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In the face of the rapid development of the new crown epidemic, China urgently needs effective anti-new crown virus drugs
.
Although Pfizer's Paxlovid (nirmatvir-ritonavir) and domestic innovator Azvudine have long received emergency conditional approval for the treatment of Covid-19, they are far from meeting clinical needs
, either due to insufficient supply or a lack of high-quality evidence.
Early this morning, Beijing time, the New England Journal of Medicine (NEJM) published a phase 3 randomized controlled trial of non-inferiority in China, the results of which showed that for adult patients with mild to moderate Covid-19 with high-risk factors, domestic VV116 was not inferior to Paxlovid (4 days) in terms of continuous clinical recovery time vs.
5 days; Risk ratio, 1.
17; 95% confidence interval, 1.
02~1.
36), and fewer
adverse events.
This trial was led by Professor Zhao Ren of Shanghai Ruijin Hospital, Professor Gao Yuan of Shanghai Renji Hospital and Academician Ning Guang of Shanghai Ruijin Hospital, and was carried out in 7 Shanghai hospitals.
It is the first "head-to-head" phase 3 clinical trial
of a domestic oral antiviral drug for Covid-19 patients during the epidemic of the omicron variant.
VV116 is a small molecule inhibitor
of RNA replicase of the new coronavirus jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Wuhan Institute of Virology, Xinjiang Institute of Physical and Chemical Technology, etc.
This is the first clinical trial of a new crown innovative drug independently developed in China published by NEJM, which was completed with high quality during the extremely difficult period in Shanghai in March ~ May, which is particularly valuable
.
Professor Ding Jian, a pharmacologist and academician of the Chinese Academy of Sciences, and Professor Cao Bin, an expert in respiratory critical care, were invited by NEJM Medical Frontiers to interpret the study from the
perspectives of pharmacology and clinical trials.
VV116 vs.
Paxlovid Head-to-Head Comparison: 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; The Institute of Respiratory Diseases, Chinese Academy of Medical Sciences* Corresponding author
: Carrying out clinical trials under public health emergencies itself has faced many difficulties, especially the need to compete with the epidemic to seize time, and complete the efficacy verification of new drugs during the outbreak window, the most important thing is fast! Such clinical trial results will provide important reference value
for subsequent outbreaks or pandemics of the infectious disease.
VV116 is China's first domestic small molecule drug inhibitor
targeting the new coronavirus RdRp.
During the epidemic in Shanghai from March to May 2022, investigators rapidly designed and conducted a head-to-head non-inferiority clinical trial (ChiCTR2200057856, NCT05341609), and the clinical trial results of the drug were peer-reviewed and published in the New England Journal of Medicine (NEJM) on December 29, Beijing time [1].
。 This study is the first to report data on the time to symptom improvement in populations with high-risk factors using VV116 and Paxlovid in omicron epidemics, which can provide important reference value
for subsequent clinical trial design and clinical medication guidance.
In order to better understand the original intention of the study and the design of the clinical trial, it is necessary to sort out the background of
the clinical trial at that time.
First, a series of high-quality clinical studies have successively demonstrated: the small molecule antiviral drug molnupiravir (monupivir; Early use within 5 days of onset), Paxlovid (within 5 days of onset), and remdesivir (within 7 days of onset) reduces the incidence
of severe disease and death in people with high-risk factors.
These clinical trials are mainly concentrated in the period 2020~2021, mainly epidemic delta strains, and most subjects have not been vaccinated
against the new crown.
However, when designing the VV116 study, there are several important factors to consider: (1) the epidemic strain in Shanghai is omicron BA.
2, which is less virulent than delta; (2) most of the population in Shanghai has completed vaccination; (3) Paxlovid has been approved by China's CDE and included in the diagnosis and treatment plan of the Health Commission, becoming a standard antiviral drug
for high-risk groups 。 The research team designed a multicenter randomized controlled non-inferior clinical trial designed to evaluate the efficacy
of the VV116 vs.
control (Pfizer Paxlovid) in patients with Covid-19 with mild and common forms with high risk factors.
The initial clinical primary endpoint set weight conversion and symptom recovery time
.
The research team compromised some rigor in order to save time, 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 eventually abandoned the double endpoint and retained only the clinical endpoint
of symptom relief time.
This may be due to the fact that the research team found a decrease in omicron pathogenicity during the trial execution, resulting in an extremely low
probability of severe events.
As expected, the results showed that the number of participants who progressed to severe disease in both groups was 0
.
In other words, the research team did not directly use the time of symptom improvement as the clinical endpoint to carry out non-inferior clinical trial design, but originally planned to carry out non-inferior design
with clinical weight conversion as the endpoint.
However, the decline in omicron pathogenicity made this endpoint unachievable, and the research team was forced to choose symptom improvement as the endpoint
.
Finally, the VV116 and Paxlovid groups recruited 384 and 387 subjects
, respectively.
Demographic information and baseline results indicate that only 23.
4% are not vaccinated; 92.
1% are lightweight
.
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 of use of antiviral drugs from the onset of disease is a key factor affecting the effectiveness of
drugs.
There was no significant difference
between the two groups in the use of antiviral drugs within 5 days of onset.
Subgroup analysis by age, vaccine, disease severity, time of onset and other factors were consistent with the results of the full analysis set (FAS), that is, VV116 and Paxlovid were comparable
in clinical symptom recovery time.
Virologic outcomes are important secondary clinical endpoints
for evaluating antivirals.
In terms of the conversion of the new coronavirus (nasopharyngeal swab) to negative, the two groups also maintained a comparable level
.
In terms of safety, VV116 also showed a similarly good safety profile with Paxlovid, and even lower than Paxlovid in the incidence of certain adverse effects, especially taste disorders
.
Paxlovid is a combination of nematevir (3CL inhibitor) and ritonavir (used to increase blood levels), in which ritonavir is metabolized by the CYP3A4 enzyme in the liver and interacts with numerous drugs (refer to the instructions for use for specifics).
It is very inconvenient
for some patients who cannot stop the basic medication.
Therefore, VV116 may be better in terms of safety and ease of administration
.
Adverse events (safety population) From the current situation, the indication of targeted reduction of severe disease is basically impossible to complete
.
Indications for symptom improvement in patients with mild disease in the new crown outpatient clinic are currently unmet clinical needs
.
Since the circulating strain is always changing, the corresponding clinical symptoms have also changed
to varying degrees.
The US FDA guidelines for clinical trials of Covid-19 drugs published in September 2020 include 14 symptoms as primary endpoints, which are for early COVID strain symptoms
.
The clinical symptom relief used in the VV116 study was modified to 11 symptom relief, excluding taste disorders, olfactory disorders, and fatigue/fatigue
.
The recent approval of ensitrelvir, a new anti-coronavirus drug by Shionogi Pharmaceutical Company in Japan, shared the results of the clinical trial on the ISIRV-AVG Webinar in October this year, which also showed that if the 14 symptoms published by the FDA were used as the primary endpoint for evaluation, positive results
would not be obtained.
The use of 5 core symptom antivirals shortened the duration of the disease by about 1 day, and the same benefit
was obtained for each symptom score.
Therefore, the changing external environment is not only a major test
for the VV116 research team, but also for other new drug clinical trial teams.
Finally, in the face of the great pressure of the epidemic, the difficulty of adhering to high standards of new drug clinical trials can be imagined, we would like to pay tribute to all the teams, subjects and families who carried out rigorous scientific research during the epidemic, thank them for their efforts to improve the diagnosis and treatment of new crown patients, and continue to accumulate reliable evidence-based evidence to ensure the clinical benefits
of patients.
Pharmacological features of VV116
of anti-new crown drugs.
Oral small molecule anti-new coronavirus drugs have the advantages of ease of use and good accessibility, and will play an important role
in the current and future epidemic prevention and control.
The results of this clinical study, led by Professor Zhao Ren of Shanghai Ruijin Hospital, Professor Gaoyuan of Shanghai Renji Hospital and Professor Ning Guang of Shanghai Ruijin Hospital, and participated by seven hospitals from Shanghai, "VV116 versus nematevir-ritonavir oral treatment for Covid-19", showed that VV116 compared with Paxlovid (nematevir-ritonavir) showed that VV116 compared with Paxlovid (nematevir-ritonavir) in patients with sustained clinical recovery time, VV116 was not inferior to Paxlovid in terms of viral nucleic acid conversion negative, and the incidence of adverse events was lower than Paxlovid [1].
VV116 is a new oral nucleoside anti-new coronavirus small molecule drug
jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Wuhan Institute of Virology, Chinese Academy of Sciences, and Xinjiang Institute of Physical and Chemical Technology, Chinese Academy of Sciences.
Some preclinical results published by the VV116 R&D team [2] show that the nucleoside triphosphate form of VV116 can inhibit the activity of RNA replicase (RdRp) of the new coronavirus at a concentration-dependent level, with a C50 of about 0.
67 μM; In the Vero E6 cell model, VV116 showed strong activity to inhibit replication of the original strain of the new coronavirus, with an ECof about 0.
35 μM.
In mouse models infected with the new coronavirus, VV116 was effectively cleared by oral administration of 50 mg/kg twice a day for 5 days
.
In addition, VV116 also shows potent antiviral activity on omicron variants, with an ECof approximately 0.
64 μM [3].
Preclinical studies have also shown that VV116 has a good safety profile and negative results from the Ames test, chromosomal aberration test, and bone marrow micronucleus test in vivo, with no risk of genotoxicity [2,4].
In three Phase 1 clinical studies completed in China, the maximum single dose was 1200 mg and the maximum multiple dose was 600 mg (twice a day for 5.
5 days).
The results of these trials showed that VV116 had a good safety profile and no serious adverse events (AEs) 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 viral mutation, and anti-new coronavirus drugs developed for this target are not susceptible to
viral mutation 。 The activity and safety of VV116 against the new coronavirus have been confirmed in preclinical studies and phase 1 clinical studies [2-4], and this clinical study comparing VV116 with Paxlovid oral treatment for Covid-19 has further verified the efficacy and safety
of VV116 in patients infected with the omicron variant.
The trial VV116 comparing oral VV116 and nematevir-ritonavir for Covid-19 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19Cao Z, Gao W, Bao H, et al.
DOI: 10.
1056/NEJMoa2208822
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 it is necessary to develop more treatment options
.
VV116 is an oral antiviral
with potent activity against SARS-CoV-2.
Methods We conducted a phase 3, non-inferiority, observer-blinded randomized trial
during outbreaks 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 5 days of VV116 or nimatevir-ritonavir
.
The primary endpoint was time up to day 28 to ongoing clinical recovery
.
Continuous clinical rehabilitation is defined as alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for each symptom for 2 consecutive days (range of 0~3 points, higher scores indicate more severe symptoms; The total score range of the 11 scales is 0~33 points).
Non-inferiority is considered to be demonstrated if the lower limit of the bilateral 95% confidence interval for the hazard ratio is greater than 0.
8 (a hazard ratio greater than 1 indicates a shorter time to continuous clinical recovery in the VV116 group than in the nematevir-ritonavir group).
Results A total of 822 participants were randomized and 771 received VV116 (384 people) or nirmatevir-ritonavir (387 people).
。 The non-inferiority of VV116 compared with nimatevir-ritonavir was demonstrated in the main analysis in terms of time to sustained clinical recovery (hazard ratio, 1.
17; 95% confidence interval [CI], 1.
01~1.
35) and maintained in the final analysis (median, 4 days in VV116 group and 5 days in nimatevir-ritonavir group; Risk ratio, 1.
17; 95% CI, 1.
02~1.
36).
In the final analysis, there was no clear difference
between groups between groups in terms of time until symptoms persisted in resolution (0 points for each of the 11 Covid-19-related target symptoms, each for 2 consecutive days) and the time to first negative SARS-CoV-2 test.
As of day 28, no participants in either group had died or progressed to severe Covid-19
.
The rate of adverse events was lower in the VV116 group than in the nematevir-ritonavir group (67.
4% vs.
77.
3%)
.
ConclusionsIn adult patients with mild to moderate Covid-19 at risk of progression, VV116 is not inferior to nematevir-ritonavir in terms of time to ongoing clinical recovery, and safety concerns are minimal.
(Funded by Suzhou Wangshan Wangshui Biomedical Co.
, Ltd.
; The registration number in the ClinicalTrials.
gov is NCT05341609; The registration number of the Chinese Clinical Trials Registry is ChiCTR2200057856
.
）
Cao Z, Gao W, Bao H, et al.
VV116 versus nirmatrelvir–ritonavir for oral treatment of Covid-19.
N Engl J Med 2022 December 28 ((Epub ahead of print).
.
Although Pfizer's Paxlovid (nirmatvir-ritonavir) and domestic innovator Azvudine have long received emergency conditional approval for the treatment of Covid-19, they are far from meeting clinical needs
, either due to insufficient supply or a lack of high-quality evidence.
Early this morning, Beijing time, the New England Journal of Medicine (NEJM) published a phase 3 randomized controlled trial of non-inferiority in China, the results of which showed that for adult patients with mild to moderate Covid-19 with high-risk factors, domestic VV116 was not inferior to Paxlovid (4 days) in terms of continuous clinical recovery time vs.
5 days; Risk ratio, 1.
17; 95% confidence interval, 1.
02~1.
36), and fewer
adverse events.
This trial was led by Professor Zhao Ren of Shanghai Ruijin Hospital, Professor Gao Yuan of Shanghai Renji Hospital and Academician Ning Guang of Shanghai Ruijin Hospital, and was carried out in 7 Shanghai hospitals.
It is the first "head-to-head" phase 3 clinical trial
of a domestic oral antiviral drug for Covid-19 patients during the epidemic of the omicron variant.
VV116 is a small molecule inhibitor
of RNA replicase of the new coronavirus jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Wuhan Institute of Virology, Xinjiang Institute of Physical and Chemical Technology, etc.
This is the first clinical trial of a new crown innovative drug independently developed in China published by NEJM, which was completed with high quality during the extremely difficult period in Shanghai in March ~ May, which is particularly valuable
.
Professor Ding Jian, a pharmacologist and academician of the Chinese Academy of Sciences, and Professor Cao Bin, an expert in respiratory critical care, were invited by NEJM Medical Frontiers to interpret the study from the
perspectives of pharmacology and clinical trials.
VV116 vs.
Paxlovid Head-to-Head Comparison: 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; The Institute of Respiratory Diseases, Chinese Academy of Medical Sciences* Corresponding author
: Carrying out clinical trials under public health emergencies itself has faced many difficulties, especially the need to compete with the epidemic to seize time, and complete the efficacy verification of new drugs during the outbreak window, the most important thing is fast! Such clinical trial results will provide important reference value
for subsequent outbreaks or pandemics of the infectious disease.
VV116 is China's first domestic small molecule drug inhibitor
targeting the new coronavirus RdRp.
During the epidemic in Shanghai from March to May 2022, investigators rapidly designed and conducted a head-to-head non-inferiority clinical trial (ChiCTR2200057856, NCT05341609), and the clinical trial results of the drug were peer-reviewed and published in the New England Journal of Medicine (NEJM) on December 29, Beijing time [1].
。 This study is the first to report data on the time to symptom improvement in populations with high-risk factors using VV116 and Paxlovid in omicron epidemics, which can provide important reference value
for subsequent clinical trial design and clinical medication guidance.
In order to better understand the original intention of the study and the design of the clinical trial, it is necessary to sort out the background of
the clinical trial at that time.
First, a series of high-quality clinical studies have successively demonstrated: the small molecule antiviral drug molnupiravir (monupivir; Early use within 5 days of onset), Paxlovid (within 5 days of onset), and remdesivir (within 7 days of onset) reduces the incidence
of severe disease and death in people with high-risk factors.
These clinical trials are mainly concentrated in the period 2020~2021, mainly epidemic delta strains, and most subjects have not been vaccinated
against the new crown.
However, when designing the VV116 study, there are several important factors to consider: (1) the epidemic strain in Shanghai is omicron BA.
2, which is less virulent than delta; (2) most of the population in Shanghai has completed vaccination; (3) Paxlovid has been approved by China's CDE and included in the diagnosis and treatment plan of the Health Commission, becoming a standard antiviral drug
for high-risk groups 。 The research team designed a multicenter randomized controlled non-inferior clinical trial designed to evaluate the efficacy
of the VV116 vs.
control (Pfizer Paxlovid) in patients with Covid-19 with mild and common forms with high risk factors.
The initial clinical primary endpoint set weight conversion and symptom recovery time
.
The research team compromised some rigor in order to save time, 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 eventually abandoned the double endpoint and retained only the clinical endpoint
of symptom relief time.
This may be due to the fact that the research team found a decrease in omicron pathogenicity during the trial execution, resulting in an extremely low
probability of severe events.
As expected, the results showed that the number of participants who progressed to severe disease in both groups was 0
.
In other words, the research team did not directly use the time of symptom improvement as the clinical endpoint to carry out non-inferior clinical trial design, but originally planned to carry out non-inferior design
with clinical weight conversion as the endpoint.
However, the decline in omicron pathogenicity made this endpoint unachievable, and the research team was forced to choose symptom improvement as the endpoint
.
Finally, the VV116 and Paxlovid groups recruited 384 and 387 subjects
, respectively.
Demographic information and baseline results indicate that only 23.
4% are not vaccinated; 92.
1% are lightweight
.
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 of use of antiviral drugs from the onset of disease is a key factor affecting the effectiveness of
drugs.
There was no significant difference
between the two groups in the use of antiviral drugs within 5 days of onset.
Subgroup analysis by age, vaccine, disease severity, time of onset and other factors were consistent with the results of the full analysis set (FAS), that is, VV116 and Paxlovid were comparable
in clinical symptom recovery time.
Virologic outcomes are important secondary clinical endpoints
for evaluating antivirals.
In terms of the conversion of the new coronavirus (nasopharyngeal swab) to negative, the two groups also maintained a comparable level
.
Time to symptom recovery
In terms of safety, VV116 also showed a similarly good safety profile with Paxlovid, and even lower than Paxlovid in the incidence of certain adverse effects, especially taste disorders
.
Paxlovid is a combination of nematevir (3CL inhibitor) and ritonavir (used to increase blood levels), in which ritonavir is metabolized by the CYP3A4 enzyme in the liver and interacts with numerous drugs (refer to the instructions for use for specifics).
It is very inconvenient
for some patients who cannot stop the basic medication.
Therefore, VV116 may be better in terms of safety and ease of administration
.
Adverse events (safety population) From the current situation, the indication of targeted reduction of severe disease is basically impossible to complete
.
Indications for symptom improvement in patients with mild disease in the new crown outpatient clinic are currently unmet clinical needs
.
Since the circulating strain is always changing, the corresponding clinical symptoms have also changed
to varying degrees.
The US FDA guidelines for clinical trials of Covid-19 drugs published in September 2020 include 14 symptoms as primary endpoints, which are for early COVID strain symptoms
.
The clinical symptom relief used in the VV116 study was modified to 11 symptom relief, excluding taste disorders, olfactory disorders, and fatigue/fatigue
.
The recent approval of ensitrelvir, a new anti-coronavirus drug by Shionogi Pharmaceutical Company in Japan, shared the results of the clinical trial on the ISIRV-AVG Webinar in October this year, which also showed that if the 14 symptoms published by the FDA were used as the primary endpoint for evaluation, positive results
would not be obtained.
The use of 5 core symptom antivirals shortened the duration of the disease by about 1 day, and the same benefit
was obtained for each symptom score.
Therefore, the changing external environment is not only a major test
for the VV116 research team, but also for other new drug clinical trial teams.
Finally, in the face of the great pressure of the epidemic, the difficulty of adhering to high standards of new drug clinical trials can be imagined, we would like to pay tribute to all the teams, subjects and families who carried out rigorous scientific research during the epidemic, thank them for their efforts to improve the diagnosis and treatment of new crown patients, and continue to accumulate reliable evidence-based evidence to ensure the clinical benefits
of patients.
Pharmacological features of VV116
DING Jian
School of Pharmacy, University of Chinese Academy of Sciences
of anti-new crown drugs.
Oral small molecule anti-new coronavirus drugs have the advantages of ease of use and good accessibility, and will play an important role
in the current and future epidemic prevention and control.
The results of this clinical study, led by Professor Zhao Ren of Shanghai Ruijin Hospital, Professor Gaoyuan of Shanghai Renji Hospital and Professor Ning Guang of Shanghai Ruijin Hospital, and participated by seven hospitals from Shanghai, "VV116 versus nematevir-ritonavir oral treatment for Covid-19", showed that VV116 compared with Paxlovid (nematevir-ritonavir) showed that VV116 compared with Paxlovid (nematevir-ritonavir) in patients with sustained clinical recovery time, VV116 was not inferior to Paxlovid in terms of viral nucleic acid conversion negative, and the incidence of adverse events was lower than Paxlovid [1].
VV116 is a new oral nucleoside anti-new coronavirus small molecule drug
jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Wuhan Institute of Virology, Chinese Academy of Sciences, and Xinjiang Institute of Physical and Chemical Technology, Chinese Academy of Sciences.
Some preclinical results published by the VV116 R&D team [2] show that the nucleoside triphosphate form of VV116 can inhibit the activity of RNA replicase (RdRp) of the new coronavirus at a concentration-dependent level, with a C50 of about 0.
67 μM; In the Vero E6 cell model, VV116 showed strong activity to inhibit replication of the original strain of the new coronavirus, with an ECof about 0.
35 μM.
In mouse models infected with the new coronavirus, VV116 was effectively cleared by oral administration of 50 mg/kg twice a day for 5 days
.
In addition, VV116 also shows potent antiviral activity on omicron variants, with an ECof approximately 0.
64 μM [3].
Preclinical studies have also shown that VV116 has a good safety profile and negative results from the Ames test, chromosomal aberration test, and bone marrow micronucleus test in vivo, with no risk of genotoxicity [2,4].
In three Phase 1 clinical studies completed in China, the maximum single dose was 1200 mg and the maximum multiple dose was 600 mg (twice a day for 5.
5 days).
The results of these trials showed that VV116 had a good safety profile and no serious adverse events (AEs) 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 viral mutation, and anti-new coronavirus drugs developed for this target are not susceptible to
viral mutation 。 The activity and safety of VV116 against the new coronavirus have been confirmed in preclinical studies and phase 1 clinical studies [2-4], and this clinical study comparing VV116 with Paxlovid oral treatment for Covid-19 has further verified the efficacy and safety
of VV116 in patients infected with the omicron variant.
The trial VV116 comparing oral VV116 and nematevir-ritonavir for Covid-19 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19Cao Z, Gao W, Bao H, et al.
DOI: 10.
1056/NEJMoa2208822
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 it is necessary to develop more treatment options
.
VV116 is an oral antiviral
with potent activity against SARS-CoV-2.
Methods We conducted a phase 3, non-inferiority, observer-blinded randomized trial
during outbreaks 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 5 days of VV116 or nimatevir-ritonavir
.
The primary endpoint was time up to day 28 to ongoing clinical recovery
.
Continuous clinical rehabilitation is defined as alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for each symptom for 2 consecutive days (range of 0~3 points, higher scores indicate more severe symptoms; The total score range of the 11 scales is 0~33 points).
Non-inferiority is considered to be demonstrated if the lower limit of the bilateral 95% confidence interval for the hazard ratio is greater than 0.
8 (a hazard ratio greater than 1 indicates a shorter time to continuous clinical recovery in the VV116 group than in the nematevir-ritonavir group).
Results A total of 822 participants were randomized and 771 received VV116 (384 people) or nirmatevir-ritonavir (387 people).
。 The non-inferiority of VV116 compared with nimatevir-ritonavir was demonstrated in the main analysis in terms of time to sustained clinical recovery (hazard ratio, 1.
17; 95% confidence interval [CI], 1.
01~1.
35) and maintained in the final analysis (median, 4 days in VV116 group and 5 days in nimatevir-ritonavir group; Risk ratio, 1.
17; 95% CI, 1.
02~1.
36).
In the final analysis, there was no clear difference
between groups between groups in terms of time until symptoms persisted in resolution (0 points for each of the 11 Covid-19-related target symptoms, each for 2 consecutive days) and the time to first negative SARS-CoV-2 test.
As of day 28, no participants in either group had died or progressed to severe Covid-19
.
The rate of adverse events was lower in the VV116 group than in the nematevir-ritonavir group (67.
4% vs.
77.
3%)
.
ConclusionsIn adult patients with mild to moderate Covid-19 at risk of progression, VV116 is not inferior to nematevir-ritonavir in terms of time to ongoing clinical recovery, and safety concerns are minimal.
(Funded by Suzhou Wangshan Wangshui Biomedical Co.
, Ltd.
; The registration number in the ClinicalTrials.
gov is NCT05341609; The registration number of the Chinese Clinical Trials Registry is ChiCTR2200057856
.
）
References
1.Cao Z, Gao W, Bao H, et al.
VV116 versus nirmatrelvir–ritonavir for oral treatment of Covid-19.
N Engl J Med 2022 December 28 ((Epub ahead of print).
2.
Xie Y, Yin W, Zhang Y, et al.
Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2.
Cell Res 2021; 31:1212-1214.
3.
Qian H, Wang Y, Zhang M, et al.
Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects.
Acta Pharmacol Sin 2022; 43:3130-3138.
4.
Zhang R, Zhang Y, Zheng W, et al.
Oral remdesivir derivative VV116 is a potent inhibitor of respiratory syncytial virus with efficacy in mouse model.
Signal Transduct Target Ther 2022; 7:123.
About the author
Ding Jian is a pharmacologist and academician of
the Chinese Academy of Engineering.
He is currently the dean of the School of Pharmacy of the University of Chinese Academy of Sciences, the director of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (2004-2013), the director of the State Key Laboratory of New Drug Research, and has successively served as a member of the overall team of the "major new drug creation" science and technology major special project, the chief scientist of the "11th Five-Year Plan" and "Twelfth Five-Year Plan" major special project "Chemical Innovative Drug R&D System Construction" large platform project, and the chief scientist
of the Chinese Academy of Sciences Strategic Pilot Class A science and technology project 。 He is also the editor-in-chief of Acta Pharmacol Sin and the editorial board of
several international academic journals such as Eur J Pharmacol and Mol Pharmacol.
He has long been committed to the research and development of molecularly targeted anti-tumor drugs and personalized research
.
He has published more than 340 papers in Cell, Cancer Cell and other journals, and has obtained more than 150 authorized invention patents at home and abroad
.
He has won more than ten important awards such as the second prize of the National Natural Science Award (2 items), the second prize of the National Science and Technology Progress Award, the second National Innovation Medal, and the Outstanding Scientific and Technological Achievement Award of the Chinese Academy of
Sciences.
Cao Bin, Chief Physician, Professor, Doctoral Supervisor, Minister of Education Jiang Scholar, Recipient of the National Science Fund for Outstanding Young
Scholars.
He is currently the vice president of China-Japan Friendship Hospital, the deputy director (executive affairs) of the respiratory center, the director of the Department of Respiratory and Critical Care Medicine and the director of the
second department.
Executive Vice President
of the Institute of Respiratory Diseases, Chinese Academy of Medical Sciences.
Vice Chairman of the Respiratory Disease
Branch of the Chinese Medical Association.
Member of
the International Working Group on Influenza and Other Respiratory Viral Infections - Antivirals.
He has served on the editorial board or editor-in-chief of various journals, including the editorial board of NEJM Medical Frontiers, the associate editor of Clinical Respiratory Journal, and the corresponding editorial board of Chinese Medical Journal
.
He has won the Wu Yang Award, Shulan Medical Youth Award, etc
.
Proficient in the diagnosis and treatment
of various respiratory infections.
Participated in or presided over the compilation of a number of international and domestic guidelines and expert consensus, such as the "Guidelines for the Diagnosis and Treatment of Community-acquired Pneumonia in Chinese Adults (2016 Edition)" and the "Diagnosis and Treatment Plan for Human Infection with H7N9 Avian Influenza (2017 First Edition)
".
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