NEJM Frontiers in Medicine
12-29 09:55
VV116 is a small molecule inhibitor of the new coronavirus RNA replicase, which is comparable to Paxlovid in the recovery time of clinical symptoms, and also shows a good safety profile similar to Paxlovid, and even lower than Paxlovid in terms of the incidence of some adverse reactions, especially Taste disturbance.
In the face of the rapidly developing new crown epidemic, my country urgently needs highly effective anti-new crown virus drugs. Although Pfizer’s Paxlovid (Nimatevir-ritonavir) and the domestic original drug Azvudine have already received emergency approval for the treatment of Covid-19, either due to insufficient supply or lack of high-quality evidence, they are far from Far from meeting clinical needs.
Early this morning, Beijing time, the “New England Journal of Medicine” (NEJM) published a non-inferiority phase 3 randomized controlled clinical trial in China. In terms of clinical recovery time, domestic VV116 was non-inferior to Paxlovid (4 days vs. 5 days; hazard ratio, 1.17; 95% confidence interval, 1.02-1.36), and had fewer adverse events.
This trial was led by Professor Zhao Ren from Shanghai Ruijin Hospital, Professor Gao Yuan from Shanghai Renji Hospital, and Academician Ning Guang from Shanghai Ruijin Hospital. It was carried out in seven Shanghai hospitals. Oral antiviral drug “head-to-head” phase 3 clinical trial.VV116 is a small molecule inhibitor of the new coronavirus RNA replicase jointly developed by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Wuhan Institute of Virology, Xinjiang Institute of Physical and Chemical Technology and other units.
This is the first clinical trial of China’s self-developed new crown innovative drug published by NEJM, which was completed with high quality during the extremely difficult period in Shanghai from March to May, is particularly commendable. “NEJM Medical Frontiers” invited pharmacologist and academician of the Chinese Academy of Sciences Professor Ding Jian and respiratory critical care expert Professor Cao Bin to interpret this study from the perspectives of pharmacology and clinical trials.
Head-to-head comparison of VV116 vs. Paxlovid—a difficult exploration of high-standard clinical trials for emergent infectious diseases
Wang Yeming, Cao Bin*
Department of Respiratory and Critical Care Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; Institute of Respiratory Diseases, Chinese Academy of Medical Sciences
*Corresponding Author
Carrying out clinical trials in the context of public health emergencies faces many difficulties, especially the need to race against the epidemic to complete the efficacy verification of new drugs during the outbreak window. The most important thing is to be fast! The results of such clinical trials will provide important reference value for subsequent outbreaks or pandemics of the infectious disease.
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 carried out a head-to-head non-inferiority clinical trial (ChiCTR2200057856, NCT05341609). Published in the New England Journal of Medicine (NEJM) on February 29[1]. This study is the first to report the data on the symptom improvement time of high-risk population groups using VV116 and Paxlovid under the epidemic situation of omicron, which can provide important reference value for follow-up clinical trial design 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 sort out the background of the clinical trial at that time. First of all, a series of high-quality clinical studies have successively proved that early use of 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 risk of Severe illness and death occurred in high-risk groups. These clinical trials are mainly concentrated during 2020~2021, the delta strain is mainly prevalent, and most of the subjects have not received the new crown vaccine.
However, when designing the VV116 study, there are several important factors to consider: (1) The prevailing strain in Shanghai is omicron BA.2, which is less pathogenic than delta; (2) Most of the population in Shanghai has completed vaccination; (3) Paxlovid has been approved by my country’s CDE and included in the diagnosis and treatment plan of the National Health Commission, becoming the 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) on mild and common Covid-19 patients with high-risk factors.
The initial clinical primary endpoints set the time to weight loss and symptom recovery. In order to save time, the research team compromised some rigor, including not carrying out a double-blind design (because double-blind requires drug preparation). From the trial process documents, we can find that the VV116 clinical trial finally abandoned the dual endpoints and only retained the clinical endpoint of symptom remission time. It may be because the research team found that the pathogenicity of omicron decreased during the execution of the test, resulting in an extremely low probability of severe events. Also as expected, the results showed that the number of subjects who developed severe disease was 0 in both groups.
That is to say, the research team did not directly use the time of symptom improvement as the clinical endpoint to conduct a non-inferiority clinical trial design, but a non-inferiority design that was originally planned to use clinical weight loss as the endpoint. However, the decline in the pathogenicity of omicron made this end point impossible to achieve, and the research team was forced to choose symptom improvement as the end point.
Finally, 384 and 387 subjects were recruited in the VV116 and Paxlovid groups, respectively. Demographic information and baseline results showed that only 23.4% had not been vaccinated against the new crown; 92.1% were mild. The results of the primary endpoint (time to recovery of clinical symptoms) showed thatThe median time to symptom recovery 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 use time of antiviral drugs from the onset of disease is a key factor affecting the drug effect. There was no significant difference between the two groups in the use of antiviral drugs within 5 days of onset.Subgroup analysis was performed according to factors such as age, vaccine, disease severity, and onset time, and the results were consistent with the results of the full analysis set (FAS), that is, VV116 and Paxlovid were equivalent in terms of recovery time of clinical symptoms.Virological outcome is an important secondary clinical endpoint for evaluating antiviral drugs. In terms of the new coronavirus (nasopharyngeal swab) turning negative, the two groups also maintained a comparable level.
In terms of safety, VV116 and Paxlovid also showed similar good safety, even lower than Paxlovid in the incidence of certain adverse reactions, especially taste disturbance.
Paxlovid is a compound preparation of Naimatevir (3CL inhibitor) and ritonavir (used to increase the blood concentration), in which ritonavir is metabolized by the CYP3A4 enzyme in the liver, and interacts with many drugs (can be specific reference manual or instructions for use). It is very inconvenient for some patients who cannot stop using basic drugs. Therefore, in terms of safety and drug convenience, VV116 may be better.
Judging from the current situation, it is almost impossible to complete the indication of targeting to reduce the occurrence of severe diseases. The symptom improvement indications for outpatients with mild symptoms of new coronary pneumonia are currently unmet clinical needs. As the epidemic strains are always changing, the corresponding clinical symptoms have also changed to varying degrees. The guidelines for clinical trials of Covid-19 drugs announced by the US FDA in September 2020 set 14 symptoms as the primary endpoint, which is aimed at early symptoms of the new coronavirus strain. The relief of clinical symptoms used in the VV116 study was modified to the relief of 11 symptoms, excluding taste disturbance, smell disturbance, and fatigue/fatigue.
Recently, the new anti-coronavirus drug enitrelvir of Shionogi Pharmaceutical Co., Ltd. of Japan was approved in Japan. Its clinical trial results shared on the ISIRV-AVG Webinar in October this year also showed that if the 14 symptoms announced by the FDA were used as the primary endpoint for evaluation, it would be more effective. Positive results cannot be obtained. However, the use of antiviral drugs for five core symptoms can shorten the course of the disease by about 1 day, and the same benefit can be obtained for each symptom score. Therefore, the ever-changing external environment is not only what the VV116 research team needs to face, but also a major test for other new drug clinical trial teams.
Finally, under the great pressure of the epidemic, it is conceivable that it is difficult to adhere to high standards to carry out clinical trials of new drugs. We pay tribute to all the teams, subjects and their families who carried out rigorous scientific research during the epidemic, and thank them for their support for the new crown. Efforts made to improve the diagnosis and treatment of patients have continuously accumulated reliable evidence-based evidence to ensure the clinical benefits of patients.
Pharmacological characteristics of VV116
Ding Jian
School of Pharmacy, University of Chinese Academy of Sciences
Anti-coronavirus drugs are one of the important means to effectively deal with the epidemic. In particular, on the basis of the positive and significant results achieved in the effective prevention and control of the epidemic, my country has introduced 20 optimization measures and 10 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 storage of anti-new crown drugs. Oral small molecule anti-new coronavirus drugs have the advantages of convenience and accessibility, and will play an important role in the current and future epidemic prevention and control.
This project was led by Professor Zhao Ren from Shanghai Ruijin Hospital, Professor Gao Yuan from Shanghai Renji Hospital, and Professor Ning Guang from Shanghai Ruijin Hospital, and 7 hospitals from Shanghai participated in the “VV116 and Naimatevir-ritonavir Oral Treatment of Covid-19 19 Comparison” clinical research results show that VV116 is not inferior to Paxlovid (Paxlovid, Nematervir-ritonavir) in terms of continuous clinical recovery time of patients and negative viral nucleic acid. , and the incidence of adverse events is lower than that of Paxlovid [1]。
VV116 is a new oral nucleoside anti-new coronavirus small molecule drug jointly developed by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Wuhan Institute of Virology, Chinese Academy of Sciences, Xinjiang Institute of Physics and Chemistry, Chinese Academy of Sciences and other units. Some preclinical research results published by the VV116 research and development team show that[2], the nucleoside triphosphate form of VV116 can inhibit the activity of the new coronavirus RNA replicase (RdRp) in a concentration-dependent manner, with an IC50 of about 0.67 μM; in the Vero E6 cell model, VV116 showed strong inhibition of the replication of the original strain of the new coronavirus The activity of VV116 is about 0.35 μM; in the mouse model infected with the new coronavirus, oral administration of 50 mg/kg of VV116, twice a day, for 5 consecutive days, can effectively clear the virus. In addition, VV116 also showed potent antiviral activity on the omicron mutant, with an EC90 of about 0.64 μM [3]。
Preclinical research results also show that VV116 is safe, and the results of Ames test, chromosomal aberration test and in vivo bone marrow micronucleus test are all negative, and there is no risk of genotoxicity[2,4]. In the three Phase 1 clinical studies completed in China, the single dose was up to 1200 mg, and the multiple dose was up to 600 mg (twice a day for 5.5 consecutive days). The results of these trials show that VV116 has a good safety profile, and no serious adverse events (AE) above grade 3 were observed[4]。
As the core component of viral transcription and replication, RNA replicase is one of the important targets for the development of anti-new coronavirus drugs, and its function is highly conserved in virus mutations. Anti-new coronavirus drugs developed for this target are not easily affected by virus mutations.Preclinical research and phase 1 clinical research have confirmed the activity and safety of VV116 against the new coronavirus[2-4]this clinical study comparing VV116 with Paxlovid in the oral treatment of Covid-19 further verified the effectiveness and safety of VV116 in treating patients infected with omicron variant strains.
Summary
background
Nematevir-ritonavir has received emergency use authorization for the treatment of Covid-19 in several countries. However, the current supply is lower than the global demand, so there is a need to develop more treatment options. VV116 is an oral antiviral drug with potent activity against SARS-CoV-2.
method
We conducted a phase 3, noninferiority, observer-blinded, randomized trial during an outbreak caused by the SARS-CoV-2 B.1.1.529 (omicron) variant. Adult patients with symptomatic mild-to-moderate Covid-19 at high risk of progression were assigned to receive either VV116 or nematevir-ritonavir for 5 days. The primary endpoint was time to sustained clinical recovery by day 28. Sustained clinical recovery was defined as reduction of all Covid-19-related target symptoms to a total score of 0 or 1 for each symptom on 2 consecutive days (range 0–3, with higher scores indicating more severe symptoms; the total score of the 11-item scale The score range is 0~33 points). Non-inferiority was considered to be demonstrated if the lower limit of the two-sided 95% confidence interval of the hazard ratio was greater than 0.8 (hazard ratio greater than 1 indicated that the time to sustained clinical recovery was shorter in the VV116 group than in the nematevir-ritonavir group).
result
A total of 822 participants underwent randomization, of which 771 received either VV116 (n = 384) or nematevir-ritonavir (n = 387).Non-inferiority of VV116 compared to nematevir-ritonavir with respect to time to sustained clinical recovery was demonstrated in the primary analysis (hazard ratio, 1.17; 95% confidence interval[CI]1.01–1.35), and was maintained in the final analysis (median, 4 days in the VV116 arm and 5 days in the nematervir–ritonavir arm; hazard ratio, 1.17; 95% CI, 1.02–1.36).
In the final analysis, the time to sustained resolution of symptoms (scored 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and the time to first negative test for SARS-CoV-2 was compared between the two groups. No significant difference between. By day 28, no participants in either group had died or had progressed to severe Covid-19. The incidence of adverse events in the VV116 group was lower than that in the nematevir-ritonavir group (67.4% vs. 77.3%).
in conclusion
In adult patients with mild-to-moderate Covid-19 at risk of progression, VV116 was noninferior to nematevir-ritonavir in terms of time to sustained clinical recovery, with few safety concerns. (Sponsored by Suzhou Wangshan Wangshui Biomedical Co., Ltd.; registration number NCT05341609 in ClinicalTrials.gov; registration number ChiCTR2200057856 in China Clinical Trial Registration Center.)
Author of this article: Ding Jian, Cao Bin, Wang Yeming, source: NEJM Frontiers in Medicine, original title: “Domestic New Crown Drugs Top NEJM: Efficacy Not Inferior to Paxlovid, and Safer”
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