times the upper limit of normal at the end of follow-up.
This study was limited by its small sample size and short follow-up period.
“Although this is a relatively low percentage of participants overall, it indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both,” the researchers noted. “Durability of response is being investigated in the B-Sure trial, which will follow participants for an additional 33 months and includes criteria for stopping NA therapy,” they concluded.
Disclosure: Multiple authors declared affiliations with industry. Please see the original reference for a full list of disclosures.
Yuen M-F, Lim S-G, Plesniak R, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection. N Engl J Med. Published online November 8, 2022. doi:10.1056/NEJMoa2210027