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THU-213
TREATMENT OF CHRONICALLY HBV-INFECTED CHIMPANZEES
WITH RNA INTERFERENCE THERAPEUTIC ARC-520 LED TO POTENT
REDUCTION OF VIRAL MRNA, DNA AND PROTEINS WITHOUT
OBSERVED DRUG RESISTANCE
Z. Xu1, D. Chavez2, B. Guerra2, M. Littlejohn3, R. Peterson1,
S. Locarnini3, R. Gish4, C. Anzalone1, S. Kanner1, J. Goetzmann5,
R. Lanford2, D. Lewis1, C.Wooddell1. 1Arrowhead Research Corporation,
Madison; 2Texas Biomedical Research Institute, San Antonio, United
States; 3Victorian Infectious Diseases Reference Laboratory, Melbourne,
Australia; 4Liver Transplant Program, Stanford University Medical
Center, San Diego; 5New Iberia Research Center, University of Louisiana
at Lafayette, New Iberia, United States
E-mail: [email protected]
Background and Aims: Worldwide >350 million people are
chronically infected with HBV. Despite effective replication
inhibitors (NUCs), functional cure is rare. We developed RNAibased
therapeutic ARC-520 to degrade viral transcripts, thereby
reducing production of viral proteins that suppress the immune
system and allow chronic infection. ARC-520, comprising RNAi
triggers siHBV-74 and siHBV-77 and an excipient that assists with
endo/lysosomal escape of the RNAi triggers, demonstrated potent
and durable knockdown in chimpanzees and in humans. The aim of
this study is to assess whether HBV develops drug resistance upon
multi-dose treatment with ARC-520.
Methods: 9 chimps received 6-11 monthly injections of ARC-520
(2–4 mg/kg) concurrent with NUC therapy. 5 were HBeAg-positive
(HBeAg+), baseline DNA 8-9 log10 IU/mL serum, and 4 were HBeAgnegative
(HBeAg-), &le3 log10 IU/mL. Chimps received NUCs for 8–24
weeks prior to ARC-520 dosing. Liver biopsies from 8 chimps were
taken at baseline, completion of NUC lead-in period and on study.
Total RNAwas isolated from the liver specimens. Parallel sequencing
(RNA-seq) and computational analyses were performed to assess the
HBV variants at each RNAi target site.
Results: Multiple HBV variants were detected in the RNA samples at
each target site prior to ARC-520 treatment. Sequences at the siHBV-
74 site were less variable than those at the siHBV-77 site. The major
variant for the siHBV-74 site accounted for greater than 96% of the
transcripts. The abundance of many minor variants was less than
0.3%, which may represent sequencing error. The relative level of the
major variant at the siHBV-77 site varied in each animal, ranging from
87% to 100% with one exception (64%).
Upon multi-dose treatment with ARC-520, HBV liver RNA, serum
DNA and serum proteins were deeply reduced in all chimps. Mean
reduction of HBsAg at nadirwas 1.7 ± 0.5 log10 in HBeAg + chimps and
0.7 ± 0.1 log10 in HBeAg- chimps. Notably, there was virtually no
change in the percentage of each major variant at each target site,
suggesting no development of drug resistance post-treatment. This
result highlights the beneficial effect of having two RNAi triggers in
the active pharmaceutical ingredient for effective knockdown of
target genes and for preventing drug resistance.
Conclusions: ARC-520 led to potent reduction of HBV mRNA, DNA
and proteins with no observed drug resistance in chimpanzees
chronically infected with HBV.
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发表于 2016-4-2 01:24