A novel orally available small molecule that inhibits hepatitis B virus expression
Authors: Henrik Mueller, Steffen Wildum, Souphalone Luangsay, Johanna Walther, Anaïs Lopez, Philipp Tropberger, Giorgio Ottaviani, Wenzhe Lu, Neil John Parrott, Jitao David Zhang, Roland Schmucki, Tomas Racek, Jean-Christophe Hoflack, Erich Kueng, Floriane Point, Xue Zhou, Guido Steiner, Marc Lütgehetmann, Gianna Rapp, Tassilo Volz, Maura Dandri, Song Yang, John A.T. Young, Hassan Javanbakht
Journal: Journal of Hepatology (2017)

Highlights•RG7834 is a novel orally bioavailable HBV viral gene expression inhibitor.•The effect of RG7834 on HBV expression levels is highly virus-specific.•The unique antiviral profile is differentiated from that of nucleos(t)ide analogues.•Combination with entecavir and/or PegIFNα improves the antiviral profile and potency.Graphical abstractAbstractBackground & AimsThe 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).MethodsRG7834 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.ResultsUnlike 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.ConclusionWe 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 summaryWe 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.