ARB-1467, a novel type of treatment for hepatitis B, reduced
levels of hepatitis B surface antigen (HBsAg) when used alone, and it may play
a role in combination therapy to cure the infection, researchers reported at the recent
2017 AASLD Liver Meeting in Washington, DC.
Current standard therapy for hepatitis B virus (HBV)
using nucleoside/nucleotide antivirals like tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication over the long term but usually does not
lead to a cure, as indicated by hepatitis B surface antigen (HBsAg) clearance and
development of anti-HBs antibodies.
ARB-1467, being developed by Arbutus Biopharma,
consists
of synthetic small interfering RNAs directed against HBV messenger RNAs,
targeting three different sites in the HBV genome.
Glossary
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
Dr Kosh Agarwal of the Institute of Liver Studies at King’s College
Hospital in London and colleagues evaluated the safety, pharmacokinetics and antiviral activity of multiple doses of ARB-1467 in a phase 2 clinical trial.
The
study included 36 people with chronic hepatitis B on stable treatment with tenofovir
DF or entecavir. A majority were men, they were predominantly white or Asian
and the median age was approximately 45 years. About 80% were hepatitis B 'e' antigen (HBeAg)-negative, a
majority had HBV genotype C and about half had undetectable HBV DNA at baseline.
Participants
were randomly assigned to receive ARB-1467 or placebo at doses of 0.2 or 0.4 mg/kg
given by intravenous infusion once a month or biweekly for 12 weeks. Participants
in cohort 4, all of whom were HBeAg-negative, started with 0.4 mg/kg biweekly
dosing and switched to once-monthly dosing for up to a year if they had HBsAg < 1000
IU/ml and at least a 1 log10 decline by week 12.
Everyone treated with ARB-1467 saw a
reduction in HBsAg from baseline. People who received the drug biweekly had larger HBsAg declines than those who
received once-monthly infusions, and the 0.4 mg/kg dose worked better than the
0.2 mg/kg dose. Most people with declines of more than 1 log10 had
undetectable HBV RNA at baseline.
HBV
RNA levels decreased modestly in all groups (by about 0.5 log10) and
hepatitis B core-related antigen (HBcrAg) levels did not change much in any
group. These measures were not correlated with HBsAg decline.
The
researchers also presented more detailed results for the HBsAg-negative
participants in cohort 4. One of the 12 participants in this group dropped out
early due to adverse events. Seven of the 11 remaining people (64%)
were classified as responders and switched from biweekly to monthly dosing.
The
largest HBsAg decline was 2.7 log10, and five people in this group reached
levels below 50 IU/ml. However, none achieved HBsAg clearance. Having a
lower baseline HBsAg
level and the IL28b CC gene variation (associated with interferon signaling)
predicted larger HBsAg declines on ARB-1467.
Treatment
was generally safe and well tolerated, with no drug-related serious adverse
events and two discontinuations due to adverse events (one with hepatitis E
super-infection and one with a mild infusion reaction, joint pain and hair
loss). ALT values remained normal throughout treatment.
The
researchers concluded that monthly dosing does not appear to be sufficient to
maintain or improve initial HBsAg reductions achieved with biweekly
administration, and suggested that combination therapy with other therapies and
longer treatment duration may be needed for a functional cure of hepatitis B.
A
forthcoming trial will evaluate ARB-1467 in combination with tenofovir and pegylated
interferon, according to an Arbutus press release.