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703
PRECLINICAL ASSESSMENT OF POTENCY AND EFFICACY OF A
NOVEL CLASS-II CAPSID ASSEMBLY MODULATOR ALG-001024
Andreas Jekle1, Yannick Debing2, Sandrine Vendeville2,
Sarah K Stevens1, Jerome Deval1, Qingling Zhang1, Tse-I Lin2,
Dinah Misner1, Sushmita Chanda1, Lawrence M Blatt1, Julian
Symons1, Pierre Raboisson2, Leonid N. Beigelman1 and David
B. Smith1, (1)Aligos Therapeutics, (2)Aligos Belgium
Background: Capsid assembly modulators (CAMs) prevent
encapsidation of the pregenomic viral RNA and block viral
replication Based on their morphology CAMs are divided
into two classes; i) class-I (aberrant structures) or ii) class-II
(empty capsids) As a part of our efforts to advance multiple
structurally distinct CAMs from both classes, we report here
on in vitro and in vivo properties of ALG-001024, a novel
Class-II CAM Methods: Antiviral activity on HBV DNA
was determined in HepG2 2 15 and HepG2 117 cells using
quantitative PCR, with and without 40% human serum
Activity was also assessed in primary human hepatocytes
infected with HBV, both with compound included in the
inoculum or added after establishment of infection A
biochemical quenching assay was used to determine the
mechanism of action of the compound Pharmacokinetic
properties were evaluated following IV and oral dosing in
mouse, rat and dog In vivo antiviral efficacy was assessed
in the AAV-HBV mouse model. Results: ALG-001024 is
a potent inhibitor of HBV DNA production in HepG2.2.15
and HepG2 117 cells with EC50/EC90 values of 4 59/14 88
nM and 1 45/44 9 nM respectively Addition of 40% human
serum in cellular assays resulted in an average 5-fold shift in
antiviral activity. This potency was confirmed in HBV-infected
primary human hepatocytes with EC50/EC90 values of 1 89 /
17.01 nM on HBV DNA. ALG-001024 retains antiviral activity
against isolates from HBV genotypes A-H. The formation of
cccDNA in human hepatocytes was also blocked with ALG-
001024 with EC50/EC90 values of 6 77 / 35 72 nM In the
biochemical quenching assay, ALG-001024 induced capsid
formation ALG-001024 showed excellent pharmacokinetic
properties across multiple species with high sustained liver
concentrations. Evaluation in the AAV/HBV mouse model
resulted in a greater than 3 log10 reduction in HBV DNA
following 14-days of dosing Conclusion: ALG-001024 is a
novel class-II CAM demonstrating potent inhibition of both
HBV capsid formation and cccDNA formation. ALG-001024
demonstrated potent antiviral activity in the mouse AAV-HBV
model The compound displays excellent pharmacokinetic
properties consistent with the potential for once-daily dosing
in humans, warranting further development.
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发表于 2019-11-4 18:46