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402
In Vitro Antiviral Activity and Mode of Action
of JNJ-64530440, a Novel Potent Hepatitis B
Virus Capsid Assembly Modulator in Clinical
Development
Jan Martin Berke, Pascale Dehertogh, Karen Vergauwen,
Thierry Verbinnen, Sandrine Vendeville, Pierre Raboisson
and Frederik Pauwels, Janssen Research & Development
Background: Hepatitis B virus (HBV) capsid assembly is a
critical step in the propagation of the virus and is mediated
by the core protein. Due to its multiple functions in the viral
life cycle, core became an attractive target for new antiviral
therapies and multiple capsid assembly modulators (CAMs)
have entered clinical trials. Recently it was shown that CAMs,
in contrast to nucleos(t)ide analogues, can block the de novo
formation of the cccDNA pool, which might translate into
improved treatment outcomes. JNJ-64530440 (JNJ-0440) is a
novel, potent HBV CAM currently being evaluated in a Phase I
clinical trial (NCT03439488). Here, the in vitro antiviral activity
and mode of action (MOA) of JNJ-0440 is reported. Methods:
Size exclusion chromatography (SEC) with the recombinant
assembly domain (aa 1-149) of HBV core and electron
microscopy (EM) was used to study the effect of JNJ-0440 on
capsid assembly. The anti-HBV activity was tested in stable
HBV replicating HepG2.117 cells and on a panel of clinical
isolates, representing HBV genotypes A-H, in a transient
HBV replication assay in HepG2 cells using quantitative real
time PCR (qPCR) as read out. Primary human hepatocytes
(PHHs) were treated with JNJ-0440 either during or after
HBV infection. HBV DNA in the cell culture supernatant and
intracellular HBV RNA were monitored by qPCR. HBsAg and
HBeAg levels in the cell culture supernatant were determined
by AlphaLISA. Results: JNJ-0440 induced the formation of
empty, but morphologically intact viral capsids as determined
by SEC and EM. JNJ-0440 is a potent inhibitor of HBV
replication in vitro with a median EC50 of 12 nM in HepG2.117
cells and a median EC50 of 5.4 nM (range of 1.3-111 nM) across
genotypes A-H clinical isolates. JNJ-0440 inhibited replication
in infected PHHs with an EC50 of 24 nM and prevented the
de novo formation of cccDNA in PHHs in a dose-dependent
fashion when added together with the viral inoculum. This
protective effect translated into a dose-dependent reduction
of intracellular HBV RNA levels and reduced HBe- and HBsAg
levels in the cell culture supernatant. Conclusion: JNJ-0440 is
a potent novel inhibitor of replication in stable HBV replicating
cell lines and HBV infected PHHs. JNJ-0440 is active across
a broad panel of genotype A-H clinical isolates and blocks the
de novo formation of the cccDNA pool in PHHs.
Disclosures:
Jan Martin Berke – Janssen Research and Development: Employment
Karen Vergauwen – Janssen Research and Development: Employment
Thierry Verbinnen – Janssen Research and Development: Employment
Frederik Pauwels – Janssen Pharmaceutica: Employment
Disclosure information not available at the time of publication: Pascale
Dehertogh, Sandrine Vendeville, Pierre Raboisson |
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发表于 2018-10-16 08:30
