The
experimental hepatitis B antiviral VIR-2218 shows potent activity against the
virus when combined with either a monoclonal antibody that targets three steps
in the hepatitis B lifecycle, or pegylated interferon, two studies presented at
last week’s AASLD Liver Meeting in Washington DC found.
VIR-2218 is an
antisense silencing RNA, a chain of nucleic acid designed to cut hepatitis B
RNA and prevent the production of new viral proteins.
VIR-3434 is
a monoclonal antibody that prevents hepatitis B entry to hepatocytes,
stimulates T-cell responses to hepatitis B virus and promotes clearance of
hepatitis B surface antigen from the bloodstream.
Both are
being developed by VIR Biotechnology, a US company, with the aim of improving
the proportion of people who achieve a functional cure – clearance of hepatitis
B surface antigen and no detectable hepatitis B virus DNA – which may allow
them to stop taking antiviral treatment.
In the MARCH
study, the efficacy and safety of three combinations of VIR-2218 and VIR-3434
were evaluated in people with hepatitis B on nucleoside or nucleotide treatment
for at least two months, with hepatitis B DNA levels below 100 IU/ml.
The study
recruited 40 participants, who were assigned to one of three dosing regimens.
The first cohort (n=17) received six 200mg doses of VIR-2218 at four-weekly
intervals and weekly doses of VIR-3434 between weeks 16 and 20.
The second
cohort (n=4) received three 200mg doses of VIR-2218 at baseline, weeks 4 and 8,
and weekly 18mg doses of VIR-3434 between weeks 0 and 12, while cohort three (n=19)
received three 200mg doses of VIR-2218 at baseline, weeks 4 and 8, and weekly 75mg
doses of VIR-3434 between weeks 0 and 12.
Both study
drugs were well tolerated with no serious adverse events and no treatment
discontinuations due to adverse events.
The primary
study outcomes were the mean reduction in hepatitis B surface antigen at the
end of treatment and the proportion of participants who achieved a hepatitis B
surface antigen below 10 IU/ml at the end of treatment.
Overall, the
mean reduction in hepatitis B surface antigen was -2.5 log 10 IU/ml, with the
greatest reduction observed in cohort 1 (-3.1 log10 IU/ml). Although
no participants experienced loss of hepatitis C surface antigen by the end of
treatment, the majority in each cohort did achieve reductions below 10 IU/ml
(64%, 100% and 84%, respectively).
A second
study compared the safety and efficacy of VIR-2218 alone or in combination with
pegylated interferon in five cohorts for periods between 24 weeks and 48 weeks,
depending on treatment response.
The study
recruited 79 people with hepatitis B on nucleoside or nucleotide treatment,
with HBV DNA levels below 90 IU/ml and detectable hepatitis B surface antigen.
Participants were assigned to one of five treatment regimens combining six
doses of VIR-2218 over periods of 20-24 weeks and between 12 and 48 weeks of
pegylated interferon. In cohort 5, participants could discontinue pegylated
interferon after week 24 if they had hepatitis B surface antigen below the limit
of quantification and hepatitis B surface antibody above 10 IU/ml at two
consecutive visits.
VIR-2218,
with or without pegylated interferon, was well tolerated with no study discontinuation due
to adverse events. Most treatment-related adverse events and laboratory marker adverse
events were associated with pegylated interferon treatment.
The greatest
reduction in hepatitis B surface antigen was seen in those who started VIR-228
and pegylated interferon at the same time, received 13 weeks of VIR-2218
treatment and 44 weeks of pegylated interferon. In this group, HBsAg fell by
-2.1 log10 IU/ml by week 24 and continued to fall, reaching -2.3 log10
IU/ml at week 36 and -2.9 log10 IU/ml at week 48. In all other treatment
groups, HBsAg began to rebound after the end of treatment at week 20 or 24, or
else suppression was not as great in those who received 48 weeks of pegylated
interferon treatment.
A longer
duration of VIR-2218 and pegylated interferon was associated with a greater
frequency of hepatitis B surface antigen clearance from the blood at week 48. Seven
participants out of 31 (30%) in the two longer-duration treatment arms achieved
hepatitis B surface antigen clearance by week 48, compared to one out of 48 in
the three other shorter-duration treatment arms.
Future studies
will explore whether other immunomodulators can improve the rate of hepatitis B
surface antigen clearance.