How Bepirovirsen Targets the Hepatitis B Viral Lifecycle

This episode, "How Bepirovirsen Targets the Hepatitis B Viral Lifecycle," features the panel debating how much of this agent's effect is direct versus immunologic.

Dr. Chung introduces the first pipeline agent for discussion, bepirovirsen, which recently reported phase 3 data, and asks Dr. Gish to walk through its mechanism of action.

Dr. Gish notes this is a bit of a controversial topic, pointing to published correspondence and editorial debate on the subject. He first explains how the virus replicates and persists, describing a mini-chromosome intermediate called cccDNA that serves as a replication template from which messenger RNA is transcribed into viral proteins. He adds that the virus also integrates into the liver cell genome, where that integrated DNA mostly produces truncated surface antigen. One strategy toward functional cure targets cccDNA directly or targets the integrated DNA, while bepirovirsen, an antisense oligonucleotide, instead targets the RNA intermediate before it can be translated into protein, binding to it and triggering a cleavage step.

Dr. Gish explains that early trials with this antisense oligonucleotide approach revealed unexpected flares and liver enzyme changes that were not well understood at the time. As development moved from a targeted formulation to an unconjugated, or naked, oligonucleotide, the ALT effect persisted, and researchers eventually attributed it to an immunologic event rather than a purely direct antiviral effect. He says the exact proportion of benefit from direct RNA binding and cleavage versus an inflammatory immune response remains unclear, placing himself in what he calls the "60-40 club," and asks Dr. Chung for his view.

Dr. Chung responds that he sees more than a casual immunologic contribution, since this compound's effects differ meaningfully from RNA interference agents that accomplish similar protein knockdown without producing the same signal. He suggests that this additional innate immune triggering may be the secret ingredient this particular drug delivers.

Our next episode, "Inside the Be-Well Trials: Design, Population, and Patient Selection," turns to the phase 3 data behind this emerging therapy.