The entry inhibitor bulevirtide (Hepcludex) led to a reduction in hepatitis delta virus (HDV) viral
load, lower liver enzyme levels and improvement in fibrosis after 48 weeks of
follow-up, according to findings presented last week at the 2022
International Liver Congress (ILC) in London. Another study of real-world
bulevirtide use in France also showed virological and biochemical improvement.
delta is a defective virus that can only replicate in the presence of hepatitis
B virus (HBV). Over time, chronic hepatitis B can lead to severe liver disease,
and people with HBV/HDV co-infection experience more aggressive disease
progression. People who carry both viruses are more likely to progress to
decompensated cirrhosis, develop liver cancer or need a liver transplant. It is
estimated that around 3% of people with hepatitis B – or about 15 million
people worldwide -- have HDV, but accurate numbers are lacking due to limited
D] is definitely the most severe form of chronic viral hepatitis. These
patients have a really high risk for developing liver cirrhosis at an early age
and also an increased risk for liver cancer. Until recently…the majority of
patients could not be treated at all,” presenter Prof. Heiner Wedemeyer of Hannover Medical School in Germany said during
press briefing. “The good message for our patients is that…the
drug works. For us in the hepatitis D field, it’s a really exciting time and it’s
game-changing for patients.”
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
from Gilead Sciences, is a first-in-class entry inhibitor that blocks surface receptors that HBV and HDV use
to enter liver cells. By interfering with the hepatitis B lifecycle, the drug
thereby also prevents HDV replication. In July 2020, the
European Medicines Agency (EMA) granted conditional approval of bulevirtide
as the first-ever treatment for hepatitis D. An application for approval by
the US Food and Drug Administration is pending.
Wedemeyer presented the latest results from the phase III MYR301 trial (ClinicalTrials.gov NCT03852719), which
enrolled 150 adults with chronic hepatitis B and D in Europe
and Russia. Nearly 60% were men, most were
White and the mean age was approximately 42 years. Most were hepatitis B ‘e’
antigen (HBeAg) negative. They had elevated ALT liver enzyme levels and nearly
half had liver cirrhosis. More than half had previously received interferon
therapy, and about 60% were concurrently treated with HBV nucleoside analogue
The participants were
randomly assigned to receive immediate treatment with 2mg (the EMA approved
dose) or 10mg once-daily injections of bulevirtide or to delay treatment for 48
weeks. The study is ongoing; the delayed treatment arm will start on the 10mg
dose of bulevirtide, and all groups will continue treatment through week 144
with an additional 96 weeks of post-treatment follow-up.
At ILC 2021, Wedemeyer reported interim data at 24 weeks, showing that 55% of people in the 2mg bulevirtide arm and 68% in
the 10mg arm either reached an undetectable plasma HDV viral load or
experienced at least a 2-log decrease in HDV RNA from baseline, compared with
just 4% in the delayed treatment arm. The likelihood of reaching a combined
endpoint of virological and biochemical response (ALT normalisation) was 37% in
the 2mg arm and 28% in the 10mg arm, but no one in the delayed treatment group
The longer-term data presented at
this year’s meeting show that responses improved with further treatment. At 48
weeks, 71% in the 2mg bulevirtide arm and 76% in the 10mg arm met the
virological endpoint, including 12% and 20%, respectively, with undetectable
HDV viral load. More than half (51% and 56%, respectively) achieved normal ALT
(Another analysis, presented at the Liver Meeting last fall, showed that intrahepatic HDV
RNA levels within the liver steeply declined in a subgroup of 66 people who
underwent paired liver biopsies, with 33% in the 2mg bulevirtide group and 52%
in the 10mg group reaching undetectable levels.)
Looking at the combined primary
endpoint, 45% in the 2mg arm and 48% in the 10mg arm achieved both viral load
reduction and ALT normalisation, as did 2% in the delayed treatment group.
Treatment benefits were generally consistent across all patient subgroups,
though people without cirrhosis had somewhat better responses. In addition,
liver stiffness (a measure of fibrosis) improved by about 3% in the two
bulevirtide dose groups while worsening slightly in the delayed treatment arm.
Bulevirtide had little effect on
hepatitis B. Small declines in HBV DNA were seen in people who were not taking
nucleoside analogues, but no one achieved hepatitis B surface antigen (HBsAg)
loss, considered a functional cure.
Bulevirtide was safe and generally
well tolerated. Severe adverse events (8%-10%), serious adverse events (2%-4%) and
severe laboratory abnormalities (10%-12%) were uncommon, and no one
discontinued treatment due to adverse events. Injection site
reactions, which were mostly mild to moderate, occurred twice as often in the
higher-dose arm (16% vs 30%). Bulevirtide blocks a bile salt transporter, and
bile salt increases were common, but no one taking either dose experienced
symptomatic elevations. A related analysis observed no resistance to
bulevirtide through 48 weeks.
Looking at the balance of benefits
and side effects, these findings confirm prior study results showing that the
10mg dose does not appear to work better overall than the 2mg dose approved by
Another analysis from the MYR301
trial, presented by Prof. Maria Buti of
Hospital Universitario Valle
Hebron in Barcelona, showed that study participants treated with the 2mg dose
of bulevirtide reported greater improvements in a variety of measures of health-related
quality of life compared with the delayed treatment group, including general health, physical and social functioning,
mental health, vitality, pain, and hepatitis-specific limitations and health
What’s more, an analysis of the French BuleDelta cohort, which comprises people with HDV who were treated with bulevirtide
since September 2019, found that these promising clinical trial results were
borne out in the real world.
This analysis included 115 patients. Most (70%) were
men, but the participants were more diverse than those in the MYR301 trial (43%
African, 29% Asian and 26% European descent). Just over half had cirrhosis. About
80% were taking nucleoside analogues, and 50 received interferon in addition to
bulevirtide. The median duration of bulevirtide treatment was about 18 months –
considerably longer than the randomised trial so far.
Overall, 58% achieved at least a 2-log decline in HDV
RNA (including 24% with an undetectable HDV viral load) and 46% experienced ALT
normalisation by 24 weeks. About a quarter met both endpoints. Virological
response rates were substantially higher in people who also received
interferon, but ALT normalisation was more likely in those who did not. The
combined virological and biochemical response rates were 34% in the bulevirtide
plus interferon group and 17% in the non-interferon group.
Among the 55 patients with 48-week data available, virological
response rates were 85% with bulevirtide plus interferon and 69% without
interferon. ALT normalisation rates were 39% and 61%, respectively, yielding
corresponding combined response rates of 35% and 31%.
events were more common in the real-world cohort than in the clinical trial.
Fifteen people (12%) experienced serious adverse events attributed to
bulevirtide, which were similarly likely with or without interferon, and 13
temporarily or permanently discontinued bulevirtide, interferon or both.
noted that there are still questions that remain to be answered, including how
long should treatment with bulevirtide continue and whether it should be combined with
interferon. But the new drug is already helping patients.
well be entering into a new golden age of hepatology science,” EASL
secretary-general Prof. Thomas Berg of Leipzig University
Medical Centre said in a press
release. “There is respite coming for those people living
with hepatitis D and we are making progress towards finding a cure for hepatitis
B, which affects millions of people around the world. The science is inching us
towards a potential public health revolution.”