The first approved drug for COVID-19 begins to be used in Russia: what is known about it - ForumDaily
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The first approved drug for COVID-19 begins to be used in Russia: what is known about it

Avifavir tablets are planned to be delivered to hospitals in June, writes Lifehacker.

Photo: Shutterstock

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

Where did it come from

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

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

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

If RNA polymerase is turned off, influenza viruses lose the ability to "print" their genetic material, RNA, in infected cells. As a result, the production of the virus, which has already penetrated the cells, stops. This is the uniqueness of the drug - usually antiviral drugs can only prevent the penetration of viruses into 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 (the so-called portion of the molecule, due to which the enzyme can, in principle, work) is the same in all RNA viruses. And since favipiravir binds specifically to the catalytic domain of RNA polymerase, the Japanese had reason to consider this substance as a broad-spectrum antiviral agent.

Toyama employees registered favipiravir under the trade name Avigan and began to study the activity of a promising drug on RNA viruses: from influenza viruses type A and B to the Ebola virus. The results were mixed. For example, in the case of the Ebola virus, it turned out that the drug worked on macaques, but during application in humans the result was not very impressive. On the one hand, the mortality rate in 73 patients from Guinea receiving favipiravir was lower than in patients who were tried to treat with other methods. On the other hand, the difference was not so great: 42,5 percent versus 57,8 percent — that is, it is impossible to guarantee that this is not just a random counting artifact due to the fact that the patient sample was very small. However, the Guinean government has approved the drug as a standard treatment against the Ebola virus.

In the homeland of the drug, in Japan, Avigan was able to register only in 2014 - and only against new strains of the influenza virus. Avigan was not used against seasonal flu.

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

A review of 29 clinical trials (4 participants), six of which were trials of the second and third phases (they are already evaluating the effectiveness of the drug), showed that favipiravir "shows a favorable safety profile": the share of serious side effects was 299 percent. However, drug safety concerns still remain.

Japanese researchers, who studied the prospects of using the drug for severe flu, emphasized that Avigan is contraindicated in pregnant women: the drug had teratogenic and embryotoxic effects in animals. Other possible problems: decreased appetite, nausea, vomiting, increased 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, stated that favipiravir "has shown good clinical efficacy against new 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 they were talking about - the original Avigan or a Chinese medicine with the same active substance) recovered faster and suffered less from complications than 45 patients who were treated with other drugs (lopinavir and ritonavir).

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

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Russian drug

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

Russian clinical trials of Avifavir are also not yet complete. Only the first and second stages of a multicenter randomized trial have been completed, confirms the interlocutor "N + 1" from the RDIF. The first stage was attended by 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 is what the developers themselves report on the results of these tests:

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

The Ministry of Health approved the start of the third phase of Avifavir trials on May 1, 2020. At this stage, according to the data on the website of the State Register of Medicines, 390 people will have to take part in total. From the same data it is clear that the tests of favipiravir are carried out by two other Russian companies - “Drug Technology” (part of the “R-Pharm” group) and “Promomed” (both began testing in late May).

Although the trials have not been completed and only partial data on the effectiveness are known, the Ministry of Health allowed to register the drug ahead of schedule - according to an accelerated procedure adopted under the Russian government decree of April 3, 2020 No. 441. This decree states that "reduction in the volume of <...> examinations" permissible "in conditions of a threat of occurrence and elimination of an emergency"

So the manufacturing company already promises to bring the first shipments of tablets to hospitals by the end of next week.

The instructions for the drug say that it is "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 pregnancy planning, pregnancy and the period of breastfeeding - a generic is also potentially teratogenic. Patients with gout and hyperuricemia should use the medicine with caution. In addition, a list of contraindications to the Russian generic 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 only be used in hospitals.

With the result that

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

The results of intermediate clinical trials show that the medicine is promising: in those small samples that have been tested, the therapeutic effect, judging by the statements of the developers, was determined. But until the clinical trials are completed and their results are published in peer-reviewed international journals, we cannot be completely sure that Avifavir really helps against coronavirus disease. The press service of ChemRara, the drug’s developer, did not answer the questions “N + 1” at the time of publication of this text.

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

The first is Remdesivir, which did not leave the front pages in May. This is a medicine that, even before the COVID-19 epidemic, was intended to treat another coronavirus infection, the 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 with early registration of AZT, the first HIV drug.

At the same time, Remdesivir never claimed the status of a “silver bullet”: tests show that it can not help people with severe symptoms who need mechanical ventilation, and those who have better symptoms can reduce the time of the disease by four days. Many other effects (for example, a decrease in the mortality rate of the disease compared with other drugs) with statistical significance were not shown in the course of these tests. The sample of trials of Remdesivir, the report of which was published at the end of May by the New England Journal of Medicine, amounted to 1 people.

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60 subjects - is it 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.

The indicators that will be taken into account during the tests are assigned. The main one, as a rule, is mortality. In the case of respiratory infections, integral indicators are used, which take into account, among other things, the number of days with fever, time in the intensive care unit or intensive care unit, on mechanical ventilation, and also coughing. According to a certain formula, all of them are converted into points, 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 is not enough.

Pilot trials may be conducted on a small group before starting clinical trials. It is not uncommon for a situation where an effect discovered in a group of several dozen people is subsequently “eroded” in larger groups,” says Elena Verbitskaya, head of the department of biomedical statistics of Academician I. P. Pavlov St. Petersburg State Medical University.

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

Yes, Russian researchers seem to have been able to catch the effect of its use in the treatment of COVID-19, but so far in a small sample of 60 people, detailed information on the selection methods and composition of which is not available.

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

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