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Bepirovirsen for Chronic Hepatitis B Infection

A phase 2b trial of patients with chronic hepatitis B virus (HBV) infections provides evidence of benefits of the antisense oligonucleotide bepirovirsen that justifies moving on to larger and longer trials, researchers report.

Participants in the investigator-unblinded trial had chronic HBV infection and were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. They were randomized to weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks (group 1), bepirovirsen 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). The composite primary outcome was a hepatitis B surface antigen (HBsAg) level below the limit of detection and an HBV DNA level below the limit of quantification maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication.

The results showed: “The intention-to-treat population comprised 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Among those receiving NA therapy, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) in group 1, in 6 (9%; 95% credible interval, 0 to 43) in group 2, in 2 (3%; 95% credible interval, 0 to 16) in group 3, and 0 (0%; post hoc credible interval, 0 to 8) in group 4. Among participants not receiving NA therapy, a primary-outcome event occurred in 7 participants (10%; 95% credible interval, 0 to 38), 4 (6%; 95% credible interval, 0 to 25), 1 (1%; post hoc credible interval, 0 to 6), and 0 (0%; post hoc credible interval, 0 to 8), respectively. During weeks 1 through 12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen (groups 1, 2, and 3) than with placebo (group 4).”

Editorial: “Critical questions remain,” an editorialist writes. “Will HBsAg negativity persist beyond 24 weeks? When can NA therapy be safely stopped? What other factors predict response? Will RNA therapy–induced loss of HBsAg materially improve long-term outcomes?

“Bepirovirsen is just one RNA-based HBV therapy now being pursued. Several other antisense RNAs as well as the more malleable small interfering RNA molecules (“-sirans”) are currently in early-phase clinical trials. A new era in the control of hepatitis B may be at hand with these most modern of therapies for this most ancient disease.”

Source: New England Journal of Medicine