Successful treatment of Marburg virus with orally administrated T-705 (Favipiravir) in a mouse model

Abstract

Filoviruses, such as Marburg and Ebola viruses, cause severe disease in humans with high case fatality rates and are therefore considered biological threat agents. To date, no licensed vaccine or therapeutic exists for their treatment. T-705 (favipiravir) is a pyrazinecarboxamide derivative that has shown broad antiviral activity against a number of viruses and is clinically licenced in Japan to treat influenza. Here we report the efficacy of T-705 against Marburg virus infection in vitro and in vivo. Notably, oral administration of T-705 beginning one or two days post-infection and continuing for eight days resulted in complete survival of mice that had been intraperitoneally infected with mouse-adapted Marburg virus (variant Angola). Moreover, lower doses of T-705 and higher doses administered later during infection (day 3 or 4 post-infection) showed partial efficacy, with at least half the infected mice surviving. Accordingly, we observed reductions in infectious virus particles and virus RNA levels following drug treatment that appeared to correlate with survival. Our findings suggest that T-705 may be an effective therapeutic against Marburg virus and might be especially promising for use in the event of an outbreak, where it could be orally administered quickly and safely even after exposure.

Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir

“…To determine the usefulness of IFNAGR KO mice as a screening model for anti-filovirus countermeasures, we treated challenged mice with the antiviral Favipiravir. Indeed, Favipiravir was previously shown to be effective against wild-type EBOV in IFN-α/β receptor KO mouse models [ 45 , 46 , 47 ], mouse-adapted EBOV and MARV in respectively C57BL/6 or BALB/c mouse model [ 47 , 48 , 49 ], guinea pig-adapted SUDV in the guinea pig model [ 50 ] and wild-type EBOV or MARV in the NHP models [ 51 , 52 ]. Here, Favipiravir treatment was initiated 1 hour post-infection and infected mice were treated twice daily for 8 days.…”

“…Both immunocompromised and wild type mouse models have proved their usefulness in antiviral drug discovery. For example, favipiravir that selectively inhibits the RNA-dependent RNA polymerase [ 63 ] has been shown to provide protection to multiple mouse models, including IFN α/β KO [ 45 ], and NHPs challenged with EBOV or MARV [ 46 , 47 , 48 , 49 , 52 ]. As a proof of concept that IFNAGR KO mice may be used for initial screens of antivirals, we chose to treat EBOV-infected mice with favipiravir.…”

Favipiravir, an anti-influenza drug against life-threatening RNA virus infections

“…Crimean-Congo hemorrhagic fever 3-30% a (Hawman, et al, 2018;Oestereich, Rieger, et al, 2014) Western equine encephalitis 3-4, 8-15% d (Julander, Smee, Morrey, & Furuta, 2009b) Marburg virus infection 50% a , 24% to 88% a (Bixler, et al, 2018;Zhu, et al, 2018) Argentine hemorrhagic fever virus infection 15-30% e Gowen, Westover, Sefing, et al, 2017b;Mendenhall, et al, 2011;Westover, et al, 2016) Rift Valley fever virus infection 1% a , hemorrhagic form 50% a (Caroline, et al, 2014;Gowen, et al, 2007;Scharton, et al, 2014) Yellow fever virus infection 7 to 65.2% c 30,000 deaths/year c (Gowen, et al, 2010;Julander, Shafer, Smee, Morrey, & Furuta, 2009a) Hemorrhagic fever with renal syndrome 5-15% b (Safronetz, et al, 2013) Hantavirus pulmonary syndrome 18.6% to 40% a , 38% b J o u r n a l P r e -p r o o f…”

Potential molecular targets of nonstructural proteins for the development of antiviral drugs against SARS-CoV-2 infection

“…Favipiravir (T-705) is a selective and potent inhibitor of the RdRp of RNA viruses that was discovered by Toyama Chemical Co., Ltd., for the treatment of influenza virus [ 119 ] through the chemical modification of a pyrazine analog. Favipiravir is a broad-spectrum inhibitor that is effective against most influenza viruses (including drug-resistant influenza [ 120 ]) and some other RNA viruses [ [121] , [122] , [123] , [124] ]. However, due to the risk of teratogenicity and embryotoxicity, it is approved for only restricted clinical use against NAI-resistant pandemic influenza viruses in Japan [ 125 ].…”