Favipiravir: a preclinical study shows lack of antiviral efficacy against SARS-CoV-2 but potential utility against Zika

07 September 2022
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A study by researchers from the French Alternative Energies and Atomic Energy Commission (CEA), Inserm and University Paris Cité, who are part of the Preclinical Studies Group (GEPC)* set up by ANRS | Emerging Infectious Diseases, evaluated the effects of favipiravir on SARS-CoV-2 and the Zika virus in the reference animal model, the cynomolgus macaque. Although the researchers have shown the drug to possess antiviral activity against Zika, it is ineffective against SARS-CoV-2 in this model and could even make the disease worse. This study was published on 30 August 2022 in Nature Communications.

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During the COVID-19 pandemic, many drugs underwent clinical trials without actually providing compelling evidence of efficacy against SARS-CoV-2. While hydroxychloroquine is what the general public first tend to think of, it is not the only molecule to have been studied by the scientific community for its potential efficacy. Favipiravir, originally developed to treat severe influenza, is now being used, particularly in Asia, to fight COVID-19. Yet the evidence of its efficacy is so far limited to in vitro tests and clinical studies that are difficult to interpret due to their size or the risks of bias.

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For several years, the French scientists of the GEPC had studied favipiravir as a potential frontline weapon against emerging viruses, particularly viral haemorrhagic fevers such as Ebola and Lassa. 

 

Armed with this experience, the researchers studied favipiravir’s antiviral activity against SARS-CoV-2 in animals by administering different doses of favipiravir or placebo to cynomolgus macaques. This experimental model of infection is very useful because it reproduces a disease very similar to that observed in humans, and had already demonstrated hydroxychloroquine’s inefficacy in a paper published in Nature in 2020. In these new experiments, no effect on viral load was observed in SARS-CoV-2-infected animals treated with favipiravir, even at high doses. What is more, a negative change was observed in four animals following administration of the molecule, in which their condition deteriorated rapidly.

 

Following the same protocol, the scientists also tested the efficacy of favipiravir against the Zika virus. Their findings showed that this time there was a significant reduction in viral load in primates, thereby underscoring the drug’s potential utility in this indication.

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‘This study once again shows the importance of the rigorous evaluation of drugs in experimental models before they are administered to humans. While favipiravir has been tested in many clinical trials, with often difficult to interpret results, our study clearly establishes its lack of antiviral efficacy against SARS-CoV-2,’ explains Romain Marlin, co-first author of the study and project manager at CEA, in charge of preclinical immunotherapy and vaccine programmes (Infectious Diseases Models for Innovative Therapies (IDMIT), François Jacob Institute of Biology of the CEA).

‘However, these findings are not predictive of favipiravir’s activity against other viruses, as our results with Zika show. Human studies are ongoing with the support of ANRS | Emerging Infectious Diseases to evaluate its potential in other indications, particularly Lassa fever virus, for which there is no antiviral treatment,’ explains Inserm research director Jérémie Guedj (Infection, Antimicrobials, Modelling, Evolution (IAME) laboratory, Inserm / Université Paris Cité / Sorbonne Paris Nord University), study co-principal investigator with Roger Le Grand, research director at the CEA (IDMIT, François Jacob Institute of Biology of the CEA).

 

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*The Preclinical Studies Group (GEPC), which brings together animal model specialists, virologists, clinicians, pharmacologists, biostatisticians, veterinarians, biochemists and modellers among others, was established by ANRS | Emerging Infectious Diseases in order to evaluate as rigorously as possible (in non-human, in vitro or in vivo models) therapeutic candidates prior to human trials, and prioritise the most promising molecules.

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This study was funded by the Foundation for Medical Research (FRM), the TRANSVAC2 European infrastructure, the Auvergne-Rhône-Alpes region, ANRS | Emerging Infectious Diseases (through the former REACTing consortium) and the ZIKAlliance project, which received funding from the European Union Horizon 2020 research and innovation programme.
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Antiviral efficacy of favipiravir against Zika and SARS-CoV-2 viruses in non-human primates

Romain Marlin (1), Delphine Desjardins (2), Vanessa Contreras (3), Guillaume Lingas (2), Caroline Solas (3), Pierre Roques (1), Thibaut Naninck (1), Quentin Pascal (1), Sylvie Behillil (4), Pauline Maisonnasse (1), Julien Lemaitre (1), Nidhal Kahlaoui (1), Benoit Delache (1), Andrés Pizzorno (6), Antoine Nougairede (7), Camille Ludot (1), Olivier Terrier (6), Nathalie Dereuddre-Bosquet (1), Francis Relouzat (1), Catherine Chapon (1), Raphael Ho Tsong Fang (1), Sylvie van der Werf (4,5), Manuel Rosa Calatrava (6,8), Denis Malvy (9), Xavier de Lamballerie (7), Jérémie Guedj (2),  Roger Le Grand (1).
 

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1.    Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases » (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
2.    Université de Paris, INSERM, IAME, F-75018, Paris, France
3.    Aix-Marseille Univ, APHM, Unité des Virus Emergents (UVE) IRD 190, INSERM 1207, Laboratoire de Pharmacocinétique et Toxicologie, Hôpital La Timone, 13005, Marseille, France
4.    Unité de Génétique Moléculaire des Virus à ARN, GMVR, Institut Pasteur, UMR CNRS 3569, Université de Paris, Paris, France
5.    Centre National de Référence des Virus des infections respiratoires (dont la grippe), Institut Pasteur, Paris, France
6.    CIRI, Centre International de Recherche en Infectiologie, (Team VirPath), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
7.    Unité des Virus Emergents, UVE: Aix Marseille Univ, IRD 190, INSERM 1207, IHU Méditerranée Infection, 13005, Marseille, France
8.    VirNext, Université Claude Bernard Lyon 1, Faculté de Médecine Laennec, Lyon, France
9.    Department of infectious ad tropical diseases, University hopsital, Bordeaux & Inserm 1219/IRD, Bordeaux University, Bordeaux, France
10.    Infectious Diseases Models for Innovative Tharapies, département de l’Institut de Biologie 
11.    François Jacob du CEA

Nature Communications, 30 août 2022
https://doi.org/10.1038/s41467-022-32565-w
 

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Contacts presse : 

ANRS | Maladies infectieuses émergentes : information@anrs.fr
www.anrs.fr

Fondation pour la Recherche Médicale (FRM) : valerie.riedinger@frm.org 
https://www.frm.org/ 

Union européenne : andreas.holtel@ec.europa.eu 
https://ec.europa.eu/info/index_fr

Région Auvergne-Rhône-Alpes : presse@auvergnerhonealpes.fr https://www.auvergnerhonealpes.fr/

CEA : marine.masse@cea.fr
https://www.cea.fr/ 

Inserm : presse@inserm.fr 
https://www.inserm.fr/

Université Paris Cité : presse@u-paris.fr 
https://u-paris.fr/