Research Article: Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models

Date Published: May 20, 2019

Publisher: Public Library of Science

Author(s): Keita Fukao, Yoshinori Ando, Takeshi Noshi, Mitsutaka Kitano, Takahiro Noda, Makoto Kawai, Ryu Yoshida, Akihiko Sato, Takao Shishido, Akira Naito, Stefan Pöhlmann.

http://doi.org/10.1371/journal.pone.0217307

Abstract

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.

Partial Text

Influenza virus can rapidly spread in populations and are responsible for seasonal influenza epidemics around the world every year [1]. Influenza virus infection can lead to serious and fatal outcomes, especially in elderly or immunocompromised patients [2]. Although influenza vaccination represents the key option for preventing influenza virus infection and some strategies have been investigated to optimize immunogenicity by exploring new vaccines, vaccination doses, timing or adjuvants, its benefit in immunocompromised individuals is somewhat controversial [3, 4]. Additionally, vaccine mismatch has frequently occurred between the vaccine strain and the circulating strain [5]. Therefore, anti-influenza drugs play an important role in the control of influenza virus infections especially for patients with or at risk of severe infection and complications.

In this study, we demonstrated that oral administration of BXM was more effective than OSP for reducing mortality and virus titers and for ameliorating influenza symptoms in mice even when treatment was delayed, offering the basis for further investigation with both immunocompetent and immunocompromised patients.

We demonstrated that oral administration of BXM had beneficial effects on survival, virus titers and signs of infection in not only immunocompetent but also immunocompromised mice infected with influenza A virus even when treatment was delayed until 4 or 5 days p.i., suggesting that treatment with BXM may extend the therapeutic window for patients with influenza virus infection.

 

Source:

http://doi.org/10.1371/journal.pone.0217307

 

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