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Exploring Combination Therapy for Curing HBV: Preclinical
Studies with Capsid Inhibitor AB-423 and a siRNA
Agent, ARB-1740
Amy C. Lee1, Ammen P. Dhillon1, Stephen P. Reid1, Emily P. Thi1,
Janet R. Phelps1, Kevin McClintock1, Alice H. Li1, Chris Pasetka1,
Kyle D. Cobarrubias1, Sara Majeski1, Agnes Jarosz1, Nagraj
Mani2, Andrzej Ardzinski2, Andrea Cuconati2, Andrew G. Cole2,
Rene Rijnbrand2, Michael J. Sofia2; 1Arbutus Biopharma Corp,
Burnaby, BC, Canada; 2Arbutus Biopharma Inc, Doylestown, PA
Chronic Hepatitis B (HBV) infection leads to liver cirrhosis and
hepatocellular carcinoma and affects approximately 240 million
individuals worldwide. The challenges associated with
developing a cure for HBV are linked to the virus’ ability
to suppress the host immune response and the presence of
a viral cccDNA reservoir. It is believed that a cure for HBV
must address multiple factors involved in viral persistence.
New direct-acting antiviral and immune modulating therapeutic
approaches are being explored that have the potential to
become part of a new treatment paradigm for HBV. These
include capsid assembly inhibitors, siRNA inhibitors of surface
antigen (HBsAg) production, cccDNA formation inhibitors, TLR
agonists and others. Examples of the first 2 categories have
recently entered clinical trials and are being tested as monotherapies
as well as in combination with standard of care. We
used HBV cell culture models in our laboratory to systematically
evaluate combinations of new compounds and the extent of
antagonism, additivity or synergy. In HepBHAe82 cells, the
combination of capsid inhibitor AB-423 with a second-generation
siRNA agent, ARB-1740, was found to have synergistic
activity against HBV relaxed circular DNA. We further investigated
this novel combination using in vivo models to examine
effects on a wider range of HBV disease markers. In a hydrodynamic
injection (HDI) mouse model as well as in chronically
infected hepato-humanized mice, this dual mechanistic combination
increased serum HBV DNA inhibition while maintaining
the serum HBsAg inhibition mediated by ARB-1740. Simultaneous
reductions of liver HBV DNA, RNA and antigens were also
measured in HDI mice. Addition of entecavir or pegylated interferon
to AB-423/ARB-1740 combination treatment resulted in
the most anti-HBV activity observed in the humanized mouse
study. By Day 28 of a 6-week treatment course, both triple
combination treatments yielded 3 log10 reductions in serum
HBV DNA along with up to 2 log10 reductions in serum HBsAg
and HBeAg. The choice of this humanized mouse model, which
is capable of innate immune responses and in which viral replication
is driven from the accumulated cccDNA, provides a
useful environment for the observation of viral recovery rates
upon cessation of treatment. Our data support the strategy of
developing drug combinations to deliver a cure for chronic
HBV infection. Inclusion of new agents with complementary
mechanisms of action such as capsid inhibitor AB-423 and the
siRNA agent, ARB-1740, alongside current standard of care
drugs could provide improved efficacy in the clinic.
Disclosures:
Amy C. Lee - Employment: Arbutus Biopharma
Emily P. Thi - Employment: Arbutus Biopharma Corporation
Kevin McClintock - Employment: Arbutus BioPharma
Nagraj Mani - Employment: Arbutus Biopharma; Stock Shareholder: Arbutus
Biopharma
Andrzej Ardzinski - Employment: Arbutus Biopharma
Andrea Cuconati - Employment: Arbutus Biopharma, Inc.; Speaking and Teaching:
Baruch Blumberg Institute
Andrew G. Cole - Employment: Arbutus Biopharma; Stock Shareholder: Arbutus
Biopharma
Rene Rijnbrand - Employment: Arbutus Bio
Michael J. Sofia - Consulting: Gilead Sciences; Management Position: Arbutus
Biopharma, Inc
The following people have nothing to disclose: Ammen P. Dhillon, Stephen P.
Reid, Janet R. Phelps, Alice H. Li, Chris Pasetka, Kyle D. Cobarrubias, Sara
Majeski, Agnes Jarosz
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发表于 2016-10-4 18:22
