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
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.
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
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
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
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