Enisamium reduces influenza virus shedding and improves patient recovery by inhibiting viral RNA polymerase activity.

Infections with respiratory viruses constitute a huge burden on our health and economy. Antivirals against some respiratory viruses are available, but further options are urgently needed. Enisamium iodide (laboratory code FAV00A, trade name Amizon®) is an antiviral marketed in countries of the Commonwealth of Independent States for the treatment of viral respiratory infections, but its clinical efficacy and mode of action are not well understood. Here, we investigated the efficacy of enisamium in patients aged between 18-60 years with confirmed influenza and other viral respiratory infections. Enisamium treatment resulted in reduced influenza virus shedding (at day 3, 71.2% in enisamium group tested negative versus 25.0% in placebo group, p < 0.0001), faster patient recovery (at day 14, 93.9% in enisamium group had recovered versus 32.5% in placebo group, p < 0.0001), and reduced disease symptoms compared to placebo (from 9.6 ± 0.7 to 4.6 ± 0.9 score points in enisamium group versus 9.7 ± 1.1 to 5.6 ± 1.1 score points in placebo group, p < 0.0001). Using mass-spectrometry, and cell-based and cell-free viral RNA synthesis assays, we identified a hydroxylated metabolite of enisamium, VR17-04. VR17-04 is capable of inhibiting influenza virus RNA synthesis and present in plasma of patients treated with enisamium. VR17-04 inhibits the activity of the influenza virus RNA polymerase more potently than its parent compound. Overall, these results suggest that enisamium is metabolized in humans to an inhibitor of the influenza virus RNA polymerase that reduces viral shedding and improves patient recovery in influenza patients.