Source: [People's Daily Central Kitchen - Jiangdong Studio] In the early morning of December 29, Beijing time, the New England Journal of Medicine (NEJM) published a Phase 3 randomized controlled clinical trial of a Chinese COVID-19 drug. The results showed that for adult patient

Phase 3 randomized controlled clinical trial of VB116 shows adverse effects on both drugs after administration

So, how difficult is it to get the research results published in the New England Journal of Medicine? Xu Huaqiang, who has nearly 30 years of scientific research experience in the United States, said: "There is a saying in the American scientific community that doctors who come out of Harvard University and Massachusetts General Hospital can dominate the world. NEJM, founded by Massachusetts General Hospital, is the unique and first authoritative journal in medical academics. The Lancet that we are familiar with can only rank second in the world. It is unanimously recognized by the academic community that it is difficult to publish Science, it is difficult to publish Nature, and NEJM is even more difficult.”

The New England Journal of Medicine is a review medical journal and a comprehensive medical journal published by the Massachusetts Medical Association. Founded in 1812, it is the medical academic journal with the highest impact factor in the world. There are countless clinical trial results every day in the world. Such rigorous Why did the picky NEJM choose the results of the Phase 3 "head-to-head" clinical trial of VV116? Xu Huaqiang believes that this fully demonstrates that this trial research is fruitful and the results are of extremely precious value. The reviewers of NEJM are all authoritative international medical experts, and most of them are not Chinese. They transcend national boundaries, without any prejudice, and judge the research results from China with a scientific perspective, which is commendable.

Medical staff at Ruijin Hospital conduct night rounds to check the pupillary reflexes of comatose and critically ill patients

New drugs will help fight the epidemic

According to the memories of researcher Xu Huaqiang, who has participated in the preclinical research and development of VV116, after the outbreak of the new crown epidemic in 2020, the famous pharmacologist and former director of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences Jiang Hualiang Academicians convened the research team in the institute and asked everyone to put aside the topics at hand and work together to tackle this urgent problem related to the health of people around the world. On January 19, 2020, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, established an anti-epidemic research team. More than 300 scientific researchers gave up their vacations to give full play to their respective scientific research advantages and jointly tackle the problem of .

A week later, a research team led by Academician Jiang Hualiang and Tsinghua UniversityRao Zihe became the first in the world to measure high-resolution crystals of the new coronavirus 3CL hydrolase (Mpro). structure, and expose this structure to the world without reservation.

now knows what the virus looks like. The next step is to figure out how it replicates, how to break through the body's immune defenses, and how to limit its replication.

"In our research, we found that RNA replicase is a core component of the transcription and replication of the new coronavirus, and its function is highly conserved in virus mutation. If the RNA replicase of the virus can be restricted and its activity is reduced, then no matter how it mutates, it will be difficult to replicate and survive in the human body. Moreover, we found that nucleoside drugs with antiviral activity are equally effective in inhibiting the new coronavirus RNA replicase. "Xu Huaqiang said.

After 46 days of hard work day and night, Xu Huaqiang's team successfully analyzed the structure of the new coronavirus RNA replicase alone and the cryo-electron microscopy structure of the complex combining RNA and the inhibitor remdesivir , and elaborated on the fine antiviral mechanism of nucleoside drugs such as remdesivir . The results were published in the International Top 10 in May 2020. Published in "Science".

Shanghai Institute of Materia MedicaShen Jingshan's team has been studying nucleoside drugs for nearly 20 years.This result of Xu Huaqiang's team has given them an important combat road map, "It is equivalent to identifying the possible targets of the new coronavirus, drawing the lock, and providing it to Teacher Shen Jingshan's team to find the key to unlock the lock." "

Shen Jingshan's team tested and screened day and night among more than 100 candidate small molecule compounds, and finally found several candidate drugs, and then improved them, usually in the form of injections, into oral drugs . "The main purpose is to improve the drugs based on the characteristics of the new coronavirus attacking the upper respiratory tract and lungs of the human body. "

According to reports, VV116 has shown significant antiviral effects in vitro against both the original strain and known mutant strains of the new coronavirus; in mouse models, low-dose VV116 can reduce the lung virus titer to below the detection limit , significantly improve the pathological changes in lung tissue, and show strong antiviral efficacy. Preclinical pharmacokinetics and other research results show that VV116 has high oral bioavailability, and after oral absorption, it is rapidly metabolized Xie is the parent nucleoside and is widely distributed in body tissues. At the end of 2021, VV116 was the first to be approved for the treatment of COVID-19 in Uzbekistan..

Pharmacologist and academician of the Chinese Academy of Engineering Professor Ding Jian commented on VV116 and pointed out that RNA replicase is one of the important targets for the development of anti-new coronavirus drugs. Anti-new coronavirus drugs developed for this target are not susceptible to virus mutation.Preclinical studies and phase 1 clinical studies have confirmed the activity and safety of VV116 against the new coronavirus. This clinical study comparing VV116 with Paxlovid oral treatment of new coronavirus further verified the effectiveness and safety of VV116 in treating patients infected with the Omicron variant..

Professor Ding Jian also said that anti-COVID-19 drugs are one of the important means to effectively respond to the epidemic. In particular, based on the positive and significant results achieved in effective epidemic prevention and control, my country has introduced 20 optimization measures and ten new epidemic prevention and control measures to implement more scientific and precise epidemic prevention and control. It is even more necessary to strengthen the research and development, production and reserve of anti-COVID-19 drugs. Oral small molecule anti-COVID-19 drugs have the advantages of ease of use and good accessibility, and will play an important role in current and future epidemic prevention and control.

Medical staff care about the elderly in the ward, pushing them to the window to feel the sunshine

High-standard trials under the weight of the epidemic

Pre-clinical research and development has gone through a lot of hardships, and once the drug actually enters the clinic, it faces one difficulty after another. In the three years since VV116 was conceived and born, Academician Jiang Hualiang never had a good night's sleep. He discussed plans round after round with various teams involved in VV116 research and expert teams from major hospitals in Shanghai. On the morning of his sudden death on December 23, 2022, he held a two-hour online coordination meeting to prepare for the VV116 drug marketing authorization application.

According to the relevant research team of Ruijin Hospital, this research was completed in the first half of this year during the Great Shanghai Defense War on . Since March this year, Ruijin Hospital has not only completed the conversion of designated hospitals and the admission of -positive -infected patients within 48 hours, but also dispatched 21 medical teams to participate in the treatment of designated hospitals and makeshift cabins to complete multiple tasks such as nucleic acid detection and . It has also gone all out to complete the Phase III non-inferiority observer-blinded randomized controlled clinical trial of VV116 while maintaining quality and quantity during the busy clinical treatment period.

Ruijin Hospital has always attached great importance to translational research that discovers problems in the clinic, solves them through scientific research, and then returns to the clinic to benefit patients. Especially after the Translational Medicine National Major Science and Technology Infrastructure (Shanghai) was put into trial operation in 2019, this 54,000-square-meter center with 300 research beds has built six major platforms, namely a standardized clinical biospecimen bank, an in-depth clinical resource analysis and mining platform, a biomarker and drug R&D and new drug creation platform, a diagnostic reagent and instrument development platform, a molecular pathology and imaging technology research platform, and a clinical research ward, focusing on the national innovation strategy and the Healthy China Strategy. It has successfully built a clinical research and platform operation system. Based on the construction of the Translational Medicine Center, a close and integrated open and cooperative mechanism with scientific research institutions, research institutes, biomedical companies, etc. has also been formed. At the same time, an excellent and efficient research team has been cultivated.

"The new coronavirus patients enrolled in the group come from the designated hospitals in northern Ruijin and the major Fangcang shelters that Ruijin Hospital is responsible for operation and management. They also receive strong support from multiple designated hospitals and Fangcang shelters in Shanghai." Zhao Ren, deputy director of Ruijin Hospital, said, "Based on the fever of Ruijin Hospital General Hospital The strong clinical reception capabilities and laboratory testing capabilities of the outpatient clinic and the virus laboratory have played an active role in the smooth enrollment of VV116 clinical trial subjects. In the clinical trial of VV116, the enrolled subjects are mainly symptomatic and at high risk of progression. For adult patients with mild to moderate COVID-19, most of these patients have underlying diseases. After being infected with COVID-19, their underlying diseases are at risk of further aggravation. After taking VV116 or control group drugs at the same time, there may also be a certain incidence of adverse drug reactions. All these require clinical close attention to changes in the patient's condition and active and effective treatment. Gao Weiyi, Medical Director of Ruijin Hospital, said that Ruijin Hospital has deployed multi-level diagnosis and treatment teams in designated hospitals, including hospital expert groups and multi-disciplinary clinical diagnosis and treatment groups, which are responsible for the clinical observation and treatment of clinical trial subjects to ensure medical safety .The expert group is personally led by Qu Jieming, chairman of the Respiratory Disease Branch of the Chinese Medical Association and Secretary of the Party Committee of Ruijin Hospital. He leads a team of hospital-level experts to "see, hear and ask questions" to guide the treatment of critically ill COVID-19 patients with the help of remote dialogue and bedside consultation visualization systems. The multidisciplinary diagnosis and treatment team is composed of clinical doctors, nurses, nutrition, psychology and other multidisciplinary medical teams. It takes into account the physical care and humanistic care of the test subjects, helping them to smoothly survive the physiological discomfort during the infection period, while relieving anxiety, and cooperating throughout the entire clinical trial process to successfully complete the clinical trial process.

At that time, Ning Guang, academician of the Chinese Academy of Engineering and president of Ruijin Hospital, led the command team and stayed at the hospital operation and management command center for more than three consecutive months. During the day, he coordinated the overall deployment of all medical resources including personnel, materials, equipment, and space in the hospital; scientific research discussions were held as scheduled every night, and the online meeting on the progress of the VV116 clinical trial at 8 o'clock every night was unstoppable.

" We were able to successfully complete this research only because all our colleagues worked hard." Ning Guang said, "Now that China's epidemic policy has changed and the country is about to open, our research will not only provide valuable data and experience for the global research and development and clinical application of anti-COVID-19 small molecule drugs, but will also contribute to China's anti-epidemic cause . "

Professor Cao Bin commented that under the severe pressure of the epidemic, it is understandable that it is difficult to still adhere to high standards in conducting clinical trials of new drugs. We pay tribute to all the teams, subjects and families who conducted rigorous scientific research during the epidemic, and thank them for their efforts to improve the diagnosis and treatment of COVID-19 patients, and to continuously accumulate reliable evidence-based evidence to ensure the clinical benefits of patients.

(pictures are provided by Shanghai Ruijin Hospital)

This article comes from [People's Daily Central Kitchen-Dajiangdong Studio] and represents only the author's opinion. The National Party Media Information Public Platform provides information release and dissemination services.

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