Xofluza

Baloxavir marboxil is a prodrug that is converted by hydrolysis to its active metabolite, baloxavir, the active form that exerts anti-influenza activity.Baloxavir acts on the cap-dependent endonuclease (CEN), an influenza virus-specific enzyme in the polymerase acidic (PA) subunit of the viral RNA polymerase complex and thereby inhibits the transcription of influenza virus genomes resulting in inhibition of influenza virus replication. The 50% inhibition concentration (IC50) of baloxavir was 1.4 to 3.1 nmol/L for influenza A viruses and 4.5 to 8.9 nmol/L for influenza B viruses in an enzyme inhibition assay. Nonclinical studies demonstrate potent antiviral activity of baloxavir against influenza A and B virus in vitro and in vivo. The antiviral activity of baloxavir against laboratory strains and clinical isolates of influenza A and B viruses was determined in the Madin-Darby Canine Kidney (MDCK) cell culture assay. The median 50% effective concentration (EC50) values of baloxavir were 0.73 nmol/L (n = 31; range: 0.20 to 1.85 nmol/L) for subtype A/H1N1 strains, 0.83 nmol/L (n = 33; range: 0.35 to 2.63 nmol/L) for subtype A/H3N2 strains, and 5.97 nmol/L (n = 30; range: 2.67 to 14.23 nmol/L) for type B strains. In a MDCK cell-based virus titre reduction assay, the 90% effective concentration (EC90) values of baloxavir were in the range of 0.46 to 0.98 nmol/L for subtype A/H1N1 and A/H3N2 viruses, 0.80 to 3.16 nmol/L for avian subtype A/H5N1 and A/H7N9 viruses, and 2.21 to 6.48 nmol/L for type B viruses. Viruses bearing the PA/I38T/M mutation selected in vitro or in clinical studies show reduced susceptibility to baloxavir. Baloxavir is active against neuraminidase inhibitor resistant strains including H274Y in A/H1N1, E119V and R292K in A/H3N2, and R152K and D198E in type B virus, H274Y in A/H5N1, R292K in A/H7N9.The relationship between antiviral activity in cell culture and inhibition of influenza virus replication in humans has not been established.