Timing-specific efficacy of antiviral baloxavir and anti-inflammatory oclacitinib monotherapies, and the benefits of their combination in treating influenza in mice

Excessive inflammation from uncontrolled pro-inflammatory cytokine release is a leading cause of mortality in influenza virus infections. Anti-inflammatory therapies, particularly Janus kinase (JAK) inhibitors, have demonstrated protective effects in murine models against lethal influenza virus infections, particularly during the later stages of infection. This study investigates the potential synergy of combining antiviral and anti-inflammatory medications to extend the treatment window for influenza. We assessed the in vivo therapeutic windows of the antiviral baloxavir and the JAK inhibitor oclacitinib, both as monotherapies and in combination. Baloxavir proved highly effective when administered early during influenza infections; however, its efficacy rapidly declined with administration 1 day post-infection (p.i.) and was nearly absent by 2 days. In contrast, administration of oclacitinib at the mid-stage of disease effectively protected mice from lethal infections. The combination therapy of baloxavir and oclacitinib significantly extended the therapeutic window compared to monotherapies alone. The data indicate that the combination of baloxavir and oclacitinib not only extends the therapeutic window for both agents but also presents a promising new approach for treating influenza virus infections. These findings highlight the potential benefits of combining antiviral and anti-inflammatory therapies to enhance patient outcomes.