The interest in favipiravir as a possible antiviral candidate targeting COVID-19 continues to grow as there are now over 30 clinical trials investigating the antiviral targeting the novel coronavirus. Moreover, the drug has been approved as a treatment for COVID-19 in India, Russia and China; the U.S. The Department of Defense invested over $200 million in clinical trials investigating the potential of favipiravir to defend the nation against influenza and bioengineered-based pandemics as recently as 2016. The drug has gone off patent and, most recently, a company in Canada, Appili Therapeutics, commenced clinical trials in the hopes of commercializing favipiravir as a therapy targeting COVID-19. The stakes are large as Remdesivir, the only emergency use authorized COVID-19 therapy (along with convalescent plasma), is projected by some analysts to generate between $1 billion to $3 billion in revenue.
Originally patented and called Avigan by FUJIFILM Toyama Chemical Co. Ltd in Japan, it was approved as an antiviral against influenza in Japan in 2014. The drug would only be used there upon an influenza outbreak in which other influenza antiviral medications aren’t effective. It went off patent in 2019.
The drug inhibits RNA polymerase necessary for influenza virus replication. Because of this mechanism of action, it has been suspected that Avigan (favipiravir) may have antiviral impacts against SARS-CoV-2; influenza viruses are single-stranded RNA viruses that are based on viral RNA polymerase. Avigan went off patent in 2019.
Approvals or Use Authorizations
As TrialSite has chronicled, Russia approved a generic version of the drug called “Avifavir.” In China, TrialSite reported that favipiravir was contributing to a strategy to fight COVID-19, according to reports that Zhejiang Hisun Pharmaceutical Co., Ltd (Hisun) secured a license to this now generic antiviral from Japanese maker FUJIFILM Toyama Chemical Co., Ltd. The Chinese company at the time reported no evidence adverse reactions. According to media accounts of the Chinese deal, China’s National Medical Products Administration (NMPA) had approved the generic manufacture of the drug for use against COVID-19. TrialSite reported that by July 24, favipiravir was approved in India and that multiple generic producers were developing branded products. TrialSite asked the question: what’s the efficacy? And, why wasn’t this drug getting more attention in the United States?
Evidence of Efficacy?
TrialSite reported that the Bangladesh Society of Medicine (BSM) concluded from a recent study that favipiravir evidences “clear cut” safety and effectivity against COVID-19. Known as the “Dhaka Trial,” in a randomized and controlled clinical trial conducted in Dhaka, the sponsors revealed that favipiravir evidences “clear cut” safety and effectiveness against COVID-19. The study did include a small sample of only 50 subjects and this undoubtedly limits the weight of the evidence.
By July, a number of Indian doctors chimed in on the use of favipiravir. They noted that the drug has only been approved by Indian authorities during the pandemic and that it would only possibly be useful for mild cases of COVID-19. Some of the doctors expressed concerns of side effects (possibly fatal) and most of the doctors surveyed positioned that not enough research was conducted as of yet for any declarative statements about the drug’s efficacy.
In Russia, back in June, as its authorities approved the use of favipiravir against COVID-19, the Russian Direct Investment Fund (RFIF) and ChemRar Group announced the delivery of 60,000 courses of Avifavir (Russia’s generic version of Avigan) to hospitals. A sizable clinical trial was conducted in Russia involving 330 patients at 35 trial sites across the country. As reported in European Pharmaceutical Review, purported intermediate data from Avifavir trials in Russia as the following:
- After 10 days of trials, the median time to eliminate COVID-19 with the Avifavir was four days, compared to nine with standard therapy
- After four days 65% of Avifavir recipients tested negative for COVID-19, by 10 days this number had increased to 90%
- The efficacy of the drug is 80%, according to a Russian study
- After 10 days of trials with Avifavir, patients reported no new side effects
TrialSite cannot conclude one way or the other if favipiravir is effective or not against COVID-19, based on the data thus far. Some studies in some countries—according to media reports—appear to reveal efficacy while other results appear questionable. But it certainly could be considered materially relevant that major nations—from China and Russia to India—have approved the drug for at least the duration of the pandemic. It’s also notable that the U.S. government via the DOD sponsored major favipiravir studies targeting influenza outbreaks but results were never shared.
U.S. Department of Defense Invests Over $200m in Favipiravir
TrialSite reported that the U.S. Department of Defense helped fund north of $200 million for at least two major clinical research investigating favipiravir as recently as 2016. By June 30, TrialSite reported that the U.S. government led the way just five years ago with favipiravir but now the U.S. seemed left out of any benefits of such research. Although public funds were used, no results were disclosed!
Given the $200m-plus in public spend, it seemed odd that as COVID-19 emerged, there was little in the media about this fact. Interestingly, The Austin Journal of Public Health Epidemiology (AJPHE) did in fact investigate this drug in their June article “Favipiravir and USA.” They noted that it “was invented as the most useful drug for bioengineered pandemics.” And while first developed in Japan, it has garnered lots of interest from the U.S. Department of Defense. U.S. trials commenced by late 2013 and completed in 2015 but there has been no U.S. FDA approval or market authorization. AJPHE’s author sought the answer and, “wrote to FDA twice, only to know that it is not possible to know anything because of federal confidentiality (personal communication).”
TrialSite found that a total of $211,303,678 was spent on the U.S. DOD favipiravir pursuit.
MDVI LLC & MediVector Connection
In a 2015 Phase 3 favipiravir clinical trial report, the sponsor is listed as MDVI, LLC; and MediVector, Inc. is noted as a collaborator. MediVector was a Department of Defense research partner for this drug. However, MDVI was a bit more mysterious with no website, etc. MediVector was led by CEO Api Rudich and executive vice president Carol Epstein (chief medical officer). Given over $200 million was invested of public money and there were no study results disclosed on Clincialtrials.gov, the AJPHE commented “The whole thing is such a mess that it needs urgent investigation.” Moreover, the biggest unanswered question is, “where had the money gone?”
The U.S. DOD Favipiravir Studies
In the first DOD-financed favipiravir study (NCT2008344), the study team, sponsored by the mysterious MDVI in collaboration with MediVector, sought to determine if a 5-day regimen of favipiravir actually would reduce the time to alleviation of influenza symptoms, resolution of fever, and viral shedding, in subjects with uncomplicated influenza as compared to those subjects on placebo. This first study commenced at the end of 2013 and ran until January 2015. With a target of 247 trial sites, chief medical officer Carol Epstein was listed as the principal investigator. Although reported in Clinicaltrials.gov as “Completed,” no results were ever uploaded.
Another study (NCT02026349), sponsored again by MDVI in collaboration with MediVector, investigated if favipiravir is in fact effective in reducing the time to resolution of influenza symptoms. The Phase 3 study targeted 860 participants for a five-day regimen of favipiravir in the hope that it would reduce the time to alleviation of influenza symptoms, resolution of fever and viral shedding. The study commenced during June 2014 and purportedly ran until March 2015. Conducted at over 200 trial sites, the study lead was MediVector’s Carol Epstein. Again, DOD funds helped pay for this and the other MediVector study.
Deep Defense Ties?
Back in 2016, Global BioDefense looked into favipiravir. In that publication, they commented that the drug was being developed by “BioDefense Therapeutics” (BD Tx), a Joint Product Manager within the Medical Countermeasure Systems (JPM-MCS) Joint Project Management Office—a component of the Joint Program Executive Office for Chemical and Biological Defense. Apparently, BioDefense Therapeutics was the general sponsor and MDVI and MediVector were the partners in the pursuit of developing favipiravir as a drug to protect the nation against massive flu epidemics and biological threats.
In touting favipiravir, Dr. Tyler Bennett, assistant product manager for BioDefense Therapeutics, commented, “We are concerned with not only naturally occurring flu strains, but also those that may be biologically engineered.” Dr. Bennett also commented, “T-705a (favipiravir) has a unique mechanism of action that works by blocking viral RNA replication within the infected cell, giving T-705a the potential to be broad spectrum…”
Enter Canada’s Appili Therapeutics as Favipiravir Developer
Dr. Armand Balboni has an impressive career serving the nation in the armed services. Back in 2015, he along with a couple others founded Appili Therapeutics, according to Crunchbase. Based on company reports, he became a Board member by 2018. By May 21, the Canadian biotech firm was cleared by Health Canada to embark on a Phase 2 clinical trial evaluating favipiravir as a prophylactic agent against COVID-19 outbreaks. With drugs donated by FUJIFILM Toyama Chemical, Appili would conduct the trial with infectious disease specialists at Sinai Health in Toronto, the University of Toronto, Sunnybrook Health Sciences Centre and Unity Health Toronto.
FUJIFILM USA Study
FUJIFILM Toyama Chemical Co. Ltd subsidiary Fujifilm Pharmaceuticals USA Inc is conducting a significant study (NCT0435549) in the United States, including a Phase 2, open label, randomized, controlled multicenter proof-of-concept study of favipiravir in hospitalized subjects with COVID-19. Subjects are randomized within their study site and stratified by the severity of the disease to receive either favipiravir plus standard of care or standard of care alone.
The dose regimen is 1800 mg favipiravir BID plus standard of care or standard of care alone on Day 1 followed by 1000 mg BID favipiravir (800 mg BID for subjects with Child-Pugh A liver impairment) plus SOC or SOC for the next 13 days. The study includes 14 days of treatment and 46 days of follow up.
The study commenced April 17, 2020 and the estimated primary completion date is this month (September 2020) so TrialSite will be inquiring about the status of this study. The study has been conducted at Honor Health, Scottsdale, AZ, University of Miami, Miller School of Medicine, Boston Medical Center, Brigham and Women’s Hospital, Massachusetts General Hospital, UMass Memorial Health Care, Atlantic Health System/Morristown Medical Center and Houston Methodist Hospital.
Call to Action: TrialSite will be monitoring for updates to these favipiravir studies.