Efficacy of favipiravir (T-705) in nonhuman primates infected with Ebola virus or Marburg virus

Abstract

Favipiravir is a broad-spectrum antiviral agent that has demonstrated efficacy against Ebola virus (EBOV) in rodents. However, there are no published reports of favipiravir efficacy for filovirus infection of nonhuman primates (NHPs). Here we evaluated the pharmacokinetic profile of favipiravir in NHPs, as well as in vivo efficacy against two filoviruses, EBOV and Marburg virus (MARV). While no survival benefit was observed in two studies employing once- or twice-daily oral dosing of favipiravir during EBOV infection of NHPs, an antiviral effect was observed in terms of extended time-to-death and reduced levels of viral RNA. However, oral dosing in biosafety level-4 (BSL-4) presents logistical and technical challenges, and repeated anesthesia events may potentially worsen survival outcome in animals. For the third study of treatment of MARV infection, we therefore made use of catheters, jackets, and tethers for intravenous (IV) dosing and blood collection, which minimized the requirement for repeated anesthesia events. When MARV infection was treated with IV favipiravir, five of six animals (83%) survived infection, while all untreated NHPs succumbed. An accompanying report presents the results of favipiravir treatment of EBOV infection in mice.

Perspectives towards antiviral drug discovery against Ebola virus

“…Favipiravir (T‐705) remained a potential anti‐EBOV candidate during the West‐Africa outbreak and has reported up to 100% survival rate in EBOV‐infected mice even with the lowest oral dose of 37.5 mg/kg once daily. In comparison, NHP resulted in 17% to 50% survival rate …”

Antivirals in medical biodefense

“…FDA approval for use of favipiravir to treat filovirus infections is pending. Several animal pilot studies, most recently in non-human primates (NHP), have shown the efficacy of favipiravir [13,14]). While extensively tested, ribavirin is not FDA approved for EBOV [65].…”

“…Broad-spectrum antivirals on the other hand show significant activity against several members of the same or distinct virus families, allowing the empirical treatment of severe viral infections prior to positive diagnosis of the viral agent. Leading examples are at his point the pyrazinecarboxamide compounds T-705 (favipiravir; [2,7,48]), T-1105 and T-1106, which are broad-spectrum viral RNA polymerase inhibitors, initially developed for the treatment of influenza virus, and found effective against bunyaviruses [21,54,59], alphaviruses [1], filoviruses [13] arenaviruses [125], paramyxoviruses [29], and flaviviruses [128]. A favipiravir resistance mechanism in influenza virus has been described [52].…”

Current status of small molecule drug development for Ebola virus and other filoviruses

“…Nucleoside analogues BXC4430, an adenosine analogue, GS-5734 (Remdesivir, Gilead, USA), a monophosphoramidate prodrug of an adenosine analogue and favipiravir (T-705, Toyama Chemical, Japan), a synthetic guanidine nucleoside analogue, exhibit anti-filovirus activity, likely through inhibition of viral polymerase activity [41][42][43]. BXC4430 was the first small molecule demonstrated to protect non-human primates from lethal filovirus challenge, even when administered up to two days post-infection [43].…”

“…It likely acts as a "pseudo purine", inhibiting influenza virus RdRp activity with selectivity towards viral over cellular polymerases [47]. Favipiravir demonstrated protection of type I interferon receptor (IFNAR) knockout mice and immunocompetent C57BL/6 mice from challenge with EBOV and mouse-adapted EBOV (MA-EBOV), respectively [41,48,49]. When tested in macaques, favipiravir administered orally once or twice daily resulted in only one survivor out of eighteen EBOV infected animals, although delayed time to death and reduced viral levels were documented [41].…”