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84
COMBINATION OF ANTISENSE OLIGONUCLEOTIDES (ASOS)
ALG-020572 AND ALG-020576 AGAINST HEPATITIS B VIRUS
(HBV) IMPROVES ACTIVITY AND CAN BE COMBINED WITH
OTHER ANTI-HBV AGENTS
Jin Hong1, Hua Tan1, Tse-I Lin2, Hyunsoon Kang1, Yuchun
Nie1, Aneerban Bhattacharya1, Rajendra Pandey1, Lawrence
M. Blatt1, Julian A. Symons1 and Leonid N. Beigelman1, (1)
Aligos Therapeutics, Inc., (2)Aligos Belgium BV
Background: HBV targeted ASOs have demonstrated efficacy
in reducing HBsAg in animal models and chronic hepatitis B
(CHB) patients1 We applied proprietary chemistries to develop
the best in class HBV ASOs, ALG-020572 and ALG-020576,
with unique N-Acetylgalactosamine 4 (GalNac4) conjugation
ALG-020572 targets the open reading frame (ORF) of the
small HBsAg, and ALG-020576, the ORF of the HBx protein
Both ASOs are significantly more potent than GSK32288361
in the AAV-HBV model. We explored the benefits of combining
the two ASOs as well as combining the ASOs with other anti-
HBV agents including the nucleos(t)ide analogs (NA) tenofovir
and entecavir (ETV), the Capsid Assembly Modulator (CAM),
ALG-0010752, parent of ALG-0001843 and the STOPSTM
molecule, ALG-0101334 Methods: In vitro profiling of
combinations were performed in HepG2 2 15 cells using an
HBsAg release or HBV DNA qPCR assay In vivo combination
studies were performed in the AAV-HBV mouse model ASOs
were administered subcutaneously (SC) with blood collections
every 5 days for HBsAg, HBV DNA and ALT assays Results:
Combination of the two ASOs improved genotypic coverage
to ~100% over all HBV genotypes Combination of the
unconjugated ASOs showed additive to synergistic effects in
reducing HBsAg in HepG2 2 15 cells In an AAV-HBV study,
ALG-020572 and ALG-020576 were dosed either alone or as
a combination at a 1:1 or 2:1 ratio With 6x10 mg/kg repeated
dosing, combination of the two ASOs (1:1) reached an HBsAg
nadir of -1 81 log10, better than the -1 17 and -1 54 log10
reductions seen from either of the ASOs alone In HepG2 2 15,
combination of the ASOs exhibited an additive effect with
the STOPSTM ALG-010133 molecule, strong synergy with
tenofovir and moderate synergy with the CAM, ALG-001075
In the AAV-HBV mouse model, a 1:1 combination of the two
ASOs demonstrated additive to synergistic effects with ETV
and the CAM, ALG-000184 Conclusion: Compared with
a single ASO, a 1:1 combination of ALG-020572 and ALG-
020576 offers enhanced in vivo potency, better genotypic
coverage, a higher resistance barrier and a greater capacity
to retain efficacy after HBV genome integration events. This
regimen can also be combined with other anti-HBV agents
References:
1 Yuen M F et al Poster 0700, AASLD 2019
2 Debing Y et al Poster 699, AASLD, 2020
3 Zhang Q et al Poster 2889, EASL, 2020
4 Hong J et al Poster 0689, AASLD, 2019
Disclosures:
Jin Hong – Aligos Therapeutics: Employment
Tse-I Lin – Aligos Therapeutics: Employment
The following people have nothing to disclose: Rajendra Pandey
Disclosure information not available at the time of publication: Hua Tan,
Hyunsoon Kang, Yuchun Nie, Aneerban Bhattacharya, Lawrence M Blatt,
Julian A Symons, Leonid N Beigelman |
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发表于 2020-10-19 16:57
