What do we know about the first Russian drug for coronavirus

The first Russian drug for coronavirus disease, Avifavir, received approval from the Ministry of Health. The developer of the drug promises that on June 11, he will send the first batches of his drug to hospitals. We figure out where these yellow pills came from, on what principle the drug works, what clinical trials it has already gone through, and whether it can be said with certainty that we have a cure for COVID-19.

Where did it come from

Avifavir is a trade name for a Russian drug developed by the Russian Direct Investment Fund (RDIF) and the ChemRar group of companies. However, the active ingredient of the drug was not invented in Russia.

Its international non-proprietary name is favipiravir. It was developed by employees of the Japanese company Toyama Chemical, a subsidiary of the FUJIFILM Pharmaceuticals corporation.

According to its chemical structure, favipiravir is a derivative of 6 ‑ fluoro ‑ 3 ‑ oxo ‑ 3, 4 ‑ dihydropyrazine ‑ 2 ‑ carboxylic acid, or pyrazinecarboxamide. During a screening of a chemical library, Toyama employees discovered that this substance may have activity against the influenza virus: once it gets into cells infected with the virus, favipiravir turns into an activated form that inhibits the activity of an important viral enzyme, RNA-dependent RNA polymerase.

If RNA polymerase is turned off, influenza viruses lose their ability to print their genetic material, RNA, in infected cells. As a result, the production of the virus that has already entered the cells stops. This is the uniqueness of the drug - usually antiviral drugs can only prevent viruses from entering cells.

RNA-dependent RNA-polymerase is present not only in influenza viruses, but also in all RNA-viruses. Moreover, the catalytic domain of RNA polymerase - this is the name of the part of the molecule, thanks to which the enzyme can in principle work - is structured in the same way in all RNA viruses. And since favipiravir binds precisely to the catalytic domain of RNA-polymerase, the Japanese had reason to consider this substance as a broad-spectrum antiviral agent.

The mechanism of action of favipiravir, on the basis of which Avifavir was developed

Toyama employees registered favipiravir under the brand name Avigan and began investigating the promising drug's activity on RNA viruses ranging from influenza A and B viruses to Ebola. The results were mixed. For example, in the case of the Ebola virus, it turned out that the drug worked in monkeys, but when used in humans, the result was not very impressive. On the one hand, the mortality rate in 73 patients from Guinea who received favipiravir was lower than in patients who were tried by other means. On the other hand, the difference was not that great - 42.5 percent versus 57.8 percent - meaning that it is impossible to guarantee that this is not just a random artifact of counting due to the fact that the sample of patients was very small. However, the Guinean government has approved this drug as the standard treatment for the Ebola virus.

In the homeland of the drug, in Japan, Avigan succeeded only in 2014 - and only against new strains of the influenza virus. Avigan has not been used against seasonal flu.

Avigan tablets - the drug on the basis of which Avifavir was created

Moreover, the drug was approved not just against the "new" flu, but exclusively for situations when existing antiviral drugs were ineffective - that is, as a last resort. For six years from the moment of approval, such a situation has not arisen even once, so that in the context of a real flu epidemic, the drug was never used.

A review of 29 clinical trials (4,299 participants), six of which were phase 2 and 3 trials (already evaluating drug efficacy), found favipiravir to “demonstrate a favorable safety profile,” with 0.4 percent serious side effects. Nevertheless, problems with the safety of the drug still remain.

Japanese researchers who studied the prospects of using the drug for severe influenza emphasized that Avigan is contraindicated in pregnant women: the drug had teratogenic and embryotoxic effects on animals. Other possible problems include decreased appetite, nausea, vomiting, an increase in the concentration of uric acid in the blood (hyperuricemia), and liver damage.

Favipiravir and COVID-19

In March 2020, Zhang Xinmin, director of the National Center for Biotechnology Development, which is part of the Chinese Ministry of Health, said favipiravir "has shown good clinical efficacy against the novel coronavirus disease (COVID-19)." According to at least one open, non-randomized study, 35 Chinese patients with coronavirus disease who received favipiravir (the study did not say which drug was discussed - the original Avigan or a Chinese drug with the same active ingredient) recovered faster and suffered less from complications than 45 patients who were treated with other drugs (lopinavir and ritonavir).

The efficacy of the drug against COVID-19 is currently being evaluated in clinical trials in Japan. On April 9, FUJIFILM announced the start of the second phase of Avigan clinical trials, which will take place in the United States, which will involve 50 patients with coronavirus disease. According to some foreign data, in April-May, favipiravir was tested in 16 more clinical trials, but there is not a single completed clinical trial that would show that favipiravir or Avigan are effective against coronavirus disease.

Russian drug

Any medicine consists of an active substance and a filler (finished dosage form). The Russian antiviral drug contains the same active ingredient as the Japanese drug - that is, 200 milligrams of favipiravir per tablet. As in a conversation with "N + 1" pointed out by the representative of the Russian Direct Investment Fund Arseniy Palagin, the filler of the Russian drug is its own. The instructions say that the excipients include microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and povidone K-30. The patent protection period for the original Japanese Avigan expired in 2019, so the drug can be considered a legally produced generic.

Russian clinical trials of Avifavir are also not finished yet. Completed only the first and second stages of a multicenter randomized study, confirms the interlocutor "N + 1" from RDIF. The first stage involved 60 people - 20 of them were included in the control group, which was treated with standard methods. Data on the age composition and severity of the condition of the subjects were not disclosed.

Here's what the developers themselves report on the results of these tests:

new side effects, in addition to those that the Japanese recorded many years ago, they did not reveal;
after four days of treatment, 65 percent of people from the experimental group tested negative for coronavirus (in the control group, such cases were about 30 percent);
after three days, 68 percent of people in the experimental group returned to normal temperature (in the control, this happened on the sixth day).

The Ministry of Health approved the start of the third phase of the Avifavir trials on May 1, 2020. In this stage, according to the data on the website of the State Register of Medicines, a total of 390 people will have to take part. The same data show that favipiravir is being tested by two more Russian companies: Drugs Technology (part of the R-Pharm group) and Promomed. Both companies began testing at the end of May.

Although the trials have not been completed and only partial data on the effectiveness are known, the Ministry of Health permitted the registration of the drug ahead of schedule - according to the accelerated procedure adopted under the RF government decree of April 3, 2020 No. 441. This decree states that “a reduction in the volume of examinations” is permissible “in the conditions of the threat of the emergence and elimination of an emergency.

So the manufacturer already promises to bring the first batches of tablets to hospitals by the end of next week.

The instructions for the drug say that it was "prepared on the basis of a limited amount of clinical data on the use of the drug and will be supplemented as new data becomes available." However, contraindications have already been identified. As in the case of the Japanese Avigan, this is planning pregnancy, pregnancy and the period of breastfeeding - the generic is also potentially teratogenic. Patients with gout and hyperuricemia should use the medication with caution. In addition, the list of contraindications to the Russian generic drug was supplemented by hypersensitivity to the active substance, age up to 18 years, severe hepatic and renal failure.

The drug will not be delivered to pharmacies: according to the instructions, the drug can be used only in hospitals.

What is the bottom line

Avifavir is a generic drug of Favipiravir, which has a distinct mechanism of action and is undergoing clinical trials in Russia and abroad.

The results of interim clinical trials show that the drug is promising: on those small samples that they managed to test, the therapeutic effect, judging by the statements of the developers, was determined. But until clinical trials are completed and their results are published in peer-reviewed international journals, we cannot be completely sure that Avifavir is truly helping against coronavirus disease. The press service of ChemRar, the drug's developer, did not answer N + 1's questions at the time of publication of this text.

Now we do not have drugs that would purposefully and effectively act against the SARS ‑ CoV ‑ 2 virus. All contenders for this title now are substances known before the emergence of the new coronavirus, which in clinical trials (which have just begun) have consistently shown some kind of positive effect with a number of limitations. There are two of them right now.

The first is Remdesivir, which hit the front pages in May, a drug that even before the COVID-19 epidemic was intended to treat another coronavirus infection, Middle East Respiratory Syndrome (MERS). The American regulator approved the clinical use of Remdesivir without waiting for the formal end of drug trials - the presence of a stable effect in preliminary research data convinced medical officials. This situation was compared to the early registration of AZT, the first HIV drug.

At the same time, Remdesivir has never claimed the status of a "silver bullet": tests show that people with severe symptoms - who need artificial ventilation of the lungs, it cannot help, and for those with lighter symptoms, it reduces the time of illness by four days. Many other effects - for example, the reduction in mortality of the disease compared with other drugs - were not shown with statistical significance in these trials. The sample of Remdesivir trials, reported in late May by the New England Journal of Medicine, was 1,059 people.

Elena Verbitskaya Head of the Department of Biomedical Statistics of St. Petersburg State Medical University named after Academician I. P. Pavlov.

60 subjects - is that a lot or a little?

The number of subjects required to test the effectiveness of the drug is calculated using special formulas that take into account many variables: for example, the characteristics of the indicators that are supposed to be taken into account, their spread, the level of deviation from the indicators of the control group, which will be considered clinically significant.

Indicators are assigned that will be taken into account during the tests. The main one is, as a rule, mortality. In the case of respiratory infections, integral indicators are used, which take into account, for example, the number of days with fever, the time in intensive care or the intensive care unit, on mechanical ventilation, and cough. All of them are converted into points according to a certain formula, and then the points of the experimental group are compared with the points of the control group.

For some research, 20 subjects will be enough. For some, 2,000 will not be enough.

Small group pilot trials may be conducted prior to clinical trials. It is not uncommon for a situation when an effect found on a group of several dozen people subsequently "erodes" in large groups.

Favipiravir, like Remdesivir, was not originally developed as a remedy specifically against the new coronavirus. The drug many years ago - so much so that the patent for it had already expired - was adapted for the treatment of influenza (strictly new viruses, not seasonal diseases) and tested against the Ebola and Zika viruses.

Yes, Russian researchers seem to have managed to catch the effect of its use in the treatment of COVID-19 - but so far on a small sample of 60 people, there is no detailed information on the methods of selection and composition of which.

So we seem to have pills. And to make sure that this is really a medicine, you will have to wait a little longer.