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1865
Development of Second Generation RNA Interference
Therapy for Hepatitis B Virus Infection
Emily P. Thi1, Xin Ye1, Ammen P. Dhillon1, Nicholas M. Snead1,
Andrew S. Kondratowicz1, Luying Pei1, Kyle D. Cobarrubias1,
Agnes Jarosz1, Joseph Wasney1, Andrea Cuconati2, Rene Rijnbrand2,
Amy C. Lee1, Michael J. Sofia2; 1Arbutus Biopharma Corp,
Burnaby, BC, Canada; 2Arbutus Biopharma Inc, Doylestown, PA
Hepatitis B virus (HBV) infection is a global health challenge
with 240 million chronically infected individuals at risk for
developing complications such as liver fibrosis and cancer.
HBV viral antigens such as surface antigen (HBsAg) are associated
with immune system impairment, leading to persistent
infection and posing a challenge for development of a functional
cure. The most common treatments for HBV are nucleotide
analog (NUC) based and are able to control HBV viral
replication but have little effect on HBV cccDNA and protein
expression; thus, seroconversion and functional cure rates are
rare with these therapies. Here we describe a second-generation
RNA interference (RNAi) therapeutic comprised of 3 small
interfering RNAs (siRNAs) directly targeting multiple loci of
hepatitis B viral transcripts, enabling inhibition of HBV replication
and suppression of all viral antigens. Like ARB-1467,
which is currently in Phase 2 clinical trials with chronic HBV
patients, ARB-1740 can inhibit HBsAg production even from
integrated HBV and utilizes lipid nanoparticle (LNP) technology
to deliver siRNA to the infected liver. In vivo, ARB-1740
is up to 10-fold more potent than ARB-1467, resulting in 2.5
log10 serum HBsAg reduction at 7 days after a single 0.3 mg/
kg dose in a hydrodynamic injection mouse model of HBV.
Duration of activity was also improved with resolution to < 1
log10 HBsAg reduction occurring more than 4 weeks post-dose,
which is twice as long as observed for ARB-1467 in this model.
Immunohistochemistry analysis revealed ARB-1740-mediated
suppression of hepatic HBV core antigen for > 35 days. Its
antiviral drug activities also included inhibition of serum HBV
DNA (2.9 log10) and HBeAg (> 2 log10) as well as hepatic
HBsAg (1.5 log10), HBV DNA (1.5 log10) and HBV RNA (>
1 log10). ARB-1740 has demonstrated pan-genotypic activity
with sub-nanomolar in vitro EC50 potencies against extracellular
HBV relaxed circular DNA and HBsAg across 12 clinical
isolates representing 4 genotypes (A-D), including 5 NUC-resistant
strains. In summary, in vivo modeling of ARB-1740, a second-
generation RNAi therapeutic with pan-genotypic activity
and a well-understood mechanism of action, has demonstrated
that it is more effective than previous therapeutic agents for
reduction of HBsAg and other HBV viral markers in both the
peripheral blood and liver.
Disclosures:
Emily P. Thi - Employment: Arbutus Biopharma Corporation
Xin Ye - Employment: Arbutus Biopharma Corporation
Nicholas M. Snead - Employment: Arbutus Biopharmaceutical Corp.
Andrew S. Kondratowicz - Employment: Arbutus Biopharma; Stock Shareholder:
Arbutus Biopharma
Andrea Cuconati - Employment: Arbutus Biopharma, Inc.; Speaking and Teaching:
Baruch Blumberg Institute
Rene Rijnbrand - Employment: Arbutus Bio
Amy C. Lee - Employment: Arbutus Biopharma
Michael J. Sofia - Consulting: Gilead Sciences; Management Position: Arbutus
Biopharma, Inc
The following people have nothing to disclose: Ammen P. Dhillon, Luying Pei,
Kyle D. Cobarrubias, Agnes Jarosz, Joseph Wasney
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发表于 2016-11-27 08:44
