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.

Highlights

  • Influenza virus can rapidly spread in populations and are responsible for seasonal influenza epidemics around the world every year [1]

  • We previously reported that Baloxavir marboxil (BXM) monotherapy or in combination with oseltamivir achieved significant reductions in virus titer and ameliorated signs of infection arising from a lethal dose of A/Puerto Rico (PR)/8/34 (H1N1) strain in a mouse model [20]

  • Significant inhibitions in body weight loss were observed in the groups treated with oseltamivir phosphate (OSP) at 24 and 48 hours p.i. compared with the control group, while the groups treated with OSP at 72 and 96 hours p.i. showed body weight loss comparable to the vehicle-treated group. These results suggest that BXM expands the therapeutic window and provides superior therapeutic benefit compared with OSP in our mouse model

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Summary

Introduction

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]. Therapeutic effect of Baloxavir marboxil in both immunocompetent and immunocompromised mouse model have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

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