entry inhibitor bulevirtide (Hepcludex)
suppressed hepatitis delta viral load and improved liver enzyme levels in a
phase III clinical trial, according to late-breaking study results presented this week at the 2021
International Liver Congress.
delta virus (HDV) is a defective virus that can only replicate in the presence
of hepatitis B virus (HBV). Over years or decades, chronic hepatitis B can lead
to advanced liver disease including cirrhosis and liver cancer. People with
HBV/HDV co-infection have more aggressive liver disease progression than those
with HBV alone. It is estimated that 12 million people worldwide have both HBV
"Hepatitis B stands for being back, because it's really
very interesting, C stands for curable, E stands for emerging, but D stands for
Heiner Wedemeyer of Hannover Medical Hospital in Germany said at a conference
press briefing. "It's the most severe form of viral hepatitis
causing a high risk of developing liver cancer and cirrhosis."
(formerly known as Myrcludex) blocks surface receptors that HBV uses to enter liver cells. This
interferes with the hepatitis B lifecycle and 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.
provisional approval was based on data from phase II studies. At the 2018 International
Liver Congress, Wedemeyer reported that bulevirtide plus tenofovir disoproxil fumarate
suppressed HDV replication more than tenofovir alone. At the 2019 International Liver Congress, he reported that about half of patients
treated with lower doses of bulevirtide (2mg or 5mg) plus pegylated interferon alfa for 48
weeks maintained an undetectable HDV RNA level six months
later. Last year,
he reported that a higher dose of bulevirtide (10mg) did
not appear to work better than the lower doses.
At this year's meeting, Wedemeyer
presented the first interim results from an ongoing phase III clinical trial,
the long-term efficacy and safety of bulevirtide versus no immediate treatment.
In this study, 150 adults with chronic
hepatitis delta in Europe, Russia and the US were randomly assigned to either
immediate treatment with daily subcutaneous injections of 2mg or 10mg
bulevirtide or delayed treatment. They could also use antivirals for hepatitis
B. The trial's primary endpoint is efficacy and safety at 48 weeks, at which
point participants in the delayed treatment arm will start 10mg bulevirtide.
The total treatment duration will be 144 weeks. Wedemeyer presented interim results
at 24 weeks.
More than half of the participants (57%)
were men, 83% were White and the mean age was approximately 42 years. Nearly
half had liver cirrhosis. ALT liver enzyme levels were elevated but below 10
times the upper limit of normal (mean of approximately 110 U/L).
After 24 weeks
of treatment, 55% of people in the 2mg bulevirtide arm and 68% in the 10mg arm
either reached an undetectable 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. However, the magnitude of the decline was similar in both
normalisation was more frequent in the 2mg arm compared with the 10mg or
delayed treatment groups (53%, 38% and 6%, respectively). The combined primary
endpoint of virological and biochemical response was achieved by 37% and 28% of
people in the 2mg and 10mg arms, respectively, but no one in the delayed
treatment group. These findings confirm than the 10mg dose does not appear to
be more effective overall than the 2mg dose approved by the EMA.
little effect on HBV viral load and no one achieved hepatitis B surface antigen
(HBsAg) loss or seroconversion, considered a functional cure.
Treatment was generally safe and well
tolerated. There were no serious adverse events related to bulevirtide and no
one stopped treatment due to side effects. Injection site reactions were
uncommon and mostly mild, but occurred more often in the higher-dose arm (6% vs
26%). Bulevirtide blocks a bile salt transporter and asymptomatic bile salt increases
were common, but no one taking either dose of bulevirtide experienced
symptomatic elevation during treatment.
monotherapy was safe and well tolerated in cirrhotic and non-cirrhotic patients
with compensated chronic HDV, with most adverse events being mild to
moderate," the researchers concluded. "These findings further support
the conditional approval of bulevirtide 2mg in the EU."
only 24-week interim data, only a very small number of patients had completely
undetectable HDV RNA and there was no effect on HBsAg," Wedemeyer said.
"This confirms we can use the drug in the real world, but we have to wait
now for the presentation of the one-year data to be performed. These are
exciting times for delta patients with a new treatment option, and safety and
efficacy were confirmed."
research team presented further results from a phase IIb study of bulevirtide
plus pegylated interferon. A total of 175 patients with chronic HDV infection
were randomly assigned to receive 2mg or 10 mg bulevirtide plus pegylated
interferon, 10mg bulevirtide alone or pegylated interferon alone.
2mg or 10mg bulevirtide plus pegylated interferon were more likely to see at
least a 2-log decline in HDV RNA and to reach an undetectable HDV viral load.
However, both ALT normalisation and combined virological and biochemical
response were highest in the bulevirtide monotherapy arm.