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Focus on phase 3 trials of bepirovirsen for chronic hepatitis B virus

Researchers conducted two trials of bepirovirsen in people with chronic hepatitis B virus (HBV) infection. These trials were code-named B-Well 1 and B-Well 2. Data from these two trials were pooled and are reported below. The trials found that the use of bepirovirsen in selected participants with HBV resulted in 20% achieving a functional cure. This is a major breakthrough.

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Study details

Researchers in many countries enrolled 1,938 adults who had chronic HBV and who had been taking standard nucleoside or nucleotide (nuke) therapy—TAF (sold as Vemlidy), TDF, entecavir or other similar drugs—for the past six months. Participants were randomly assigned in a 2:1 ratio to receive the following interventions:

  • bepirovirsen (bepi) – 1,224 people 
  • placebo – 614 people

All participants had blood test results with levels of an HBV-related protein called hepatitis B surface antigen (HBsAg) that ranged between 100 and 3,000 IU/mL. Also, all participants had a level of HBV DNA below the 90 IU/mL mark.

Participants with certain co-existing issues were excluded from the study, including the following:

  • a history of or suspected severe liver injury (cirrhosis)
  • a history of using interferon-alpha in the past 12 months
  • viral co-infections such as hepatitis C virus (HCV), HIV or hepatitis D virus

Participants received either bepi or placebo, ultimately administered as two injections weekly. Bepi was given in a dose of 300 mg. Injections were administered just under the skin (subcutaneously) for six consecutive months. During this time, participants continued their nuke anti-HBV therapy. Lab analysis of blood was done throughout the study.

During weeks 24 to 46, participants who had all the following lab test results could discontinue nuke therapy at week 48:

  • undetectable HBsAg
  • a level of HBV DNA that was less than 20 IU/mL
  • a level of the liver enzyme ALT that was no greater than two times the upper limit of normal
  • undetectable levels of another HBV protein called the e antigen (HBeAg) at week 46

Participants who discontinued nukes were assessed at week 72 (24 weeks after discontinuing nukes).

The average age of participants was 50 years old, about 70% were cisgender males, and a majority were of Asian descent (68%).

Results 

Effectiveness

Overall, about 20% of participants had a functional cure of HBV. That is, after discontinuing nukes, there was no detectable HBV. 

Safety

The term “adverse events” is used in clinical trials to describe unfortunate events that can occur. Such events can include side effects, issues unrelated to the study drug, or even issues unrelated to the study (such as accidents).

For the first 24 weeks of the study, adverse events were reported in 89% of participants on bepi and 65% of those on placebo. Most of these adverse events occurred during the first 12 weeks of the study.

Common adverse events were related to injections—53% in people receiving bepi and 14% in people who received placebo. In general, these adverse events were mild and tended to cluster during the first four weeks of the study.

Severe or life-threatening adverse events during the first 24 weeks of the study were distributed as follows:

  • bepi – 16%
  • placebo – 3%

The most common type of such adverse events in people receiving bepi was an increase in levels of the liver enzyme ALT (alanine aminotransferase) in their blood samples (6%). As bepi activates cells of the immune system resident in the liver, these immune cells would then attack HBV-infected cells. The net effect is temporary inflammation in the liver as HBV-infected liver cells become inflamed and die. The rise in ALT levels was temporary and no participants developed permanent bepi-related liver injury. 

Others developed immunological-related reactions, such as inflamed blood vessels in the skin. In some cases, this was accompanied by purple spots under the skin, suggestive of small amounts of bleeding, with or without joint pain. These issues all resolved after cessation of bepi.

In total, 3% of participants on bepi discontinued the study because of severe adverse events vs. 1% on placebo.

Two people who received bepi died. One participant developed pancreatic cancer, and another developed a tear in their artery (a complication arising from cardiovascular disease found on autopsy). Investigators considered these unrelated to bepi exposure. 

Platelets are necessary for blood to clot. About 10% of participants on bepi developed a platelet count of less than 100,000 per mL compared to less than 1% of people on placebo. However, the study researchers stated that “no clinically meaningful bleeding events attributed to [bepi] were reported.”

The estimated glomerular filtration rate (eGFR) is used to assess kidney function. Decreases in eGFR occurred during the period of bepi administration. This is to be expected as other clinical trials with drugs similar to bepi also cause a decrease in kidney function. This occurs because drugs such as bepi are broken down by the kidneys. The researchers stated that by week 72 eGFR levels had largely returned to normal. Other assessments of kidney health did not reveal any injury. 

—Sean R. Hosein

REFERENCE:

Hou J, Lim SG, Buti M, Phase 3 results of bepirovirsen treatment for chronic hepatitis B virus infection. New England Journal of Medicine. 2026 Jun 25;394(24):2395-2406.