The new crown oral medicine is here! "Two slices work" is it a dream?
The world's first oral new crown drug approved for emergency use is the US Merck's monupavir, which was approved for marketing in the UK in November last year, followed by the new crown virus treatment drug paciclovir produced by Pfizer in the United States on December 22, 2021. Approved for emergency use in the United States.
The two drugs were subsequently licensed for use in Israel, Canada and other countries.
my country's original new crown oral drug VV116 was recently approved for marketing in Uzbekistan.
Produced by Deep Eye Studio
Written by: Our reporter Zhang Jiaxing
Planning: Liu Li
Have you ever thought that if there is a special medicine for the new crown, would you choose an injection or a medicine?
The research and development of specific drugs for the new coronavirus has been in full swing in the past two years.
The recent confidence in epidemic prevention and control is small molecule oral drugs——
Since November 2021, oral new crown drugs have been brought to the front from behind the scenes from time to time.
First, the US Merck's Molnupiravir and Pfizer's Paxlovid were approved for marketing or emergency use one after another; followed by my country's original new crown oral drug VV116, which was recently launched in China with excellent clinical trial data. Uzbekistan was approved for listing.
Compared with macromolecular drugs (such as neutralizing antibody drugs for injection, etc.), small-molecule oral drugs have the advantages of direct antiviral effect, low production cost and drug cost, easy storage and transportation conditions, and convenient administration. of high hopes.
"At present, patients infected with the new coronavirus are mainly patients with mild and moderate symptoms, and they account for more than 85%. If these people can use small molecule oral drugs for treatment at home, they can not only quickly eliminate the virus, but also transmit the virus to other people. The risk to others is minimized, and the isolation time can be shortened, which may play an important role in changing my country's existing epidemic prevention and control strategies." Zhong Wu, a researcher at the National Emergency Prevention and Control Drug Engineering Technology Research Center, told a reporter from Science and Technology Daily. This is more beneficial to the prevention and control of the entire epidemic.
"New crown drugs, especially oral drugs that can be taken at home early in the course of the disease, will be a powerful tool to fight the pandemic and save lives." White House Chief Medical Adviser Anthony Fauci said.
"An easy-to-administer oral antiviral drug will be an important part of our treatment arsenal." David Kessler, chief scientific officer of the US government's new crown pneumonia response, also repeatedly emphasized the importance of oral drugs.
Is it possible for "two tablets to work"?
In the 1980s, "Two Pieces" advertisements for deworming drugs became a household name.
Because it can "starve" a wide variety of parasites, the small-molecule drug Changchongqing (albendazole) has been included in the World Health Organization Model List of Essential Medicines, thus becoming one of the most important essential health medicines, commonly known as "Special medicine".
To deal with parasites, "two pieces" to clear worms, and to deal with the new coronavirus, is it possible to "two pieces" to eliminate the virus?
The new coronavirus oral specific drug also wants to achieve a similar effect: after taking the medicine, the viral load in the body is measured, and there is a sudden drop or no detection at all.
is it possible?
"Whether a drug can be taken orally depends on its own chemical and biological properties." Zhong Wu explained that the main measure is bioavailability. If the oral method affects the absorption and metabolism of the active ingredients of the drug The utilization is very low and there is no way to make it into an oral drug.
In other words, the journey and environment to be taken by oral drugs to "fight" against the virus in the body are more twists and turns than injections. The drug is consumed before it "goes head-to-head" with the virus, or is metabolized to another inactive substance, and it won't be able to be taken orally.
The well-known Remdesivir is a typical representative of difficult to become an oral drug.
On October 22, 2020, the U.S. Food and Drug Administration (FDA) approved Gilead’s remdesivir for the treatment of hospitalized patients with new crowns.
Different from the emergency use license of other drugs, remdesivir has become the first officially approved new crown treatment drug in the United States, and it is also the only small molecule drug officially approved in the United States so far.
However, the bioavailability of oral remdesivir is very low, only about 2%. It is difficult to make oral medicine to exert its efficacy. Therefore, it can only be made into an injection and injected directly into the blood to exert its efficacy.
Injectable use imposes certain limitations on the convenience of drug use.
Gilead also realized this and began to explore the way of drug delivery through a nebulizer, but it still did not make up for the huge gap between its convenience and oral drugs.
It can be seen that when looking for an oral specific drug for the new crown, the pharmaceutical field not only needs to understand the mechanism of action and choose different "attack points" to suppress the virus, but also needs to work hard on the most essential chemical properties to develop a global pandemic, easy to large-scale. Scale-produced, easy-to-use medicines at scale.
After a number of neutralizing antibody drugs in the form of injections were approved for emergency use, it is not surprising that small-molecule oral new crown drugs are late.
The world's first approved oral new crown drug for emergency use is the US Merck's monupavir, which was approved for marketing in the United Kingdom in November 2021, followed by the new crown virus treatment drug paciclovir produced by Pfizer in the United States on December 22, 2021. Approved for emergency use in the United States.
The two drugs were subsequently licensed for use in Israel, Canada and other countries.
The new crown oral drug VV116 jointly developed by Chinese scientific research institutes and enterprises was approved for marketing in Uzbekistan on December 30, 2021, and has been approved to enter clinical trials in China.
Can China's "116" become a dark horse?
Relevant R&D units disclosed that VV116 has performed well in preclinical pharmacodynamic studies.
Shen Jingshan, a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and other teams found in experiments on an adenovirus mouse model that oral administration of VV116 could reduce the virus titer below the detection limit and significantly improve the pathological changes in the lung tissue of experimental model animals.
Experiments on model mice have proved that VV116 has the potential to become a dark horse of special drugs, which can greatly reduce the viral load in the body after taking it.
"The VV116 developed by the Shanghai Institute of Materia Medica as the main R&D force is more promising to become an effective drug for the treatment of the new crown virus." Zhong Wu expressed his confidence in this domestic small molecule oral drug. He explained that the basic principle of VV116 attacking the new crown virus Similar to remdesivir, both are the core enzymes that attack the new coronavirus. The clinical treatment effect of remdesivir in the United States and other places shows that the principle of action of this drug is effective against the new coronavirus, and the greater advantage of VV116 is to do to oral.
In principle, VV116 targets the polymerase (RdRp, RNA-dependent RNA polymerase) of the new coronavirus, and "encircles and suppresses" the virus by destroying the self-replication pipeline of the new coronavirus.
How to do it specifically?
As a nucleoside analog of the new coronavirus, VV116 can disguise as a nucleotide required by the virus.
After the virus invades, it will "recruit" various production materials in human cells, and VV116 disguisely "incorporates" into key "parts" nucleotides. When RNA polymerase acts as a large production machine to assemble the new coronavirus, VV116 As soon as it enters, it will cause the big machine to "stuck", making the virus self-replication assembly line "strike" and unable to reproduce in the human body.
The more thoroughly the working mechanism of the viral protein machine is studied, and the finer the parts and gears are, the higher the efficiency of "camouflage-entering-stuck" small-molecule drugs will be.
2020年3月之前，由于缺乏新型冠状病毒RNA聚合酶的三维结构信息，核苷酸类似物如何精确靶向病毒RNA聚合酶的机制并不明确。
两年来，中国科学家对于RNA聚合酶的运转机理做了细致剖析，可以说是“了如指掌”。我国饶子和院士团队持续对新冠病毒的RNA聚合酶及其复合物的精密结构进行解析，并不断“拍下”其在“运转”过程中的高清“照片”，通过冷冻电镜技术找到核心靶点，并阐明了相关药物的作用机理以及副作用机理。例如，2021年刊《细胞》刊文称，研究团队发现了病毒竟可以通过“反式回溯”的方式对错配碱基和抗病毒药物进行“剔除”，这阐明了核苷酸类似物药物(瑞德西韦)效果不良的分子机制。
基础研究中的发现，帮助针对聚合酶的抗病毒药物不断优化，将其“打磨”得越来越接近特效药。
特效药的研发需要不断打磨、不断改进缺点。例如，此前由于瑞德西韦可能会产生严重副作用，世界卫生组织曾评估不建议使用该药物进行治疗。而VV116在保持了核苷酸类似物骨架的同时，在化学基团的修饰和优化中做了关键性的工作。一系列临床前安全性评价实验显示，VV116的安全性较好且无遗传毒性。
“通过分子水平上的基团改进和优化，VV116还解决了无法口服的问题。”钟武解释，VV116作为全新的核苷类似物小分子，口服以后不会被分解，能够快速进入血液，发挥抗病毒作用，大大提高了生物利用度，这一点是其核心优势。
“老药新用”是另一条路？
除了专门针对新冠病毒努力研制新药外，很多科学家也着力从老药中寻找对抗新冠病毒的“佼佼者”。
在两年前的疫情初期，我国在重大新药创制国家科技重大专项支持的平台上迅速筛选了大量原本用于治疗其他疾病的“老药”：法匹拉韦、磷酸氯喹、可利霉素等能在体外有效抑制新冠病毒的药物脱颖而出。它们中有的在实践中没有展现出抗击新冠病毒的实力，有的仍活跃在疫情防控一线，有的正在开展新适应症的临床试验……
So far, in Russia, Turkey, Saudi Arabia, India, Thailand, Laos, Vietnam... Favipiravir tablets have been approved for the treatment of new crowns, and are distributed free of charge to some people.
Thailand.com reported that Songsa, director of the Thai Medical Department, responded to the media on January 18, saying that if the patient's condition changes, favipiravir should be assigned to him as soon as possible.
However, the effectiveness of these old drugs against the new crown has not been generally recognized by the academic community.
what about this?
"Taking favipiravir as an example, there is still a lack of evidence-based evidence with the highest level of evidence, such as double-blind and randomized control. However, many open studies and retrospective studies have shown that favipiravir is effective." Zhong Wu He said that in the real world, many countries such as Russia, Saudi Arabia, Turkey, and India are using favipiravir to treat the new crown, and the effect is also good.
In the two years since the new crown epidemic, there have been many examples of new use of old drugs.
The scientific research on the new use of old drugs has never stopped.
A drug called "Qianjintiansu" has recently become popular in academia.
Two years ago, Chinese scientists discovered that it has high activity against the new coronavirus. Two years later, Canadian pharmaceutical companies finally started clinical trials.
"Sencephalin is an old drug for the treatment of leukopenia, and it showed higher anti-new coronavirus activity than other drugs such as remdesivir on our screening platform." Beijing University of Chemical Technology Life Science and Technology Tong Yigang, the dean of the school and the Chinese team leader of the Animal and Environment Group of the China-WHO Joint Research Expert Team on Novel Coronavirus Origin Traceability, said.
In the past two years, a number of international teams including the National Institute of Infectious Diseases in Japan and the research team at the University of Chicago in the United States have successively proved the anti-new crown ability of fenugreek.
A related paper was published in the journal Science.
On the last day of 2021, Tong Yigang's laboratory issued a bulletin: The Canadian pharmaceutical company's clinical trial plan of fenugreek was approved by the US FDA.
"Theoretical verification has finally progressed to the test of clinical practice, and further research and development still needs the support of the state and the leadership of experienced and powerful pharmaceutical companies." Tong Yigang expects that the results of clinical trials of Qianjintiansu in the future will be able to find the "golden key for mankind to overcome the new crown epidemic." ".
The delightful research results have come one after another.
"Combining the old and the new" is also an idea.
An interesting new study shows that the combination treatment with the "old drug" favipiravir and "new star" monupavir not only made the virus undetectable in 60% of the sick animals, but also prevented the close contact animals from being infected.
Is it feasible to follow the "rut" of hepatitis C?
Looking for oral specific medicines, there is another trick called "following the past".
The new coronavirus is a single-stranded positive-stranded RNA virus (a type of virus), so are there any viruses of the same type that humans have dealt with before?
There really is.
The hepatitis C virus that can be completely cured today is also a single-stranded positive-stranded RNA virus. The two viruses are a bit similar from a certain point of view. Is it possible to use the medicine for treating hepatitis C to treat the new crown?
Many international scholars have published the view of "reuse of hepatitis C drugs to treat new crowns", and there are also many studies comparing the efficacy of new crowns of various hepatitis C drugs.
Cai Haodong, chief physician of Beijing Ditan Hospital, in her "Can direct antiviral drugs for hepatitis C treat new coronary pneumonia?
"Introduces a number of international research results, showing that many anti-hepatitis C virus drugs have anti-new crown effects.
With the support of the National Science and Technology Major Project for the Creation of Major New Drugs, the "sister drug" combined use program independently developed by the Chinese pharmaceutical company Asli can cure hepatitis C within 12 weeks by taking a full oral drug.
With its research and development experience in hepatitis C drugs, Ascletis has developed two oral anti-COVID-19 drugs, ASC10 and ASC11.
The mechanism of action of the two new drugs is consistent with the two drugs that have been approved for emergency use in the United States. They both act on the core enzyme of the new coronavirus, and reduce the viral load by inhibiting the action of the enzyme.
"The two anti-coronavirus compounds developed by Ascletis are completely new and different from those of Merck & Co. and Pfizer. We have applied for a number of compound and use patents." The relevant person in charge of Ascletis said, "Our animal test data show that ASC10 is compatible with Merck & Co. has better bioavailability than monupavir."
Following the "rut" of hepatitis C specific drugs, will the new crown specific drugs be far behind?
What is the price of upcoming oral medicines?
In response to the increasingly severe new crown epidemic, the United States and the European Union have deployed huge plans to promote the research and development, testing, production and promotion of drugs.
On January 18, Pfizer announced that it plans to invest 520 million euros in the next five years to strengthen production, in order to achieve the goal of producing 120 million courses of oral drug paciclovir globally in 2022.
On January 20, Merck signed an agreement with 27 generic drug manufacturing companies to license the supply or imitation to produce and supply monupavir to 105 low- and middle-income countries or regions around the world, including 5 Chinese companies.
So what is the price of the upcoming oral drugs?
According to data analysis, based on the US government's $5.29 billion order for 10 million courses of treatment, the price of Pfizer's paciclovir per course of treatment is as high as $529.
At the price of $2.2 billion to buy 3.1 million courses of monupavir, the price of each course of Merck's new crown oral drug monupavir is about $700.
Still, this is more than half the price of a neutralizing antibody drug for injection in developed countries, which costs $2,100 per dose.
The price of the new oral drug VV116 in my country is currently not disclosed, but in terms of cost, small molecule drugs are easy to produce on a large scale, and the cost will be much lower than that of neutralizing antibody drugs.
In addition to the research and development progress mentioned earlier by the reporter, there are two oral new crown drugs in my country that have attracted much attention - azvudine and proclutamide.
According to the data, Real Bio's Azvudine has completed the Phase III clinical trial and is applying for data unblinding, and clinical data is expected to be released in February; while the interim analysis of the Phase III clinical trial of Kintor Pharmaceutical's Prolukamide in the treatment of non-hospitalized patients with COVID-19 Statistical significance was not reached, and plans to adjust the clinical trial protocol continue to advance.
The process of new drug research and development has been a cycle of more than ten years in the past. During the new crown pandemic, all links in the chain including pharmaceutical molecular screening, animal testing, preclinical research, clinical trials, marketing application approval, etc. The clockwork has been tightened”, and the R&D resources and R&D efforts invested by various countries are unprecedented.
With the experience accumulated in the global pharmaceutical industry over the past century, it may not take too long to stop the epidemic in the fight against the surprise and fickleness of the new crown virus.