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What is the truth about the new crown oral medicine? Pfizer p, azvudine, VV116 are not fighting relationships! What medicine can ordinary people take?

 Last Update: 2023-02-01
 Source: Internet
 Author: User

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Paxlovid can be called an "effective drug",

But by no means a "special drug"

Without high-level physician evaluation,

Individuals should never take it privately

In many people's expectations, when is the best time to fully liberalize the domestic epidemic prevention policy? The answer is that when the elderly over 80 years old are fully vaccinated (whether it is inactivated, protein recombinant, or RNA vaccine, it is okay), and some domestic pharmaceutical companies have developed more mature domestic new crown drugs, and then fully liberalized after the emergency and intensive medical resources of the hospital are more sufficient, it will be a very calm state
.
But due to some pressure and emotions, these are the ideals and failed good plans
at the national level.
Take the new crown treatment drugs, with the advent of the urban tide of severe disease, as the world's most concerned new crown oral antiviral drug, Pfizer Paxlovid has frequently become a miracle drug in the eyes of Chinese, which led to the original temporary medical insurance payment price of 1890 yuan a box of drugs was once speculated by scalpers to more than 10,000 a box
.
In the propaganda, it seems that individuals can be safe from covid infection as long as they eat Paxlovid is frightening
.
Paxlovid is indeed effective in reducing in-hospital mortality and severe disease, there's
no doubt about it.
But it can only be called effective, not even a special effect, because its main role is to reduce severe disease early, but not to treat severe disease, so far, there is no real new crown specific drug
in the world.
There are two main scientific studies on the effectiveness of Paxlovid, one is a study released by Pfizer on November 5, 2021, claiming that in the analysis of phase II and III clinical trials, Paxlovid reduced the risk of hospitalization or death by 89%, while another clinical trial drug, MSD's monogravir, reduced the risk of hospitalization or death in mild and moderate COVID patients by about 50%.

。 Another study was an October 8, 2022 article in The Lancet that published a real-world study
in Hong Kong on the effectiveness of two oral coronavirus drugs, monoravir and Paxlovid, in treating Omicron infection.

Monoravir "The Lancet" by Monoravir Paxlovid

In the study, between February 26 and June 26, 2022, 11,847 non-hospitalized new crown patients were treated with monolavir or Paxlovid early, most of whom were in the high-risk group of new crown infection, and were over 60 years old and had not completed vaccination.

The results showed that the all-cause mortality rate in the monoravir-treated group was 17.
9 per 100,000 person-days, a 24% reduction compared with the placebo control group; The Paxlovid treatment group was 4.
2 per 100,000 person-days, which was 66% lower than the control group, the risk of hospitalization was reduced by 24%, and the risk of disease progression after hospitalization was reduced by 43%.

And in September 2022, Israel, the first batch of approved to use Paxlovid, its largest healthcare organization, Clalit research team, released real-world data
at NEJM.

NEJM

The study found that among about 110,000 infected people who were eligible and had no contraindications to medication, only 3,902 people actually received Paxlovid treatment, accounting for less than 4%, Paxlovid has almost no effect on people aged 40-65 years, and can only reduce the risk of severe disease and hospitalization death in the elderly over 65 years old, Paxlovid reduces the risk of hospitalization or 79%
of death risk in the elderly aged 65 and older 。 To be sure, Paxlovid is stronger than monoravir and stronger than any drug in reducing severe and in-hospital mortality in the elderly, as given by various research data, but in terms of safety and contraindications, its performance is not satisfactory
.
Let's start with Paxlovid ingredients
.
Paxlovid is a combination of nematevir and ritonavir, which are not mixed, but separated, and have different
colors.
Among them, the pink pill is nematevir, which is a Pfizer patented product, each pill contains 150mg of active ingredient, and the white pill ritonavir contains 100mg
of active ingredient.

Paxlovid has little effect on people aged 40-65 years and only alleviates the risk of severe illness and in-hospital death in people over 65 years of age, and nemateveretorinavir is reduced

Paxlovid is an oral medication that should be swallowed whole, not chewed, broken or crushed
.
The recommended dose is nirmatevir 300 mg (150 mg × 2 tablets) plus ritonavir 100 mg (100 mg × 1 tablet) orally every 12 hours for 5 days
.
Nematevir does not inhibit the replication of the virus, but it can inhibit the final assembly
of the virus.
In addition to genetic RNA, the new coronavirus also has four proteins
: spike protein, which comes into contact with human cells, nucleochondrin that wraps RNA, and envelope protein and membrane protein, which are responsible for virus assembly and release of viruses outside cells.

Nematevir

The four proteins are copied together and need 3CL protease and PL protease to disassemble and assemble them to perform their respective functions, of which 3CL protease is responsible for the cleavage
of 11 sites.
Nimatevir inhibits 3CL protease activity to prevent the final assembly
of parts produced by the virus.

3CL protease PL protease

However, after nematevir enters the human body, it will soon be metabolized and lose its due role, and the metabolic enzyme CYP3A in the human body is responsible for the metabolism
of nematevir.
At this time, the white pill ritonavir taken at the same time, although not directly related to the inhibition of the virus, can inhibit the activity of CYP3A metabolic enzyme and ensure that nematevir will not be metabolized so quickly
.
Therefore, taking two pink nematevir tablets requires taking one white ritonavir at the same time to ensure the effective amount of
nematevir in the blood.
However, the CYP3A metabolizing enzyme not only metabolizes nematevir, but also metabolizes 50% of drugs currently on the market, and there are many
contraindications when taking Paxlovid combinations.

Nematevir metabolizes the enzyme CYP3A ritonavir

The above drugs cannot be taken at the same time as Paxlovid (partial)

The above drugs need to be used at least 2-3 days after Paxlovid is discontinued (partial)

We should know that Paxlovid mainly works on the elderly, and the elderly will definitely take various drugs regularly due to underlying diseases, so elderly patients who combine the use of other drugs need to be extra careful
in choosing Paxlovid 。 As a prescription drug with strict contraindications, Paxlovid is strictly forbidden to self-take without adequate evaluation by a senior doctor! In addition, in clinical trials, Paxlovid has many common adverse reactions, including taste changes, diarrhea, high blood pressure, muscle pain, abdominal pain, nausea, etc.
, so it is not recommended for patients with severe liver disease and kidney disease
.

How about our own domestic medicines?

The countrymen have high hopes for Azvudine

Pfizer Paxlovid is expensive and not in health insurance, although it is obvious in reducing severe disease and hospital deaths, but there are still many people who reject Paxlovid very much, they always ask, what is the effect of domestic azvudine? How is the scientific research going? Azvudine is known as China's "first oral small molecule new coronavirus treatment drug with completely independent intellectual property rights"
.
In July 2022, Henan Real Biotechnology Co.
, Ltd.
announced that the results of the phase III clinical trial registration of azvudine tablets for the treatment of novel coronavirus pneumonia met expectations, and officially submitted a marketing application
to the National Medical Products Administration.
On July 25, the State Food and Drug Administration conditionally approved the new indication of azvudine tablets for the treatment of adult patients
with common COVID-19.
On August 9, the General Office of the National Health Commission and the Office of the State Administration of Traditional Chinese Medicine issued a notice to include azvudine tablets in the "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Ninth Edition)", and patients can take drugs
strictly according to the instructions under the guidance of physicians.

Azvudine is a broad-spectrum RNA Viral inhibitors, at the beginning of research and development, mainly exist as an HIV reverse transcriptase (RT) inhibitor, which is the world's advanced and the first new generation of domestic AIDS treatment drugs
。 It was later found that azvudine, as a nucleoside analogue of viral RNA polymerase (RdRp), was metabolized into a 5'-triphosphate metabolite with antiviral activity (azvudine triphosphate) in cells, which can also act specifically on the new coronavirus polymerase (RdRp), which is in the new coronavirus During RNA synthesis, it can interfere with reverse transcription, thereby inhibiting the replication of the new coronavirus and achieving the role of
treating new coronavirus infection.
So, what are the clinical findings of azvudine? At the 17th National Conference of Infectious Diseases of the Chinese Medical Association and the 14th Conference of Infectious Diseases of the Chinese Medical Doctor Association, Professor Zhang Fujie of Beijing Ditan Hospital affiliated to Capital Medical University introduced
the clinical research of azvudine at home and abroad.
Professor Zhang Fujie said that at present, Azvudine has carried out global clinical trials
against the new crown virus in China, Russia and Brazil.
The phase III study in China, led by Beijing Ditan Hospital affiliated to Capital Medical University, is a multi-center, randomized, double-blind, placebo-controlled clinical trial involving 11 centers across the country, including a total of 348 patients aged 18~75 years with mild and common COVID-19, according to 1:1 randomized administration of azvudine 5mg, once a day + basic treatment and placebo + basic treatment, the trial protocol treatment for up to 14 days
.
The results of the study showed that the viral load decreased significantly higher than in the control group on day 5 after azvudine treatment
.
In the phase III clinical study in Russia, a total of 314 patients were included to observe the proportion and time
of symptom improvement on day 7.
The results showed that the proportion of clinical condition improvement in the experimental group was significantly higher than that in the control group (40.
43% vs.
10.
87%), achieving clinically effective results, and the time of clinical improvement was significantly lower than that of the control group (10 days vs 13 days, p<0.
001).
<b17> In the clinical study conducted in Brazil, a total of 180 patients were included, and the results showed that the proportion of final clinical state improvement in the experimental group was significantly higher than that in the control group, and the nucleic acid negative time and hospital stay were significantly lower than those in the control group
。 However, as the most famous domestic new crown oral drug, azvudine has also been controversial, the most bad is that its phase III clinical study has not been officially published in academic journals, its research data has not been carried out in large-scale populations, and its possible liver toxicity, creatine kinase elevation, mitochondrial toxicity (such as muscle damage, lactate dehydrogenase elevation) have not been revealed
in the new version of the instructions.
According to the content of the "New Crown Diagnosis and Treatment Plan (Trial Version 10)", the consensus does not recommend the use of azvudine during pregnancy and lactation, and patients with moderate to severe liver and kidney function impairment should be used
with caution.
Therefore, the good expectations of Chinese people for Azvudine still need more research data and research details to be published and supported
.

Azvudine is a broad-spectrum RNA Virus inhibitor, Zhang Fujie Zhang Fujie "New crown diagnosis and treatment plan (trial version 10)"

NEJM Announces Phase III Clinical Data for VV116,

Not inferior to Paxlovid?

VV116 is a novel oral nucleoside anti-SARS-CoV-2 drug jointly developed by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Wuhan Institute of Virology, Chinese Academy of Sciences, Wangshan Wangshui Biomedical Co.
, Ltd.
and other institutions, which inhibits the synthesis
of viral RNA by targeting RNA-dependent RNA polymerase (RdRp).
In September 2021, Junshi Biologics and Wangshan Wangshui reached a cooperation agreement to jointly undertake the clinical development and industrialization of VV116 worldwide
.
On December 30, 2021, VV116 received emergency use authorization
in Uzbekistan.
Studies have shown that VV116 exhibits antiviral activity against Alpha, Beta, Delta, and Omicron, while having high oral bioavailability and good chemical stability
.
Because of this, on April 19, 2022, according to the China Clinical Trials Registry, Suzhou Wangshan Wangshui Biomedical registered a multicenter, single-blind, randomized, controlled phase III clinical study
evaluating the efficacy and safety of JT001 (VV116) compared with Pfizer Paxlovid in the early treatment of mild-to-moderate novel coronavirus pneumonia (COVID-19).
This is a head-to-head phase III comparative trial, and if there is not enough evidence and data to show that VV116 is effective enough in inhibiting viral replication, then this study is not going to be done lightly
.
What is the final result of the study? On December 29, the top journal NEJM published the data from
this study.

NEJM

This study was completed during the outbreak caused by the Omicron variant (B.
1.
1.
529) in Shanghai in March~May and was designed to evaluate VV116 versus Paxlovid Efficacy and safety
for early treatment of patients with mild to moderate COVID-19.
Researchers from Shanghai, China, 7 Participants in hospitals were assessed for eligibility in a multicenter, observer-blinded, randomized, controlled trial of 822 people at high risk of progression with mild to moderate symptoms with COVID-19 Adult patients were divided into trial groups
.
In the end, 771 participants received oral medication
.
Of these, 384 were in the VV116 study group, which took 600 every 12 hours on day 1 mg, 300 mg every 12 hours on days 2~5; 387 called Paxovid group, taking 300 mg nimatevir + 100 mg Ritonavir, every 12 hours for 5 days
.
The results of this clinical study showed VV116 for mild to moderate COVID-19 of early treatment to achieve the primary endpoint preset by the clinical protocol (time to sustained clinical recovery): median time to clinical recovery was 4 days in the VV116 group and 5 days in the Paxlovid group Day (hazard ratio, 1.
17; 95%) CI, 1.
02~1.
36; lower limit, >0.
8).

At each preset time point (days 5, 7, 10, 14, 28), the proportion of patients in the VV116 group who responded to symptoms was higher than that in the Paxlovid group
.
Neither group progressed to severe/critical COVID-19 or died
.

Of these, 384 were in the VV116 study group, which took 600 every 12 hours on day 1 mg, 300 mg 387 every 12 hours on days 2~5 called Paxovid group, 300 mg nematevir + 100 mg Ritonavir, every 12 hours for 5 days
.

Time to ongoing clinical recovery

In terms of safety, with 28-day follow-up, participants who received VV116 reported fewer adverse events (67.
4%) than participants who received Paxlovid (77.
3%), compared to 3 The incidence of grade / grade 4 adverse events, VV116 was also reported in lower numbers (2.
6%) than Paxlovid (5.
7%)
.

Adverse event rate

The above results show that the therapeutic effect of VV116 is not inferior to Paxlovid, but then, some people also expressed doubts
.
For example, the phase III clinical trial initially set two primary endpoints, namely "severe disease" and "symptom recovery" While in the trial, the researchers abandoned the "double endpoint" and only explored the patient's
recovery time for persistent symptoms.
Why was the clinical study endpoint "percentage of subjects progressing to severe/critical COVID-19 or all-cause death" removed? Is it because of the lack of self-confidence that leads to a weakness of heart? In response, the researchers responded that this is because during the epidemic in Shanghai, the pathogenicity of Omicron was found to decrease during the implementation of the experiment, resulting in an extremely low probability of severe events, and researchers could only give up the experimental indicator
of "severe disease".
As expected, the results showed that the number of subjects in both groups (VV116 and Paxlovid) progressing to severe was zero
.
Some people always hold the concept of either/or, always comparing the quality of different new crown treatment drugs, simply thinking that which drug has good efficacy, which one is used, and which one is not good is resolutely not used
.
In fact, the mechanism of action of these three therapeutic drugs against the new crown virus is different, not a state of struggle between you and me, in theory, they may be able to combine and cooperate with each other to play a better and stronger therapeutic effect
.
Therefore, our debate should not be which drug is better, it can be believed that these drugs have a certain efficacy, what we lack most at present is more and more comprehensive clinical research and data on drug efficacy and safety, not only azvudine and VV116, even Paxlovid, this data and evidence-based medical evidence is far from enough!

The two primary endpoints of these three therapeutic drugs have different mechanisms of action against the new crown virus, not a state of struggle between you and me, but theoretically may be able to combine and cooperate with each other to play a better and stronger therapeutic effect
.
Azvudine VV116Paxlovid

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