International Session(Workshop)1(JSGE・JSH・JSGCS)
Thu. November 2nd   14:30 - 17:00   Room 11: Portopia Hotel South Wing Topaz
Combination therapies with synergistic therapeutic effects to achieve functional cure by RNA destabilizer
Takehisa Watanabe1, Sanae Hayashi1, Yasuhito Tanaka1
1Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
Background and Aim: We have developed and are conducting preclinical studies of SAG compounds (SAG-comp), which is novel oral drug with excellent HBsAg-lowering activity and tolerability, to achieve a functional cure. However, the best combination of SAG-comp with other drugs is still under investigation. The aim of this study was to investigate the possibility of combining SAG-comp with nucleos(t)ide analogue (NUC) or capsid assembly modulator (CAM), replication inhibitors.
Methods: The therapeutic efficacy of combination therapy with SAG-comp and entecavir (ETV) was evaluated in a human liver chimeric mouse model (PXB mouse). cccDNA in hepatocytes was quantified by digital PCR. The combined effect of SAG-comp and GLS4, a CAM, was analysed by Northern blotting using HepAD38 cells.
Results: The efficacy of SAG-comp in combination therapy with ETV significantly reduced both serum HBsAg and HBV-DNA, and as well as cccDNA in hepatocytes. GLS4 monotherapy did not reduce intracellular HBV-RNA. In contrast, SAG-comp monotherapy significantly reduced HBV-RNA, but pgRNA was detectable. GLS4+SAG-comp combination therapy further reduced HBV-RNA, and then pgRNA bands were undetectable. These data were supported by in vivo PXB mice.
Conclusions: SAG-comp potently suppressed HBsAg and reduced cccDNA in combination with NUC. In addition, SAG-comp showed an enhanced effect on HBV-pgRNA when combined with CAM, suggesting that SAG-comp in combination with NUC and/or CAM would have synergistic effects for functional cure.
Index Term 1: RNA destabilizer
Index Term 2: HBV
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