Russia’s Ministry of Health recently issued a temporary registration certificate announcing that a form of favipiravir (Avigan) called Avifavir would be approved for the treatment of COVID-19. The Russian approval represents a significant milestone in the battle against COVID-19. But Russia isn’t alone. Apparently, China also approved the drug for use against COVID-19, and as reported recently by TrialSite News, so has India with a version called Fabiflu produced by Glenmark Pharmaceuticals. That Russia, China and India have approved favipiravir as a treatment against COVID-19 suggests a closer look at this antiviral targeting the novel coronavirus. Why aren’t there more clinical trials targeting this drug?
What is Favipiravir?
Sold under the trade name Avigan or Abigan, favipiravir is an antiviral medication used to treat influenza in Japan. The orally administered novel anti-viral compound includes a unique mechanism of action including action against a wide range of RNA-based viruses in laboratory tests. Presently, under study for a number of viral infections, it is a pyrazinecarboxamide derivative developed and manufactured by Toyama Chemical (Fujifilm Group) in Japan. The drug was actually approved for medical use in Japan back in 2014. The drug went into generic status in 2019.
Regulatory Filings Including DOD Investments in the Drug
Interestingly, the U.S. Department of Defense (DOD) invested initially injected $138.5 million in a partnership with MediVector, Inc. to develop favipiravir against the influenza virus. Based on completed clinical trials backed by the U.S. government, the drug evidenced safety in humans and efficacy against the influenza virus. Although the drug exhibited great promise with over 2,000 patients evidencing accelerated clearance of their influenza virus by 6 to 14 hours in the Phase III clinical trials, the U.S. sponsor MediVector and their DOD backers for whatever reason did not pursue a regulatory filing.
By 2014, Japan approved the drug for influenza strains that were found to be unresponsive to other antiviral medications. The drug’s developer, Toyama Chemical sought to use favipiravir as a replacement for Tamiflu however in animal experiments the drug revealed teratogenic effects and consequently the Japanese health authorities limited to only emergency use.
By March 15, 2020, China approved the drug for the treatment of COVID-19 and TrialSite News reported recently India approved the drug for COVID-19 as well under the name “FabiFlu.”
In a study published recently on preprint server bioRxiv titled, “Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase” a group of French and German researchers posit that “favipiravir exerts an antiviral effect as a nucleotide analogue through a combination of chain termination, slowed RNA synthesis and lethal mutagenesis.” Researchers in Italy reported that favipiravir (among other drugs including remdesivir) show promise on patients with COVID-19. Moreover, a study in China involving 80 patients evidenced that those receiving favipiravir experienced a significant reduction in the time to SARS-CoV-2 viral clearance as compared to those patients with historical controls treated with lopinavir/ritonavir.
Ongoing Clinical Trials
There are at least 23 clinical trials planned or ongoing that are based on the use of favipiravir targeting COVID-19. What follows is a brief survey of these studies by continent.
There are currently two favipiravir clinical trials targeting COVID-19 patients in the United States. TrialSite News reported on the Phase II, 50 patient favipiravir study led b Brigham and Women’s Hospital, Massachusetts General Hospital and University of Massachusetts Medical School back on April 9, 2020. The study actually started April 17 and is planned to run till the end of the year when hopefully results will follow. Participation in this study has expanded to Boston Medical Center, MA, Honor Health in Scottsdale, AZ as well as Atlantic Health System, NJ and Houston Methodist Hospital in Texas. Sponsored by Fujifilm Pharmaceuticals, U.S.A., Inc. the primary outcome measure is based on the determination of the effect of favipiravir and standard of care versus the standard of care on viral clearance of COVID-19 as measured by nasopharyngeal and oropharyngeal sampling. A number of secondary outcomes measures are targeted as well.
Stanford University is planning to initiate a Phase II clinical trial in June planned to continue till June, 2021. Stanford seeks to evaluate the efficacy of oral favipiravir plus the standard of care treatment compared with placebo plus standard of care in reducing the duration of viral shedding of SARS-CoV-2 in 120 patients with mild or asymptomatic COVID-19. The study will be led by Yvonne (Bonnie) A. Maldonado, MD.
A Milan, Italy-based hospital system called ASST Fatebenefratelli Sacco launched a double-blinded, placebo controlled, multicenter study evaluating the performance and safety of favipiravir combined with supportive care for adults with moderate COVID-19. Led by Giuliano Rizzardini, MD, the 100 patient study was planned to start in March, 2020 and run through July 2020. The study team seeks to evaluate the duration from the start of the treatment to normalization of pyrexia, respiratory rate and SPO2 and relief of cough maintained for at least 72 hours.
UK & Belgium
The Chelsea and Westminster NHS Foundation Trust in collaboration with NEAT ID Foundation, Fujifilm Toyama Chemical Co., Ltd., Imperial College London and Universitaire Ziekenhuizen Leuven started a Phase III clinical trial in May, 2020 investigating whether randomizing patients to either a combination of azithromycin, hydroxychloroquine and zinc or favipiravir alongside standard of care can help patients with suspected or proven COVID-19 infection. The study team sought to recruit 450 patients in the “PIONEER” study. The London arm of the study is led by Professor Pallav Shah while the Belgium arm is led by Professor Paul De Munter.
In France University Hospital, Bordeaux leads the “Coverage” clinical trial or “Treatments to Decrease the Risk of Hospitalization or Death in Elderly Outpatients with Symptomatic SARS-CoV-2 Infection (COVID-19). In this Phase III study, the sponsor seeks to estimate the efficacy and tolerance of several experimental treatments to prevent hospitalization or death in outpatients aged 65 or above with symptomatic COVID-19 infection. Those treatments include favipiravir. Initiating July 2020, the trial runs through January 28, 2021 and targets 1,057 patients. Led by the study chair, Laura Richert, MD, and study director Xavier Anglaret, the principal investigator is Denis Malvy, MD.
A dozen plus other studies are ongoing in Tukey (4), China (3), as well as Saudi Arabia, Egypt and others.
Favipiravir has been approved for use against COVID-19 in Russia, China, and India. The drug actually exhibited promise in influenza trials about five years ago in the United States backed by the U.S. DOD and a now defunct biotech company. Presently, at least twenty-three favipiravir clinical trials are planned or are actively ongoing targeting COVID-19; two of them are in the United States. Gilead’s remdesivir has certainly enjoyed far more attention that this now generic anti-viral drug approved in multiple countries including the two most populated in the word.