Facing the rapidly developing COVID-19 epidemic, our country is in urgent need of highly effective anti-COVID-19 drugs. Although Pfizer's Paxlovid (nematvir-ritonavir) and the domestic original drug Azivudine have already received emergency conditional approval for the treatment of Covid-19, they are far from meeting clinical needs due to insufficient supply or lack of high-quality evidence.
Early this morning Beijing time, the New England Journal of Medicine (NEJM) published a Chinese non-inferiority phase 3 randomized controlled clinical trial. The results showed that for adult patients with mild to moderate Covid-19 with high-risk factors, domestic VV116 was non-inferior to Paxlovid (4 days vs. 5 days; risk ratio, 1.17; 95% confidence interval, 1.02~1.36), and fewer adverse events .
This trial was conducted by Professor Zhao Ren of Ruijin Hospital in Shanghai and Gaoyuan of Renji Hospital in Shanghai. Led by Professor and Academician Ningguang of Shanghai Ruijin Hospital, was carried out in 7 Shanghai hospitals. It was the first "head-to-head" phase 3 clinical trial of a domestic oral antiviral drug for Covid-19 patients during the epidemic of omicron mutant strains. VV116 is a new coronavirus RNA replicase small molecule inhibitor jointly developed by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, , Wuhan Institute of Virology, Xinjiang Institute of Physics and Chemistry Technology, and other units.
This is NEJM published the first clinical trial of an innovative new coronavirus drug independently developed by China. It was completed with high quality during the extremely difficult period in Shanghai from March to May, which is particularly commendable. "NEJM Medical Frontiers" invited pharmacologist, Academician of the Chinese Academy of Sciences Professor Ding Jian and respiratory critical illness expert Professor Cao Bin to interpret this study from the perspectives of pharmacology and clinical trials respectively.
The world's top authoritative journal "The New England Journal of Medicine, NEJM, impact factor: 176.079"
Wang Yeming, Cao Bin* Department of Respiratory and Critical Care Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine ; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences * Corresponding author
VV116 is my country’s first domestically produced small molecule drug inhibitor targeting the RdRp of the new coronavirus. During the Shanghai epidemic from March to May 2022, researchers quickly designed and conducted a head-to-head non-inferiority clinical trial (ChiCTR2200057856, NCT05341609). Currently, the clinical trial results of the drug have passed peer review and were published in the New England Journal of Medicine (NEJM) on December 29, Beijing time [1]. This study is the first to report the data on the symptom improvement time of VV116 and Paxlovid in people with high-risk factors under the epidemic situation of omicron, which can provide important reference value for the design of subsequent clinical trials and clinical medication guidance.
In order to better understand the original intention of the research and the design of the clinical trial, it is necessary to first sort out the background of the clinical trial at that time. First of all, a series of high-quality clinical studies have successively proven that early use of the small molecule antiviral drugs molnupiravir (monupiravir; within 5 days of onset), Paxlovid (within 5 days of onset) and remdesivir (within 7 days of onset) can reduce the occurrence of severe illness and death in people with high-risk factors. These clinical trials are mainly concentrated between 2020 and 2021, and the delta strain is mainly prevalent, and most of the subjects have not been vaccinated with the new crown vaccine .
However, there are several important factors to consider when designing the VV116 study: (1) The prevalent strain in Shanghai is omicron BA.2, which has lower pathogenicity than delta; (2) Most of the population in Shanghai, my country, has completed vaccination; (3) Paxlovid has been approved by my country's CDE and included in the diagnosis and treatment plan of the Health Commission, becoming a standard antiviral drug for people with high-risk factors. The research team designed a multi-center randomized controlled non-inferiority clinical trial to evaluate the efficacy of VV116 vs. the control drug (Pfizer Paxlovid) in patients with mild and common Covid-19 with high-risk factors.
The final VV116 and Paxlovid groups recruited 384 and 387 subjects respectively. Demographic information and baseline situation results show that only 23.4% have not received the new coronavirus vaccine; 92.1% are mild. The results of the primary endpoint (clinical symptom recovery time) showed that the median symptom recovery time was 4 days in the VV116 group and 5 days in the Paxlovid group (hazard ratio, 1.17; 95% confidence interval, 1.02-1.36). As we all know, the time between the use of antiviral drugs and the onset of disease is a key factor affecting the effectiveness of the drugs. There was no significant difference between the two groups in the use of antiviral drugs within 5 days of onset. Subgroup analysis was conducted according to factors such as age, vaccine , disease severity, onset time, etc. The results were consistent with the results of the full analysis set (FAS), that is, VV116 and Paxlovid have similar clinical symptom recovery times. virology results are an important secondary clinical endpoint for evaluating antiviral drugs. The two groups also maintained a comparable level in terms of negative conversion of the new coronavirus (nasopharyngeal swab).
to symptom recovery time
In terms of safety, VV116 and Paxlovid also show similar good safety, even lower than Paxlovid in the incidence of some adverse reactions, especially taste disorder. Paxlovid is a compound preparation of nematvir (3CL inhibitor) and ritonavir (used to increase blood drug concentration). Ritonavir is metabolized by the CYP3A4 enzyme in the liver and interacts with many drugs (please refer to the instructions or instructions for use for details). It is very inconvenient for some patients who cannot stop taking basic medications. Therefore, in terms of safety and medication convenience, VV116 may be better.Adverse events (safety group)
Ding Jian
School of Pharmacy, University of Chinese Academy of Sciences
Anti-coronavirus drugs are one of the important means to effectively respond to the epidemic. Especially on the basis of the positive and significant results 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-coronavirus 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.
This "VV116 and Nematvir-Lito" project was led by Shanghai Ruijin HospitalProfessor Zhao Ren, Shanghai Renji HospitalProfessor Gaoyuan and Shanghai Ruijin Hospital Professor Ning Guang, and 7 hospitals from Shanghai participated. The clinical study results of "Comparison of Navir Oral Treatment for Covid-19" show that compared with Paxlovid (Paxlovid, nematvir-ritonavir), VV116 is non-inferior to Paxlovid in terms of patient's sustained clinical recovery time, viral nucleic acid negative conversion, etc., and the incidence of adverse events is lower than Paxlovid [1].
Source: VIP says
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