Russian coronavirus drugs Avifavir and Coronavir are considered Russian developments, and Kremlin propagandists have called them a revolution in medicine comparable in scale to the invention of penicillin. State contracts for their supply have already exceeded $ 14 million. But as it turned out, Russian pharmaceutical companies actually bought the active ingredients from Chinese companies represented on the Alibaba marketplace for meager sums, and there is still no evidence of the effectiveness of these drugs. Moreover, the drugs are extremely toxic and dangerous, but are widely used despite serious side effects, including fetal development problems and motor disorders. The trade in dangerous pacifiers has already brought pharmaceutical companies millions in profits.
“Russia is the first in the world to date to register two drugs with direct antiviral action with proven effectiveness,” – said the propagandist Dmitry Kiselyov on the news in July 2020. ”Avifavir from HimRar and Areplivir from Promomed are the strongest ones against COVID-19 today. They prevent the virus from multiplying in the body, and the effectiveness of these pills in clinical trials is 90%. No other drug in the world has the best results against COVID-19 yet. ”
However, the propagandist said there was only one thing: in the spring of 2020, the Ministry of Health did approve “Avifavir”, “Areplivir” and “Coronavir” for coronavirus treatment, and indeed nowhere in the world “antiviral” drugs against coronavirus were used. These drugs are actually based on the active ingredient favipiravir, which was invented and patented in Japan in the early 2000s as a remedy for severe influenza, and also tested on patients with Ebola virus, but in mass production favipiravir has never been in Japan itself was not used because its effectiveness could not be proven.
However, in mid-March 2020, Chinese officials suddenly announced the high efficacy of favipivir against coronavirus. It was then that a number of large Russian companies – “R-Pharm”, “Promomed”, as well as the company “KhimRar” with the support of the Russian Fund for Direct Investment decided to establish production of the Russian analogue.
In just one month, with the support of the government, KhimRar’s subsidiary Kromis not only reproduced the drug, but on April 23 registered with the Ministry of Health the start of a clinical trial of Avifavir with 60 volunteers. It officially lasted until December 31, 2020, and the number of participants was expanded to 300 people. But in fact, no one expected the results of the study: in late May 2020, the drug began to be used to treat patients.
This success was explained by the manufacturers at KhimRar by the fact that five years ago the company was already working on a similar drug and synthesizing the chemistry of favipivir. ChemRar insisted that they were able to synthesize the active substance on their own and test its effectiveness in the shortest possible time. In May, Russia-1 TV channel showed a story about the fact that the synthesis of drugs in “KhimRar” took two weeks, and to buy neither the drug itself nor the raw materials for it “failed in any country in the world.”
Tons of substances from China
As reporters found out, Avifavir was actually of Chinese origin. Russian pharmaceutical companies simply bought “ingredients” cheaply on the Chinese market.
Other Russian corporations operated similarly to KhimRar. Judging by the data of the customs, on May 30, 2020 the subsidiary company “R-Pharm” – “Drug Technology” – received 5 barrels of 50 kg of ready-made favipiravir. The substance cost the company 640 thousand dollars. In total, as it turned out, since the beginning of 2020, R-Pharm has imported almost 4 tons of substance to Russia for the preparation of favipivir tablets. This is evidenced by the database of customs declarations Import Genius.
The substance purchased by Russian companies is an intermediate product that is obtained closer to the end of the synthesis of the final substance. This conclusion was reached by Ravil Niyazov, a specialist in drug development and regulation at the Scientific Advisory Center, and a synthetic chemist, who wished to remain anonymous, one of the Russian pharmaceutical manufacturers who studied the declarations of R-Pharm.
“Usually the synthesis starts with simpler molecules that do not have such a complex-branched structure,” explains Niyazov. From the substances purchased by R-Pharm, favipivir is obtained in three stages, says the synthetic chemist, and he estimates that this amount should be enough for 460 courses or 33,000 tablets. “But such purchases have risks. At the beginning of the synthesis of the intermediate, some conditions could not be met and the reactions were not in ideal conditions, which means that the product may contain impurities, ”says Niyazov.
Meanwhile, sellers of the substance, who supplied the substance from China to Russian pharmaceutical companies, could not confirm to reporters that they produce the drug themselves and do not buy it elsewhere. Instead, they claim that the substance is in great demand from buyers in Russia, and that it is supplied in tons from China.
Misty patent and dangerous modifications
But could Russian companies still really synthesize the substance on their own?
Theoretically, in a short time to reproduce the molecule of the active substance is possible. In such cases, a patent of the original manufacturer is used, but the description of the synthesis in it is usually vague, says a researcher from one of the Russian pharmaceutical manufacturers (synthetic chemist). Companies specifically draw up patents to protect their intellectual property.
Vasyl Vlasov, President of the Society of Evidence-Based Medicine, believes that a substance can be synthesized in a month, but the establishment of industrial synthesis can take months. Ravil Niyazov, a specialist in drug development and regulation at the Center for Scientific Advice, shares the same opinion. “It is impossible to develop industrial production technology quickly. When it is created, commissioning tests are carried out, not one or two experimental series, no one will start using the tried-and-tested technology, which exists only on paper, to obtain the drug, ”says Niyazov.
Some questions in the professional community are caused by the report of the general director of “KhimRar” Ivashchenko that the company managed to modify the drug. “Regarding drugs, no hidden modifications are allowed. If they have modified something, what antiviral activity does this drug have? ”Says Niyazov. Vlasov agrees: “If the drug is not changed and reproduced not favipiravir, then these drugs must undergo a full cycle of clinical trials.”
Research on volunteers
The first favipivir test for efficacy against COVID-19 was registered in China in mid-February 2020. The first results seemed quite encouraging: hospitalized patients got rid of the virus faster, and chest images showed positive dynamics. The study with the largest sample of patients was also conducted in China in late February. In it, favipiravir was compared with arbidol (as with placebo), and the drug did not show efficacy. The study involved 240 people.
Studies of the efficacy of favipiravir have been performed in the United Kingdom, France, the United States, the Middle East, and South Asia. However, first, they studied the original Japanese drug, which is manufactured under the brand name “Avigan” or Indian licensed generics. Second, although some of these studies have shown efficacy compared to other antiviral drugs (eg, remdesivir), they were mild to moderate coronavirus, so even if these results could be trusted, they are still irrelevant – the drug is very toxic, and therefore, it still cannot be used to treat mild forms of coronavirus.
The world’s largest database of clinical trials of ClinicalTrials contains information that the Avifavir study in June 2020 was conducted simultaneously in 22 hospitals by MSU Professor Olena Pavlikova and MD Nikita Lomakin. In August 2020, they published the results of a study in the journal Clinical Infectious Diseases.
However, it turned out that the study was sponsored by the Skolkovo Innovation Center, whose resident is the drug manufacturer KhimRar. A total of 60 people participated in the study, 40 of who received avifavir and other drugs (which are not specified), and 20 – various antiviral drugs, mainly hydroxychloroquine, along with antibiotics and antipyretics. Two people with severe disease died during the study. The authors conclude that Avifavir works better than “standard therapy”, although after 10 days of treatment, the p-test (the significance level of the results, which determines how statistically significant the result of the experiment) was 0.155. The higher this figure, the more likely it is that the result is accidental rather than the result of manipulations. In medicine, it is usually used as a threshold of the p-criterion is not more than 0.05, sometimes 0.01, ie Russian researchers have deviated by an order of magnitude from the standard requirements. The authors of the study emphasize that these clinical trials on 60 volunteers were the reason that the drug was included in the recommendations of the Ministry of Health.
Back in September 2020, the Japanese company Fujifilm Toyama Chemical reported low efficacy of favipivir – according to their study, those who took the drug were discharged from the hospital after 12 days, those who were given a placebo – after 15. “It turns out that the amount of $ 400 you pay for a reduction of treatment for two days. And at the same time there is no data on the reduction of mortality: whether this drug reduces it or not, “- said in an interview with Doctor of Biological Sciences, Professor, Head of the Laboratory of Biotechnology and Virology, Faculty of Natural Sciences NSU Sergei Netesov.
The results of a clinical study of one of the largest pharmaceutical companies in Russia, JSC “R-Pharm” were published in September 2020 in the Russian journal “Medical Opponent”. Olga Filon, Director of Drug Technology LLC, took part in the study, and the study was funded by R-Pharm. The trials also involved 60 people, 40 of whom received favipiravir, and another 20 other drugs were not disclosed by the authors. In addition, almost all patients received antibiotics, anticoagulants and antipyretics, ie standard MOH-approved therapy. Unlike the KhimRara study, the specialists did not involve seriously ill patients in the trials, and no patient died. The time of eradication of the virus in the body of patients receiving favipiravir didn’t almost differ from other patients, the improvement of patients occurred 3 days earlier.
The practice by which pharmaceutical companies fund clinical trials of their own drugs is considered questionable in the scientific community. For example, the British author Ben Goldacre in his book “The whole truth about drugs: a global conspiracy of pharmaceutical companies” (Bad Pharma) provides statistics that such studies are often complementary, and studies in which the effectiveness of the drug has not been proven, simply not published
Poison rather than medicine
While the efficacy of favipivir is highly questionable, its dangerous side effects, by contrast, are well established. Due to its toxicity, the drug is prohibited for children, pregnant women, nursing mothers, as well as for people with severe hepatic or renal insufficiency. Due to the high probability of adverse effects on the fetus of people who took the drug, it is recommended to pay special attention to contraception for several months. Also in the study in Japan, it was found that the use of the drug can lead to motor disorders in patients: tired legs syndrome, as well as an increased risk of falls. Experts believe that this may be due to the effect of drugs on the central nervous system.
Drugs with such high toxicity are usually used only in cases where their effectiveness is high and the patient is in a serious condition, ie the risks of the disease outweigh the risks of using the drug. In addition, toxic drugs are used only in hospitals under strict medical supervision. In the case of Russian generics favipiravir, all these requirements were violated.
Several employees of Moscow hospitals specializing in the treatment of coronavirus confirmed to reporters that drugs based on favipivir (“Coronavir” and “Avifavir”) are regularly given to patients. “Initially, pharmaceutical companies registered Russian analogues as drugs against severe cases of the disease, which, due to its toxicity, should be used in hospitals. But in practice, it is issued in a mild form [during treatment at home], “- said Vlasov.
A physician at a Moscow clinic also persuaded that all confirmed cases of Covid-19 are now being treated with Russian generics favipivir, even at home in Moscow.
Money is not contagious
Mass deliveries of Avifavir to the regions of Russia began in June 2020 and have been increasing since then. According to journalists’ calculations based on the data of the public procurement portal, by August 1, 2021, the authorities have purchased a Russian generic for at least $ 140 million. R-Pharm alone delivered the drug directly to the hospital for about $ 70 million. Most bidding was arranged as a purchase from a single supplier. The first packs of Avifavir on the market were sold to hospitals for $ 310 for 40 tablets – a fantastically high price given the purchase price of favipivir in China (not to mention that any price for ineffective drugs is too high). When Coronavir hit the market, its price for various hospitals ranged from $ 40 to $ 70 per pack of 50 tablets. In the fall of 2020, the drug went on sale at retail, in pharmacies it costs about $ 75 per pack. At the same time, in the homeland of the drug in Japan, its retail sale is strictly prohibited and only use in the hospital is allowed.