experimental hepatitis B virus (HBV) core protein inhibitor led to greater
reductions in HBV viral load and residual HBV genetic material when added to
nucleoside/nucleotide analogues, which could lead to a functional cure with
longer follow-up, according to a study presented at the 2019
International Liver Congress last week in Vienna.
from Assembly Biosciences,
was well tolerated, and the rapid, deep declines in HBV DNA and HBV RNA
could promote the loss of cccDNA (covalently
closed circular DNA), an intermediate form that persists in the nucleus of
liver cells and presents a barrier to a cure, said Dr Jay Lalezari of Quest
Clinical Research in San Francisco.
can lie dormant in liver cells, establishing a reservoir of viral genetic
material that evades both the immune system and standard treatment. Over years
or decades, chronic HBV infection can lead to liver cirrhosis, hepatocellular
carcinoma and end-stage liver failure requiring a transplant.
antivirals such as tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy)
and entecavir (Baraclude) can suppress HBV replication during long-term therapy but
they do not completely eliminate the virus, do not prevent formation of
cccDNA and usually do not lead to a cure, as indicated by hepatitis B surface
antigen (HBsAg) loss.
ABI-H0731 is a core protein allosteric modifier (CpAM) that targets
the HBV core protein and interferes with multiples steps of the viral lifecycle,
including cccDNA formation.
presented interim findings from a pair of phase IIa studies evaluating ABI-H0731
in people with chronic hepatitis B and absent to moderate (stage F0-F2) liver
included 47 hepatitis B 'e' antigen (HBeAg) positive and 26 HBeAg negative
people on nucleoside/nucleotide analogues (mostly tenofovir) with suppressed
HBV DNA. They were randomised to add either once-daily oral ABI-H0731 or
included 25 previously untreated HBeAg positive people with unsuppressed HBV. They
were randomised to receive entecavir plus either ABI-H0731 or placebo. After 24
weeks, people in both studies could opt to join an ongoing open-label
extension study (Study 211).
studies, the combination regimen led to faster, steeper and larger declines in
HBV viral load starting at week 2. In Study 201, people who added ABI-H0731
had a mean HBV RNA decline of 2.34 log10 at 12 weeks, compared with
0.05 log10 in the placebo group. Although most people had not yet
reached this time point, the declines at 24 weeks were 2.20 log10
and 0.15 log10, respectively.
202 – those who started treatment with unsuppressed virus – HBV DNA declined by
4.54 log10 at week 12 and by 5.94 log10 at week 24 in the
combination therapy group, compared with 3.2910 log and 3.99 log10,
respectively, in the entecavir monotherapy group. Looking at HBV RNA, levels
fell by 2.27 log10 at week 12 and 2.54 log10 at week 12
in the combination group versus 0.44 log10 and 0.61 log10,
respectively, in the entecavir-only group.
Study 201 participants who reached the 24-week time point, sensitive tests to
detect low-level HBV DNA, capable of measuring down to 2-5 IU/ml, showed that
residual virus was not eliminated using nucleoside/nucleotide analogues alone,
but fell below the level of detection in five of six people who added ABI-H0731.
was generally safe and well tolerated and no serious adverse events, treatment
interruptions or treatment-related discontinuations were reported.
residual HBV DNA will likely be required to prevent new cccDNA formation, and
this will be a critical milestone for a cure, according to Lalezari. He said that
decay of cccDNA and declines in HBeAg and and HBsAg are anticipated to follow
the elimination of residual virus, and this will be explored in the extension
"Although decreases in HBeAg and
HBsAg in some individuals have been observed in both studies, it is too early
to draw meaningful conclusions about this endpoint," Lalezari said in a conference
press release. "The accelerated decline and significant loss of
baseline RNA and DNA viraemia suggest that combination therapy with a core
inhibitor plus [nucleoside/nucleotide analogues] may enhance loss of cccDNA and
viral antigen once residual viraemia has been fully cleared."
these promising findings, Assembly has reportedly decided not to further
develop ABI-H0731 in favour of more potent core protein inhibitors including
ABI-H2158 and ABI-H3733. A late-breaking
poster at the conference reported that ABI-H2158 was well tolerated and
demonstrated favourable pharmacokinetics in a Phase Ia trial; a Phase
Ib dose-finding study is underway. ABI-H3733
is expected to enter Phase Ia studies early next year, according to the