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Replies to post #224662 on Biotech Values
04/15/19 12:48 PM
EDP-514, a novel HBV core inhibitor with potent antiviral activity both in vitro and in vivo
Background and aims: Current therapies for hepatitis B virus (HBV) can effectively suppress viral replication but rarely lead to a functional cure, which necessitates the development of new antiviral drugs. The HBV core protein plays an essential role in multiple steps of viral life cycle and has been proposed as a potential therapeutic target. EDP-514 is a novel HBV core inhibitor with favorable pharmacokinetic and safety profile. Here, we describe the anti-HBV activities of EDP-514 in vitro and in a chimeric mouse model with humanized liver.
Method: The effect of EDP-514 on viral capsid assembly was determined in vitro. Its anti-HBV activities at different stages of the viral lifecycle were characterized in stable cell lines (HepG2.2.15, HepAD38 and HepDE19) and primary human hepatocytes. Activities against different HBV genotypes and resistance mutants were assessed in transiently transfected HepG2 cells. The in vivo efficacy of EDP-514 was evaluated in HBV genotype C-infected PXB mice
which were generated by transplantation of urokinase-type plas- minogen activator/severe combined immunodeficiency (uPA/SCID) mice with human hepatocytes.
Results: EDP-514 induced the assembly of empty capsids in vitro and in HBV infected cells but did not lead to core protein aggregation or degradation, confirming it is a class II core inhibitor. EDP-514 inhibited HBV DNA replication with an EC50 of 18, 27 and 17 nM in HepAD38, HepDE19 and HepG2.2.15 cells, respectively. In addition, EDP-514 prevented the de novo formation of cccDNA in primary human hepatocytes with an EC50 of 35 nM. The compound was active across HBV genotypes A-H with potencies ranging from 9-32 nM and its efficacy was not affected by known nucleos(t)ide resistant variants. Combination of EDP-514 with nucleos(t)ide or class I core inhibitors led to synergistic antiviral effect in vitro. Moreover, EDP- 514, given orally at 25, 50, 75 and 100 mg/kg BID, reduced HBV DNA by 2.75, 3.42, 3.27 and 4.13 logs, respectively, in PXB mice after 10 weeks of treatment.
[Graph of HBV DNA degradation vs time]
Conclusion: EDP-514 is a novel HBV core inhibitor with an attractive preclinical profile. It is a potent inhibitor of HBV replication and prevents de novo cccDNA formation. In vivo, EDP-514 treatment of HBV-infected PXB mice results in a rapid and sustained viral load reduction of >4-log. Overall, these data support the further development of EDP-514 as a therapeutic candidate for the treatment of HBV.
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