| International Session（Workshop）1(JSGE・JSH) |
| Fri. November 1st 15:30 - 17:00 Room 9: Portopia Hotel Main Building Kairaku 3 |
| Potential therapeutic effects of SAG-524, an orally available HBV destabilizer, against chronic hepatitis B | |||
| Sanae Hayashi1, Takehisa Watanabe1, Yasuhito Tanaka1 | |||
| 1Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University | |||
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| Nucleos(t)ide analogs(NAs) and pegylated interferon alpha rarely achieve a functional cure for hepatitis B. Here we determined the potential clinical development of SAG-524, which reduces HBsAg by destabilizing HBV RNA. We first evaluated whether orally gavaged with SAG-524 either alone or in combination with ETV blocked HBV production over 9 weeks in HBV-infected PXB mice. SAG-524 monotherapy(20 mg/kg/day BID) reduced HBV-DNA, HBsAg, HBeAg and HBcrAg in sera by day 3 and ETV monotherapy(0.02 mg/kg/day QD) almost immediately reduced HBV-DNA titer. Particularly, the combination of SAG-524(20 mg/kg/day BID) and ETV(0.02 mg/kg/day QD) exhibited high therapeutic activities all serum HBV markers, resulting in around 1 log reduction of HBV-DNA than the ETV monotherapy at the end of treatment. Furthermore, the combination therapy more favorably reduced cccDNA/hepatocyte compared to each monotherapy. The diminished effect of SAG-524 after PAPD5 knockdown suggested the involvement of PAPD5 in the MoA of SAG-524. We also determined that the toxicological profile of SAG-524 in monkeys for a non-GLP 13-week oral toxicity study. Any adverse events including sustained neurobehavioral effects and neurotoxicity as a serious adverse event were not observed in SAG-524 monotherapy(1000 mg/kg/day BID). Collectively, the SAG-524 is an orally available and well-tolerated anti-HBV therapeutic agent that potently suppresses HBsAg. It has the potential to destabilize HBV-RNA and possibly induce functional cure in combination therapy with NA. |
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Index Term 1: HBV destabilizer Index Term 2: a functional cure |
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