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699
PRECLINICAL ASSESSMENT OF A NOVEL CAPSID ASSEMBLY
MODULATOR, ALG-001075, DEMONSTRATES BEST-IN-CLASS
IN VITRO POTENCY AND IN VIVO ANTIVIRAL EFFICACY
Yannick Debing1, Andreas Jekle2, Sandrine Vendeville1, Sarah
K Stevens2, Jerome Deval2, Qingling Zhang2, Tse-I Lin1, Dinah
Misner2, Sushmita Chanda2, Raymond F Schinazi3, Pierre
Raboisson1, Julian Symons2, Lawrence M Blatt2, Leonid N.
Beigelman2 and David B. Smith2, (1)Aligos Belgium, (2)Aligos
Therapeutics, (3)Emory University, Children’s Healthcare of
Atlanta
Background: The hepatitis B virus (HBV) capsid assembly
process has emerged as a key target for the treatment of
chronic hepatitis B Capsid assembly modulators (CAMs)
affect HBV core protein assembly into aberrant structures
(class-I) or empty capsids (class-II) inhibiting HBV RNA
encapsidation As a part of our efforts to advance multiple
structurally diverse CAMs from both classes, we report on
ALG-001075, a novel class-II CAM with excellent antiviral
potency, pharmacokinetic properties and efficacy in the
mouse AAV-HBV model. 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-001075 was
found to be a potent inhibiter of HBV DNA production in
HepG2 2 15 and HepG2 117 cells with EC50/EC90 values of
0 53/1 84 nM and 0 77/3 79 nM respectively Inclusion of 40%
human serum 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 36 / 8 46 nM
on HBV DNA. The formation of cccDNA in human hepatocytes
was blocked with ALG-001075 with EC50/EC90 values of 2 34 /
13 55 nM ALG-001075 retains potent antiviral activity against
isolates from HBV genotypes A-H. ALG-001075 induced
capsid formation in the biochemical quenching assay ALG-
001075 showed excellent pharmacokinetic properties across
species indicating the potential for QD dosing in humans.
Evaluation of ALG-001075 in the AAV/HBV model resulted
in a dose dependent reduction in HBV DNA with a mean
maximum 5-log10 drop in HBV DNA following 8 weeks of
dosing Conclusion: With sub-nanomolar activity in cellbased
assays, ALG-001075 is among the most potent class-II
CAM reported to date, efficiently blocking both HBV genome
encapsidation and de novo cccDNA formation ALG-001075
displays excellent preclinical efficacy and pharmacokinetic
properties predicting once daily dosing in humans ALG-
001075 warrants further development as a potential best-inclass
CAM.
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发表于 2019-11-3 18:51