Bepirovirsen suppresses hepatitis B surface antigen, moves forward to larger functional cure studies

Keith Alcorn
Published:
29 June 2022

Bepirovirsen, an experimental drug with a novel mode of action, suppressed hepatitis B surface antigen below the limits of detection in approximately 30% of patients after 24 weeks of treatment and is ready to move to larger studies as part of a strategy to develop a cure for hepatitis B, the International Liver Congress heard last week.

Bepirovirsen (GSK-3228836) is an antisense oligonucleotide, a chain of nucleic acid designed to cut hepatitis B RNA, preventing the transcription of viral proteins.

The drug was developed by the biotechnology company Ionis and has been licensed to GlaxoSmithKline (GSK) for development, along with a second antisense oligonucleotide, GSK3389404. GSK aims to develop a functional cure – long-term virus suppression after a fixed course of treatment – using a combination of agents.

A functional cure is judged to have been achieved if hepatitis B surface antigen is cleared from the blood and remains undetectable after stopping all treatment. Although a functional cure doesn’t rid the body of hepatitis B virus, it is evidence that the virus is no longer replicating and causing liver damage. Current treatment suppresses hepatitis B virus for as long as it is taken, but very few people achieve a functional cure after stopping nucleoside or nucleotide analogue (NA) treatment.

Studies are investigating whether combinations of NAs and experimental drugs that have different modes of action can suppress HBsAg so profoundly that the virus will not rebound after treatment discontinuation. Most studies are still at the stage of investigating the impact of experimental drugs on HBsAg during treatment. Only one study, a trial of the combination of a silencing RNA and a capsid assembly modulator with an NA, has tested what happens when treatment stops.

A phase 2a study reported in 2020 that bepirovirsen reduced hepatitis B surface antigen (HBsAg) levels when given alongside tenofovir or entecavir.

Professor Man-Fung Yuen of the Queen Mary Hospital, University of Hong Kong presented 24-week interim results of the phase 2b B-CLEAR study, in which two groups of people with hepatitis B – people already taking tenofovir or entecavir and people with no previous treatment experienced – were randomised to receive various doses of bepirovirsen.

People already taking stable NA treatment were eligible to join the study if they had HBV DNA below 90 IU/ml, ALT no more than 2 times the upper limit of normal and HBsAg above 100 IU/ml.

People not taking NAs were eligible to join the study if they had HBV DNA above 2000 IU/ml, ALT no more than 3 times the upper limit of normal and HBsAg above 100 IU/ml.

The study recruited 227 people to the NA arm and 230 people to the previously untreated arm.

Participants were randomised to one of four dosing regimens. Bepirovirsen is administered by injection and participants received loading doses of 400mg at days 4 and 11 followed by weekly doses or placebo injections during the 24-week treatment period.

The primary outcome of the study was the proportion of participants who achieved an HBsAg below the limit of quantitation and an HBV DNA < 20 IU/ml 24 weeks after discontinuing study treatment. The interim analysis presented at the 2022 International Liver Congress reported outcomes at the end of study treatment, prior to discontinuation.

The study population was approximately three-quarters male in the NA arm and approximately half male in the previously untreated arm. The median HBsAg was approximately 3.5 log10 IU/ml in both arms but HBV DNA was approximately ten times higher in the previously untreated arm than in the NA arm (5 log10 IU/ml versus 0.5 log10 IU/ml).

HBsAg suppression occurred more frequently in the study arm with the greatest exposure to bepirovirsen. Twenty-eight per cent of NA-treated and 29% of NA-untreated participants who received 24 weeks of treatment with bepirovirsen at a dose of 300mg achieved both HBsAg and HBV suppression below the limit of quantitation. In contrast, 9% and 7% of NA-treated and untreated achieved suppression in the study arm that received 12 weeks of bepirovirsen 300mg followed by placebo for 12 weeks.

Greater exposure to bepirovirsen was also associated with a higher proportion of participants achieving HBsAg suppression below 100 IU/ml. Sixty-eight per cent of those who received 24 weeks of bepirovirsen 300mg in the NA-treated arm had HBsAg below 100 IU/ml by week 24 compared to 20% of those who received 300mg for 12 weeks followed by placebo.

HBsAg suppression was more likely to occur in those with lower baseline HBsAg levels and more research is needed to investigate whether the proportion of people who can achieve HBsAg suppression can be improved by different drug combinations or treatment durations, or whether immunotherapeutic strategies are needed alongside antiviral drugs to achieve the goal of a functional cure.

The most common adverse event was an injection site reaction. Four serious adverse events related to study treatment were reported (three ALT elevations). In the NA-treated group, ALT elevations coincided with the time of sharpest decline in HBsAg levels. ALT flares in those randomised to receive no active treatment after week 12 were infrequent but numbers randomised to this option were small, so it will be important to observe what happens to ALT levels after treatment discontinuation, Professor Yuen agreed in a post-presentation discussion.

Phase 3 studies of bepirovirsen are due to start later this year and will test the drug alone, as well as in combination with pegylated interferon. Several speakers at the conference speculated that pegylated interferon may still have a role to play in hepatitis B treatment as a means of restoring HBV-specific T-cell responses.

Reference

Yuen MF et al. Efficacy and safety of bepirovirsen in patients with chronic hepatitis B virus infection: interim results from the randomised phase 2b B-Clear study. International Liver Congress, London, abstract LB004A, 2022.