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36
GalNAc-siRNA conjugate ALN-HBV targets a highly
conserved, pan-genotypic X-orf viral site and mediates
profound and durable HBsAg silencing in vitro and in
vivo
Laura Sepp-Lorenzino, Andrew G. Sprague, Tara Mayo, Tuyen
M. Nguyen, Svetlana Shulga Morskaya, Huilei Xu, Stuart Milstein,
Greg Hinkle, Pia Kasperkovitz, Richard G. Duncan, Natalie Keirstead,
Brenda Carito, Lauren Moran, Prasoon Chaturvedi, Krishna
C. Aluri, Husain Attarwala, Renta M. Hutabarat, Ju Liu, Chris Tran,
Qianfan Wang, Benjamin S. Brigham, Akin Akinc, Klaus B. Charisse,
Vasant Jadhav, Satya Kuchimanchi, Martin A. Maier, Muthiah
Manoharan, Rachel Meyers, Tadeusz Wyrzykiewicz, Haroon
Hashmi, Julie Donovan, Tim Mooney, Daniel Freedman, Tanya
P. Sengupta, Karin Galil, Eoin Coakley, Patrick Haslett; Alnylam
Pharmaceuticals, Cambridge, MA
Background: Despite the prevalence of chronic HBV infection
(CHB), there are no highly effective therapies allowing sustained
off-treatment viral control and/or cure of HBV infection.
An RNAi therapeutic targeting the HBV genome has the potential
to achieve a “functional cure” by effectively decreasing
expression of all viral gene products, including tolerogenic viral
antigens, e.g., HBsAg. Methods and Results: ALN-HBV is a
hepatocyte-targeted GalNAc-siRNA conjugate with Enhanced
Stabilization Chemistry (ESC) for subcutaneous (SC) administration.
It targets a site in the HBV X protein open reading
frame (ORF), thereby targeting all four HBV RNA transcripts
for degradation by RNA interference. Bioinformatic analyses
indicate a >95% perfect sequence homology with a database
of 3,950 full length HBV viral genomes incorporating genotypes
A through J, and a low potential for off-target activity
against host genes. Pan-genotypic activity was confirmed in
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 225A
In vitro, using reporter constructs representative of genotypes A-J.
In HepG2.2.15 cells, ALN-HBV mediates viral transcript silencing
with ED50s of 12-19 pM, as determined for amplicons in
the P and S ORFs. In vivo, in an AAV-HBV mouse model, a
single 3 mg/kg SC dose of ANL-HBV resulted in mean 1.6
log10 reduction in plasma HBsAg (3.6 log10 max reduction) at
10-15 days post dosing. After 3 weekly doses of 3 mg/kg SC,
mean HBsAg silencing >2.9 log10 was observed, with several
animals being below the level of quantitation (<0.05 ng/mL).
HBsAg knockdown persisted for >100 days after the last dose.
In vitro metabolic stability, and mouse and rat pharmacokinetics
and liver exposure were consistent with ESC chemistry
which enables the long-lived pharmacologic response. Exploratory
toxicology and histopathology were performed in rats
sacrificed 24 hr after 3 weekly doses of 30 and 100 mg/kg
SC, and revealed excellent tolerability. Additional pharmacology
studies are in progress, including combination studies
with ALN-PDL, an RNAi drug targeting PD-L1 in hepatocytes.
ALN-PDL is expected to result in augmentation of HBV-specific
cellular immunity in the liver, thereby improving immunological
control of HBV infection locally, while avoiding the immunotoxicity
of systemic immune checkpoint blockade. Conclusion:
ALN-HBV is a single, hepatocyte-targeted siRNA conjugate
targeting a highly conserved region in the HBV genome. It
mediates specific, potent and durable silencing of HBV viral
transcripts and HBsAg expression. ALN-HBV is being developed
as finite treatment in combination with standard-of-care
nucleos(t)ide analogs as a means for inducing a functional cure
in CHB patients. A CTA filing is planned for late 2015.
Disclosures:
Laura Sepp-Lorenzino - Employment: Alnylam
Andrew G. Sprague - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Tuyen M. Nguyen - Employment: Alnylam Pharmaceutical; Stock Shareholder:
Alnylam Pharmaceutical
Svetlana Shulga Morskaya - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Stuart Milstein - Employment: Alnylam
Greg Hinkle - Employment: Alnylam Pharmaceuticals
Richard G. Duncan - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Krishna C. Aluri - Employment: Alnylam Pharmaceuticals
Husain Attarwala - Employment: Alnylam Pharmaceuticals
Renta M. Hutabarat - Employment: Alnylam Pharmaceuticals
Ju Liu - Employment: Alnylam
Benjamin S. Brigham - Employment: Alnylam Pharmaceuticals
Akin Akinc - Employment: Alnylam Pharmaceuticals
Klaus B. Charisse - Employment: Alnylam Pharmaceuticals
Vasant Jadhav - Employment: Alnylam Pharmaceuticals
Satya Kuchimanchi - Employment: Alnylam Pharmaceuticals
Martin A. Maier - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Muthiah Manoharan - Employment: Alnylam
Rachel Meyers - Employment: Alnylam Pharmaceuticals
Haroon Hashmi - Employment: Alnylam Pharmaceuticals; Stock Shareholder:
Alnylam Pharmaceuticals
Daniel Freedman - Employment: Alnylam Pharmaceuticals
Tanya P. Sengupta - Employment: Alnylam Pharmaceuticals
Karin Galil - Consulting: Alnylam Pharmaceuticals
Eoin Coakley - Employment: AbbVie; Stock Shareholder: AbbVie
Patrick Haslett - Employment: Alnylam Pharmaceuticals
The following authors have nothing to disclose: Tara Mayo, Huilei Xu, Pia
Kasperkovitz, Natalie Keirstead, Brenda Carito, Lauren Moran, Prasoon
Chaturvedi, Chris Tran, Qianfan Wang, Tadeusz Wyrzykiewicz, Julie Donovan,
Tim Mooney
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发表于 2015-10-3 09:04