The combined treatment of Molnupiravir and Favipiravir results in a marked potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model

Abstract

Since its emergence in Wuhan, China in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide resulting in a global pandemic with >2 million deaths within a year of the emergence of the virus. In the search for small molecule inhibitors of SARS-CoV-2 Molnupiravir (EIDD-2801), an orally bioavailable nucleoside analog that was originally developed as an antiviral against influenza viruses but that exerts also activity against a number of other RNA viruses, including SARS-CoV2 and other coronaviruses. We here report on the effect of EIDD-2801 in a well-established Syrian hamster SARS-CoV-2 infection model. Oral treatment of SARS-CoV-2-infected hamsters with EIDD-2801 for four consecutive days, starting from the day of infection, significantly reduced infectious virus titers and viral RNA loads in the lungs and markedly improved lung histopathology in a dose-dependent manner when assessed at 4 dpi. When onset of treatment with 500 mg/kg/dose was delayed until 24h post-infection, a modest but significant antiviral effect was observed. When suboptimal doses of both favipiravir (300 mg/kg, BID) and EIDD-2801 (150 mg/kg, BID) were combined, a complete reduction (~5 log10) of infectious virus titers was observed in the lungs of most of the combo-treated animals whereas either compound alone resulted in a reduction of respectively 1.2 and 1.3 log10. The potential of EIDD-2801 for the treatment and/or prevention of SARS-CoV-2 alone or in combination with favipiravir deserves further attention.

Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model

“…With the efficacy of molnupiravir unaffected by mutations in VoCs B.1.1.7 and B.1.351, and taking into consideration that molnupiravir showed promising initial results in a phase 2 clinical trial in COVID-19 patients, this compound could potentially be a panlineage SARS-CoV-2 antiviral agent as more VoCs emerge in the future. Recently, we reported on the potent antiviral effect of the combination of molnupiravir and favipiravir in the SARS-CoV-2 hamster infection model [ 7 ]. By employing it as part of combination therapy, concerns for the development of resistance to molnupiravir when this drug is used alone could be greatly reduced.…”

“…The molecule exerts its antiviral activity via incorporation into viral RNA, resulting in the accumulation of deleterious transition mutations in the nascent viral RNA, leading to error catastrophe [ 5 ]. Molnupiravir (EIDD-2801, MK-4482), the orally bioavailable prodrug counterpart of N 4 -hydroxycytidine [ 6 ], is effective against SARS-CoV-2 infections in Syrian hamsters [ 7 ], mice [ 8 ], and ferrets [ 9 ]. Data from a first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers indicate that the drug is well tolerated and that plasma exposures exceed the expected efficacious doses based on scaling from animal models [ 10 ].…”

Nelfinavir markedly improves lung pathology in SARS-CoV-2-infected Syrian hamsters despite lack of an antiviral effect

“…The model is well-suited to assess the impact of antiviral drugs as we and others have demonstrated. Notably, we have demonstrated that Favipiravir and Molnupiravir (EIDD-2801) markedly reduce SARS-CoV-2 replication in hamsters, whereas hydroxychloroquine does not (14,15).…”

“…The model is well-suited to assess the impact of antiviral drugs as we and others have demonstrated. Notably, we have demonstrated that Favipiravir and Molnupiravir (EIDD-2801) markedly reduce SARS-CoV-2 replication in hamsters, whereas hydroxychloroquine does not (14,15). Six to eight weeks female Syrian Golden hamsters were treated with Nelfinavir (15 mg/kg/dose or 50 mg/kg/dose) or the vehicle control by intraperitoneal injection (IP) within one hour before intranasal infection with 50 µl containing 2x10 6 TCID50 of SARS-CoV-2 [BetaCov/Belgium/GHB-03021/2020 (EPI ISL 109 72 407976|2020-02-03)] (Fig.…”

Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19

“…There has been some recent promising data from small clinical trials for proxalutamide treatment in men with COVID-19, another anti-androgen [22,23], and for molnupiravir, a repurposed anti-viral therapy (EIDD-2801) originally tested against influenza. Molnupiravir appears effective in-vitro and in-vivo models against COVID-19 [44], and preliminary data from small clinical trials showed improved rates of viral clearance in humans [42]. No export and drug price data for both molnupiravir and proxalutamide were found.…”