The Russian Federal Service for Surveillance in Healthcare recently announced the permanent registration of three drugs targeting COVID-19, all based on Favipiravir. This generic antiviral drug originates from a Japanese pharmaceutical company that brands the product as Avigan—which is currently approved only for influenza. Back in June, TrialSite updated all of the approval of the Russian generic Avifavir. Other approved Favipiravir-based drugs targeting COVID-19 include Areplivir and Coronavir. The implication for this recent announcement, reports Viktor Fisenko, Russian Deputy Health Minister, Favipiravir, is now permanently approved as a therapy to treat COVID-19. Additionally, Russia has authorized the commercial distribution of Remdesivir (Gilead) and Levilimab, a drug indicated for mitigating the dangerous cytokine storm associated with COVID-19. This latter registration, Levilimab, is surprising given the registration occurred in June, and the Phase 3 clinical trial associated with the drug started just in late April. This incredibly condensed timeline raises an eyebrow or two.
TrialSite offers a brief breakdown of this recent news released by the Russian news agency Tass. The Russian authorities appear concerned that that nation needs to offer comprehensive outpatient treatment options for less-severe COVID-19 cases as well. One critique of the current situation in the U.S. centers on the lack of a comprehensive emphasis to date on economical and highly available treatments for mild cases with the aim of preventing the escalation of infection.
Background of Favipiravir Drugs
TrialSite’s first introduction to Avigan (Favipiravir) triggered interest around the world. Called Avigan by FUJIFILM Toyama Chemical of Japan, the drug is apparently effective against many RNA viruses. See more on Avigan at FUJIFILM’s website.
TrialSite has chronicled the development and introduction of Favipiravir, based on the generic version of the Japanese antiviral drug Avigan. See the link.
On Oct. 19, TrialSite reported that makers of the underlying drug, FUJIFILM Toyama Chemical of Japan, have applied to register the drug in that nation for the COVID-19 indication, but the Japanese authorities are far closer to the U.S. Food and Drug Administration (FDA) in approach and philosophy, meaning they apply Gold Standard reviews of data for compliance. Although the FDA has made a couple of questionable moves during the pandemic—more than likely involving political pressure—the agency represents the Gold Standard in approving and regulating drugs, devices, diagnostics, as well as medical devices and appliances, food, etc. Consequently, the Japanese regulatory authorities, more than likely, will not come to a premature conclusion concerning Avigan.
Some Questions in Russia
Now, an ongoing clinical trial in Russia purportedly produced positive improvements in COVID-19 patients after seven days of treatment, 1.5 times superior to the control group but TrialSite has found an anomaly in this process.
In the case of Avifavir, a Russian generic version made by ChemRar Group and the Russia Direct Investment Fund (RDIF) is not only registered and authorized for distribution in that large country, but it’s now also associated with distribution deals in Belarus and Kazakhstan. TrialSite reported on the registration of Avifavir on June 1.
Areplivir, also a Russian-originated Favipiravir-based drug, is now available retail in that nation. Its manufacturer, Promomed, confirmed this in a Russian news daily called Kommersant.
What is Levilimab?
An experimental monoclonal antibody developed in Russia by a company called Biocad. The company apparently announced positive progress during the European investigators during the 21st Annual Congress of the European League Against Rheumatism (EULAR-2020).
Ostensibly, the positive data is derived from the ongoing multicenter, comparative, randomized, double-blind, placebo-controlled and importantly, adaptive-design clinical trial (NCT04397562) mentioned above.
In this study, the sponsor investigates the study drug’s safety and efficacy in patients 18+ hospitalized with severe COVID-19 pneumonia; the treatment includes standard of care (SOC) therapy and 324 mg/sc of the investigational drug or placebo. The 204 participant study commenced at the end of April 2020, running through the end of April 2021, according to the company’s disclosure in Clinicaltrials.gov.
A Raised Eyebrow?
Has the drug already approved been for at least emergency use? Apparently so! Interestingly, on June 17, the Antibody Society reported that the Ministry of Health of the Russian Federation “registered” the drug with the trade name IIsira. This news was confirmed on June 8 by CGTN.
In that report, the head of the infectious ward at the Central Clinical Hospital in Moscow, Ekaterina Trifonova, told the press that the drug “…has proven itself as effective as its foreign counterparts and increased the speed of recovery of patients.” A TrialSite timeout for a review of the “foreign counterparts,” not to mention an unbelievably condensed clinical trials timeline.
During that time, there was significant speculation in the West that IL-6 inhibitors may be effective against COVID-19, at least in severe cases. That could have been one reason why Dr. Trifonova compared this Russian variety to the “foreign” ones, which means “Western” ones. But these powerful biologic drugs have failed to prove efficacy in COVID-19 cases.
For example, prominent pharmaceutical companies Regeneron and Sanofi reported on July 6 the failure of the IL-6 inhibitor Kevzara in a Phase 3 clinical trial. Moreover, on July 30, TrialSite shared that Roche reported that its IL-6 inhibitor drug known as Actemra (Tocilizumab) failed to demonstrate efficacy in patients with COVID-19.
Although this was powerful evidence that influenced the National Institutes of Health (NIH) COVID-19 Guidelines, some countries continue to drive major demand, such as India, where the drug was not only approved but demand soared, at least amongst the upper and middle classes there.
But back to Russia, apparently based on the ongoing study referenced above, the human monoclonal antibody targeting membrane-bound and soluble forms of the interleukin 6 receptor, originally developed to target rheumatoid arthritis was approved for use, even though the study literally just started two months prior. This seems nearly physically and logistically impossible to pull off. After all, if the study started at the end of April and the approval occurred during early June, imagine the logistics necessary to work toward a drug approval in just over a month. It frankly boggles the mind. But it could be that the authorities had other data and observational studies and just made an executive call to approve?
Again extremely well-capitalized, sophisticated and ultimately best-in-class companies such as Regeneron, Sanofi, and Roche have found that the use of IL-6 inhibitors targeting COVID-19 doesn’t produce positive results. See the TrialSite Watchlist Series on this topic.
The developer of Levilimab, Biocad, positions itself as a cutting-edge biotech company in Russia. Its focuses include oncology, HIV and Hepatitis C, as well as multiple sclerosis. The Saint Petersburg-based company was founded in 2001.
‘Better Safe than Sorry’
TrialSite, as it turns out, is biased, although the online media company’s tagline includes independent and unbiased news and information. The very ethos of the company is to remain objective and as unbiased as possible, but the founders are from the United States, and hence that experience and world view shapes the deep assumptions of its core content creators.
In “Better Safe than Sorry,” TrialSite expressed the concern for the material short cuts, seeming workarounds and various drug development anomalies associated with the rapid vaccine and therapy development and registration in the East (e.g. Russia, China).
Generally, populations in individualist-leaning Western democracies (or those that aspire to follow the general model) appear to express a heightened, overt concern that Gold Standard safety and regulatory best practices are enforced in the drug and vaccine development process overall, and of course specifically during the crisis. Of course, populations in many nations lack the same level of ability to critically question government and the dominant narratives.
TrialSite is critical however, of some actions and decisions by American regulatory bodies and research agencies evidencing bias in at least some cases however, and the media platform will continue to identify, chronicle and showcase any material or serious issues as they manifest during this crisis and beyond.