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s 687
COMBINATION TREATMENT OF LIVER-TARGETED HBV
LOCKED NUCLEIC ACID ANTISENSE OLIGONUCLEOTIDE AND
TLR7 AGONIST RO7020531 LEADS TO PROLONGED OFFTREATMENT
ANTIVIRAL EFFECT IN THE AAV-HBV MOUSE
MODEL.
Julie Blaising1, Youjun Yu2, Xue Zhou2, Lykke Pedersen3,
Steffen Wildum1, Soren Ottosen3, Cynthia Wat4, Lu Gao2
and Henrik Mueller1, (1)Roche Pharma Research and
Early Development, Roche Innovation Center Basel,
Basel, Switzerland, (2)Roche Pharma Research and Early
Development, Roche Innovation Center Shanghai, Shanghai,
China, (3)Roche Pharma Research and Early Development,
Roche Innovation Center Copenhagen, Hørsholm, Denmark,
(4)Roche Products Ltd, Welwyn, United Kingdom
Background: Currently available treatments for chronic
hepatitis B are associated with low rates of HBsAg loss, a key
marker for viral functional cure Therefore, new therapeutic
strategies with finite treatment duration need to be developed.
While various new molecular entities are currently being
assessed clinically, it is anticipated that even higher functional
cure rates could be achieved by combination therapy In
this context, we investigated the combination of a livertargeted
HBV locked nucleic acid antisense oligonucleotide
(HBV-LNA ASO) with RO7020531, a TLR7-agonist, in
the AAV-HBV mouse model. Methods: HBV-LNA ASO is
targeting all viral RNA transcripts, using a covalently linked
cluster of three N-acetylgalactosamine-moieties to ensure
hepatocyte-specific delivery. RO7020531 is a prodrug of
a toll-like receptor 7 (TLR7) agonist. We evaluated efficacy
of the molecules in mono- and combination therapy at two
different LNA dose levels and two TLR7 dosing frequencies
in the AAV-HBV mouse model. Mice were treated for 8 weeks
and subsequently monitored for additional 9 weeks. Viral,
immunologic and safety relevant markers were measured
Results: All combinations of RO7020531 and HBV-LNA ASO
showed a clear benefit over the respective monotherapy
groups. While HBV-LNA ASO monotherapy reduced HBsAg
up to 2.8log (<LLOQ) and HBV DNA levels up to 3.4log
(<LLOQ) during therapy, both rebounded quickly during the
off-treatment phase RO7020531 monotherapy reduced
HBsAg and HBV DNA up to 2.5log and 3.1log, respectively.
But also in this case viral markers rebounded off-treatment,
although at a slower rate. In contrast, combination of HBVLNA
ASO and RO7020531 delayed rebound for several
weeks after end of treatment and viral markers had not
returned to baseline by the end of the study. We also detected
high levels of anti-HBs IgG and sustained anti-HBs B cell
responses, as measured by B-cell ELISpot, in mice treated
in combination Conclusion: New therapies for chronic
hepatitis B with higher rates of functional cure are urgently
needed. The pre-clinical data from the combination of a HBVLNA
ASO and TLR7 agonist RO7020531 demonstrates a
prolonged reduction of HBV-DNA and HBsAg compared to
monotherapy and is associated with a robust immunological
response Using these two different modalities in combination
provides evidence for potential higher cure rates.
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发表于 2019-11-1 18:50