No Robust Evidence for Favipiravir to Treat COVID-19

There has been a lot of hype in media news outlets and twitter about any possible medication that can be repurposed to treat COVID-19. However, in times like these we need to fully evaluate the evidence to discern what is fact and fiction.

One medication that received a lot of excitement in the past couple days is favipiravir, a Japanese antiviral drug that was originally designed to treat influenza. For example, here are the headlines you find if you search twitter for this drug:

Source: Twitter

In this post, I’ll describe the latest research literature I found for favipiravir in COVID-19.

Background

Favipiravir was developed in a joint industry collaboration with Toyama Chemical with the hopes of developing a medication better than Tamiflu (oseltamivir) to treat influenza.

In mice, Takahashi et al. showed that favipiravir is more effective than oseltamivir for lethal influenza and does not easily produce drug-resistant virus strains.

Source Takahashi et al. Antiviral Chemistry and Chemotherapy, 2003

However, favipiravir was found to have significant teratogenic and embryotoxic side effects, so this medication was not recommended for general use, but the Japanese government stockpiled this drug in case they needed it for future influenza pandemics.

Mechanism of Action

Favipiravir is a selective and potent inhibitor RNA-dependent RNA polymerase (RdRp), which halts replication of the viral genome. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC549233/

Favipiravir reduces production of RNA polymerase
Source: Furuta et al. 2005

This is why clinicians and scientists thought that this medication can be repurposed to treat other RNA viruses.

Anti-Viral Activity Against RNA Viruses

Favipiravir has been tried against a variety of RNA viruses including arena-, bunya-, falvi-, and filo- viruses, all of which are without a vaccine or existing effective antiviral therapy. In all of these cases, favipiravir did show mortality improvement in mice infected with virus. Notably, there has been no substantial evidence that showed efficacy for favipiravir in animal models of coronavirus like SARS or MERS. Source: https://www.ncbi.nlm.nih.gov/pubmed/28769016

A summary of the prior uses of favipiravir against other RNA viruses is tabled below. More detail is here: https://www.ncbi.nlm.nih.gov/pubmed/32097670

Source: Shiraki and Daikoku. Pharmacological Therapy 2020.

No Robust Support of Favipiravir in COVID-19

The evidence for favipiravir in COVID-19 has been limited to date.

Wang et al. showed that the selective antiviral activity against COVID-19 in vitro was relatively weak (EC = 62 mM) and came at the cost of significant cytotoxicity. In their experience, Wang et al. showed that remdesivir and chloroquine were far more effective antiviral medications. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054408/

Source: Wang et al. Cell Research 2020

The clinical experience with favipiravir has not been definitive. Most of the reported experiences have been from anecdote and media reports quoting individual doctor experiences, such as the following:

One clinical study I found online showed that favipiravir was not more effective than arbidol, another broad spectrum antiviral drug. Full details are here: https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v1.full.pdf

Source: Chen et al. 2020
https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v1.full.pdf

Another clinical study I found online showed that favipiravir was more effective than lopinavir/rotonavir in treating COVID-19. The authors claimed that patients who received favipiravir had a shorter viral clearance time and greater improvement in chest imaging findings. They excluded all pregnant women and reported minimal adverse side effects with this therapy. More details here: https://www.sciencedirect.com/science/article/pii/S2095809920300631. I personally struggle in interpreting this trial because we recently saw from NEJM that the lopinavir/rotonavir is not better than placebo, so I am not sure how to interpret this research. I would need to see another study to make a claim one way or the other.

Source: Cai et al. 2020
https://www.sciencedirect.com/science/article/pii/S2095809920300631#f0015

Summary

Favipiravir is an antiviral drug that was optimized to treat against influenza. However, there has been no significant evidence showing that this drug is effective against coronavirus, especially considering this drug comes with significant cytotoxic and teratogenic side effects.

We still are awaiting more evidence for favipiravir, but I do not anticipate positive results for this drug given that the in vitro experiments and current clinical experience are not robustly supportive.

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