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A Novel Orally Available Small Molecule That Inhibits Hepatitis B Virus Expression

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A Novel Orally Available Small Molecule That Inhibits Hepatitis B Virus Expression. / Mueller, Henrik; Wildum, Steffen; Luangsay, Souphalone; Walther, Johanna; Lopez, Anais; Tropberger, Philipp; Ottaviani, Giorgio; Lu, Wenzhe; John Parrott, Neil; Zhang, Jitao David; Schmucki, Roland; Racek, Tomas; Hoflack, Jean-Christophe; Kueng, Erich; Point, Floriane; Zhou, Xue; Steiner, Guido; Lütgehetmann, Marc; Rapp, Gianna; Volz, Tassilo; Dandri, Maura; Yang, Song; Young, John A T; Javanbakht, Hassan.

In: J HEPATOL, Vol. 68, No. 3, 03.2018, p. 412-420.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Mueller, H, Wildum, S, Luangsay, S, Walther, J, Lopez, A, Tropberger, P, Ottaviani, G, Lu, W, John Parrott, N, Zhang, JD, Schmucki, R, Racek, T, Hoflack, J-C, Kueng, E, Point, F, Zhou, X, Steiner, G, Lütgehetmann, M, Rapp, G, Volz, T, Dandri, M, Yang, S, Young, JAT & Javanbakht, H 2018, 'A Novel Orally Available Small Molecule That Inhibits Hepatitis B Virus Expression', J HEPATOL, vol. 68, no. 3, pp. 412-420. https://doi.org/10.1016/j.jhep.2017.10.014

APA

Mueller, H., Wildum, S., Luangsay, S., Walther, J., Lopez, A., Tropberger, P., Ottaviani, G., Lu, W., John Parrott, N., Zhang, J. D., Schmucki, R., Racek, T., Hoflack, J-C., Kueng, E., Point, F., Zhou, X., Steiner, G., Lütgehetmann, M., Rapp, G., ... Javanbakht, H. (2018). A Novel Orally Available Small Molecule That Inhibits Hepatitis B Virus Expression. J HEPATOL, 68(3), 412-420. https://doi.org/10.1016/j.jhep.2017.10.014

Vancouver

Mueller H, Wildum S, Luangsay S, Walther J, Lopez A, Tropberger P et al. A Novel Orally Available Small Molecule That Inhibits Hepatitis B Virus Expression. J HEPATOL. 2018 Mar;68(3):412-420. https://doi.org/10.1016/j.jhep.2017.10.014

Bibtex

@article{02d3c260392343688e6fcaa452d8b141,
title = "A Novel Orally Available Small Molecule That Inhibits Hepatitis B Virus Expression",
abstract = "BACKGROUND & AIMS: The hallmarks of chronic HBV infection are a high viral load (HBV DNA) and even higher levels (>100-fold in excess of virions) of non-infectious membranous particles containing the tolerogenic viral S antigen (HBsAg). Currently, standard treatment effectively reduces viremia but only rarely results in a functional cure (defined as sustained HBsAg loss). There is an urgent need to identify novel therapies that reduce HBsAg levels and restore virus-specific immune responsiveness in patients. We report the discovery of a novel, potent and orally bioavailable small molecule inhibitor of HBV gene expression (RG7834).METHODS: RG7834 antiviral characteristics and selectivity against HBV were evaluated in HBV natural infection assays and in a urokinase-type plasminogen activator/severe combined immunodeficiency humanized mouse model of HBV infection, either alone or in combination with entecavir.RESULTS: Unlike nucleos(t)ide therapies, which reduce viremia but do not lead to an effective reduction in HBV antigen expression, RG7834 significantly reduced the levels of viral proteins (including HBsAg), as well as lowering viremia. Consistent with its proposed mechanism of action, time course RNA-seq analysis revealed a fast and selective reduction in HBV mRNAs in response to RG7834 treatment. Furthermore, oral treatment of HBV-infected humanized mice with RG7834 led to a mean HBsAg reduction of 1.09 log10 compared to entecavir, which had no significant effect on HBsAg levels. Combination of RG7834, entecavir and pegylated interferon α-2a led to significant reductions of both HBV DNA and HBsAg levels in humanized mice.CONCLUSION: We have identified a novel oral HBV viral gene expression inhibitor that blocks viral antigen and virion production, that is highly selective for HBV, and has a unique antiviral profile that is clearly differentiated from nucleos(t)ide analogues.LAY SUMMARY: We discovered a novel small molecule viral expression inhibitor that is highly selective for HBV and unlike current therapy inhibits the expression of viral proteins by specifically reducing HBV mRNAs. RG7834 can therefore potentially provide anti-HBV benefits and increase HBV cure rates, by direct reduction of viral agents needed to complete the viral life cycle, as well as a reduction of viral agents involved in evasion of the host immune responses.",
keywords = "Journal Article",
author = "Henrik Mueller and Steffen Wildum and Souphalone Luangsay and Johanna Walther and Anais Lopez and Philipp Tropberger and Giorgio Ottaviani and Wenzhe Lu and {John Parrott}, Neil and Zhang, {Jitao David} and Roland Schmucki and Tomas Racek and Jean-Christophe Hoflack and Erich Kueng and Floriane Point and Xue Zhou and Guido Steiner and Marc L{\"u}tgehetmann and Gianna Rapp and Tassilo Volz and Maura Dandri and Song Yang and Young, {John A T} and Hassan Javanbakht",
note = "Copyright {\textcopyright} 2017. Published by Elsevier B.V.",
year = "2018",
month = mar,
doi = "10.1016/j.jhep.2017.10.014",
language = "English",
volume = "68",
pages = "412--420",
journal = "J HEPATOL",
issn = "0168-8278",
publisher = "Elsevier",
number = "3",

}

RIS

TY - JOUR

T1 - A Novel Orally Available Small Molecule That Inhibits Hepatitis B Virus Expression

AU - Mueller, Henrik

AU - Wildum, Steffen

AU - Luangsay, Souphalone

AU - Walther, Johanna

AU - Lopez, Anais

AU - Tropberger, Philipp

AU - Ottaviani, Giorgio

AU - Lu, Wenzhe

AU - John Parrott, Neil

AU - Zhang, Jitao David

AU - Schmucki, Roland

AU - Racek, Tomas

AU - Hoflack, Jean-Christophe

AU - Kueng, Erich

AU - Point, Floriane

AU - Zhou, Xue

AU - Steiner, Guido

AU - Lütgehetmann, Marc

AU - Rapp, Gianna

AU - Volz, Tassilo

AU - Dandri, Maura

AU - Yang, Song

AU - Young, John A T

AU - Javanbakht, Hassan

N1 - Copyright © 2017. Published by Elsevier B.V.

PY - 2018/3

Y1 - 2018/3

N2 - BACKGROUND & AIMS: The hallmarks of chronic HBV infection are a high viral load (HBV DNA) and even higher levels (>100-fold in excess of virions) of non-infectious membranous particles containing the tolerogenic viral S antigen (HBsAg). Currently, standard treatment effectively reduces viremia but only rarely results in a functional cure (defined as sustained HBsAg loss). There is an urgent need to identify novel therapies that reduce HBsAg levels and restore virus-specific immune responsiveness in patients. We report the discovery of a novel, potent and orally bioavailable small molecule inhibitor of HBV gene expression (RG7834).METHODS: RG7834 antiviral characteristics and selectivity against HBV were evaluated in HBV natural infection assays and in a urokinase-type plasminogen activator/severe combined immunodeficiency humanized mouse model of HBV infection, either alone or in combination with entecavir.RESULTS: Unlike nucleos(t)ide therapies, which reduce viremia but do not lead to an effective reduction in HBV antigen expression, RG7834 significantly reduced the levels of viral proteins (including HBsAg), as well as lowering viremia. Consistent with its proposed mechanism of action, time course RNA-seq analysis revealed a fast and selective reduction in HBV mRNAs in response to RG7834 treatment. Furthermore, oral treatment of HBV-infected humanized mice with RG7834 led to a mean HBsAg reduction of 1.09 log10 compared to entecavir, which had no significant effect on HBsAg levels. Combination of RG7834, entecavir and pegylated interferon α-2a led to significant reductions of both HBV DNA and HBsAg levels in humanized mice.CONCLUSION: We have identified a novel oral HBV viral gene expression inhibitor that blocks viral antigen and virion production, that is highly selective for HBV, and has a unique antiviral profile that is clearly differentiated from nucleos(t)ide analogues.LAY SUMMARY: We discovered a novel small molecule viral expression inhibitor that is highly selective for HBV and unlike current therapy inhibits the expression of viral proteins by specifically reducing HBV mRNAs. RG7834 can therefore potentially provide anti-HBV benefits and increase HBV cure rates, by direct reduction of viral agents needed to complete the viral life cycle, as well as a reduction of viral agents involved in evasion of the host immune responses.

AB - BACKGROUND & AIMS: The hallmarks of chronic HBV infection are a high viral load (HBV DNA) and even higher levels (>100-fold in excess of virions) of non-infectious membranous particles containing the tolerogenic viral S antigen (HBsAg). Currently, standard treatment effectively reduces viremia but only rarely results in a functional cure (defined as sustained HBsAg loss). There is an urgent need to identify novel therapies that reduce HBsAg levels and restore virus-specific immune responsiveness in patients. We report the discovery of a novel, potent and orally bioavailable small molecule inhibitor of HBV gene expression (RG7834).METHODS: RG7834 antiviral characteristics and selectivity against HBV were evaluated in HBV natural infection assays and in a urokinase-type plasminogen activator/severe combined immunodeficiency humanized mouse model of HBV infection, either alone or in combination with entecavir.RESULTS: Unlike nucleos(t)ide therapies, which reduce viremia but do not lead to an effective reduction in HBV antigen expression, RG7834 significantly reduced the levels of viral proteins (including HBsAg), as well as lowering viremia. Consistent with its proposed mechanism of action, time course RNA-seq analysis revealed a fast and selective reduction in HBV mRNAs in response to RG7834 treatment. Furthermore, oral treatment of HBV-infected humanized mice with RG7834 led to a mean HBsAg reduction of 1.09 log10 compared to entecavir, which had no significant effect on HBsAg levels. Combination of RG7834, entecavir and pegylated interferon α-2a led to significant reductions of both HBV DNA and HBsAg levels in humanized mice.CONCLUSION: We have identified a novel oral HBV viral gene expression inhibitor that blocks viral antigen and virion production, that is highly selective for HBV, and has a unique antiviral profile that is clearly differentiated from nucleos(t)ide analogues.LAY SUMMARY: We discovered a novel small molecule viral expression inhibitor that is highly selective for HBV and unlike current therapy inhibits the expression of viral proteins by specifically reducing HBV mRNAs. RG7834 can therefore potentially provide anti-HBV benefits and increase HBV cure rates, by direct reduction of viral agents needed to complete the viral life cycle, as well as a reduction of viral agents involved in evasion of the host immune responses.

KW - Journal Article

U2 - 10.1016/j.jhep.2017.10.014

DO - 10.1016/j.jhep.2017.10.014

M3 - SCORING: Journal article

C2 - 29079285

VL - 68

SP - 412

EP - 420

JO - J HEPATOL

JF - J HEPATOL

SN - 0168-8278

IS - 3

ER -