This article is written by Fang Jingyu
On February 11, the NmPA approved the import registration of Pfizer's covid-19 therapeutic drug, Nematvir tablets/ritonavir tablets combination packaging (i.e., Paxlovid), for the treatment of adults with mild to moderate COVID-19 patients with a high risk factor for progression to severe illness.
Image source: Screenshot of the official website of the State Food and Drug Administration
Paxlovid was also the first small molecule antiviral drug approved on the mainland.
Small molecule antivirals: coming to the top?
Prior to Paxlovid, the NMPA approved Temshengbo's ampavirinumab/romimavir maclizumab for the treatment of adult and adolescent COVID-19 infections with progression to severe high-risk factors on December 8 last year.
Although also used to treat COVID-19, the two drugs fall into two categories – antivirals and antibody drugs.
Small molecule antiviral drugs are synthetic compounds that can be administered by oral administration, injection and other routes; while the new crown virus neutralizing antibody is derived from the monoclonal antibody against the new crown virus in the convalescent plasma of the new crown infected person, which is made by antibody purification, structural modification and other steps, and can only be administered by injection.
At the beginning, the main research and development force in various countries was antibody drugs. For example, Regen-COV of Regeneration Yuan Company obtained an Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA) as early as November 21, 2020.
REGEN-COV, the first "cocktail" of COVID-19 neutralizing antibodies to receive the FDA's EUA, was once known for its treatment of former US President Donald Trump (Source: The Guardian)
However, with the continuation of the epidemic, scientists have more time to study the specific replication mechanism of the new crown virus and develop targeted antiviral drugs, and small molecule antiviral drugs have a great potential to "catch up later".
However, the development process of new crown antiviral drugs is significantly lagging behind that of antibody drugs. Even Merck and Pfizer, which lead the world, only disclosed Phase III data and got the FDA's EUA in December last year, almost a year later than antibody drugs.
On the mainland, the main ones that have made significant progress are also antibody drugs. Such as the Institute of Microbiology of the Chinese Academy of Sciences and Junshi Bio's etesevimab, and the already approved Tengsheng Bo's ampavirinumab/romisvir maclizumab.
In terms of antiviral drugs, there are also some candidate varieties that have entered the preclinical or clinical research stage, such as VV116 of Junshi Bio, FB2001 of shanghai Institute of Materia Medica of the Chinese Academy of Sciences, and ASC11 of Celees Pharmaceuticals.
On April 22, 2020, the research of mainland scientists on the development of new coronavirus Mpro protein inhibitors was selected as the cover article of Science, and FB2001 was the research result (Source: Chinese Academy of Sciences)
However, before Pfizer's Paxlovid was approved, there was not yet a new crown antiviral drug of its own in China.
Why is R&D so hard?
As early as May 1, 2020, the FDA approved the EUA of the first small molecule new coronavirus antiviral drug remdesivir, which was once developed at a speed that made people think that antiviral drugs would soon end the epidemic, and even called "the hope of the people".
However, the performance of remdesivir in subsequent large clinical studies has been disappointing – the results of the study showed that the drug only shortened the course of the disease in non-severe PATIENTS with COVID-19, but had no effect on mortality or severe disease rates.
How hard is it to develop small molecule antiviral drugs? It is mainly reflected in three aspects.
First, it's about finding drug targets.
Viruses that cause human diseases only carry genetic material and proteins, and their fusion, replication, maturation and other life activities are highly dependent on host cells, which makes many targets that can block the life course of viruses also vital to the survival of host cells, and it is easy to be "mistakenly injured" by antiviral drugs.
For example, many nucleoside antivirals used to treat AIDS and hepatitis B target viral retrotransferases, but human cellular DNA polymerases can also be combined with some nucleoside drugs, resulting in many drugs that inhibit reverse transcriptases at the same time inhibiting human cellular DNA polymerase at therapeutic doses, causing damage to blood cells, muscle cell mitochondria, etc.
In the development of new crown antiviral drugs, monupilvir was also suspended for a time due to the risk of "accidentally injuring" human cells, and after a large number of cell experiments confirmed that its effect on human cells was not clinically significant, the research was "released".
At one point, monupilvir was asked to be suspended by the FDA for its mutagenicity (Source: Nature)
Second, it is to design the molecules that best match the target.
The development of antiviral drugs often requires the use of modern molecular library screening, that is, by comparing the molecules recorded in the library with the target, so as to discover potentially active drugs.
Although this approach can improve the efficiency of new drug development, it will lead to insufficient fit between the drug and the target, which may affect the efficacy and even induce virus resistance. Therefore, the drug design process often needs to repeatedly modify the drug molecules, and even through the cooperation of structural biology and other means, to design the molecules that best match the target.
For example, the hepatitis C antiviral drug daclatasvir, due to the limited understanding of its target (hepatitis C virus NS5A protein) at the time of development, this drug that was screened entirely from the molecular pool soon became clinically resistant.
After structural biology research cracked the structure of the NS5A protein, several other drugs that improved the structure and increased the affinity of compounds and targets quickly stood out and became the mainstream of the market.
Structure of the hepatitis C virus NS5A protein, which directly helped scientists overcome years of drug resistance (Source: Reference [13])
Finally, even if you pass the two levels of target screening and drug structure improvement, it does not necessarily mean that drug development is necessarily successful.
Due to the huge differences between the intracellular environment and the human environment, drugs that are "passed" in the laboratory but "unsatisfactory" in clinical research are very common.
For example, Favipiravir (also known as favipiravir), a small molecule antiviral drug that was once regarded as the "nemesis" of the new crown virus, has a certain inhibitory activity against the new crown virus in cell and animal studies, but all large clinical trials have failed.
Subsequent in vitro studies have shown that favilvir itself needs to be converted into the active product favilvir nucleoside triphosphate in the cell to be effective, but this transformation process is extremely inefficient in human respiratory cells, directly making favilvir have no antiviral activity in the human body.
On the battlefield of COVID-19, researching antiviral drugs is a challenge with an infinite failure rate of nearly 100%. Humans are lucky enough to have monupivir and nematvir within two years of the outbreak.
Why do we need antivirals?
After Pfizer's Paxlovid was approved, it also triggered a lot of expectations and discussions in China. Some people have questioned: In today's highly effective non-drug prevention and control strategies and rich types of antibody drugs, why does the mainland need to spend a lot of energy to independently develop small molecule antiviral drugs?
In fact, the reason why small molecule antiviral drugs are favored is from the following aspects.
First of all, compared with antibody drugs, small molecule antiviral drugs have better efficacy and have obvious activity against many new coronavirus variants.
At present, a large number of clinical studies and practical evidence indicate that the effect of antibody drugs will decline with the emergence of new variants. On January 24, 2022, the FDA announced that it had suspended the use of two new coronavirus neutralizing antibody "cocktails" in the United States, REGEN-COV and Bam-Ete, due to the large increase in the number of antibody-resistant strains of the new coronavirus ( mainly the Omilon strain ) .
In small molecule antiviral drugs, in the case of nematvir, in a study in which 98% of the delta variants were infected, the probability of progression (admission or death due to COVID-19) in people with a high risk of disease progression was reduced by 88%, and none of the patients in the treatment group died of COVID-19.
Secondly, the administration of small molecule antiviral drugs is more flexible and can be flexibly changed with the epidemic situation.
Compared with the new coronavirus neutralizing antibodies that require intravenous administration, small molecule antiviral drugs (except remdesivir) can be administered orally, saving the cost and time spent on intravenous administration by healthcare workers and patients, and reducing the adverse reactions associated with intravenous administration (such as infusion reactions).
In the United States and other areas where medical resources have been severely squeezed due to the new crown epidemic and a large number of non-critical patients cannot be admitted to the hospital for treatment, oral administration is significantly more convenient for epidemic management, and can also reduce the risk of secondary exposure caused by patients traveling to and from infusion centers.
In addition, the capacity of small molecule antiviral drugs has expanded much faster than that of antibody drugs.
Compared with the need for specialized biopharmaceutical factories to produce large-scale production of new coronavirus neutralizing antibodies, small molecule antiviral drugs can be produced by general qualified pharmaceutical companies after mastering a detailed synthesis path, which is more convenient for mass production and use during the epidemic.
Image source: Visual China
Finally, and most importantly, one promising future for small molecule antivirals is post-exposure prevention of covid-19.
The current preliminary study of antiviral drugs has been shown to have some potential to prevent new crown virus infection. Research on the use of small antiviral drugs such as the MOVe-AHEAD study and the EPIC-PEP study for post-exposure prevention of covid-19 has been conducted, and once positive results are achieved, it is likely to further change the global response strategy.
This is more meaningful for the prevention and control of the epidemic in the mainland - the first time to give the contact, sub-close contact and other potential exposure of preventive drug treatment, will help us more quickly to block the chain of transmission, earlier extinguish the local epidemic, the exposure of the new crown pneumonia and even severe new crown pneumonia probability will be greatly reduced.
However, while small molecule antiviral drugs give us a lot of hope, we must recognize that from the experience of human beings in the fight against previous viral disease pandemics, the idea of ending the new crown epidemic with antiviral drugs alone is not realistic.
Small molecule antivirals have certain side effects, are not 100% effective, may be unexpectedly resistant, and are not affordable treatments for people in every corner of the world.
In order to completely win the "war" with the new crown virus, a meticulous non-drug epidemic prevention strategy, wide coverage of vaccination and effective therapeutic drugs are equally important and indispensable.
The good news is that the mainland has also made breakthroughs in research on small molecule antiviral drugs for the new crown virus. According to reports, VV116, jointly developed by Shanghai Pharmaceutical Institute and others, has been approved for clinical trials and has been authorized for emergency use in Uzbekistan, and is expected to submit a listing application in the second half of 2022.
Acknowledgements: This article has been professionally reviewed by Dr. Lei Na, Ph.D. in Pathogenic Biology, Chinese Center for Disease Control and Prevention
【Note】
Dr. Pathogenic Biology of the Chinese Center for Disease Control and Prevention Lei Na Review Opinion:
The main mechanism of action of vaccines (inducing antibodies to be produced in vivo) and antibody drugs is to neutralize the binding of antibodies to the S protein of the new crown virus to prevent the virus from infecting the human body. The emergence of variants such as Delta and Opmi kerong has greatly reduced the protective effect of vaccines and neutralizing antibody drugs.
The mechanism of small molecule antivirals is to reduce the replication ability of viruses by blocking or mutagenesis. For example, Pfizer's new coronavirus antiviral (PAXLOVID) is an enzyme (3CL protease) needed to prevent replication of the new coronavirus, while Merck's antiviral drug (Molnupiravir) is a nucleotide analogue that competes substrates with RNA polymerases to inhibit replication.
It is the broad spectrum of small molecule antiviral drugs that works on viral variants and makes people look forward to it even more. Moreover, small molecule antiviral drugs are comprehensively considered from the aspects of production (large production capacity and low cost), use conditions (normal temperature), price, etc., which are suitable for normal application and long-term protection. Vaccines, antibody drugs, etc., are more like emergency heroes, and the spread of the virus is quickly contained in the early stage of the epidemic.
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Executive Producer: Gyouza
Title image source: Visual China
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