Does monupiravir bring new hope to the development of new coronavirus-19 drugs?

With mRNA vaccines, Moderna’s market value quickly surpassed GSK.

Countries all over the world are looking for new hope for the prevention and treatment of new coronavirus pneumonia

Now, Merck’s oral antiviral drug Molnupiravir has new hope

Can Merck's Molnupiravir defeat COVID-19?

No, but it can reduce hospitalization and mortality

Merck announced on October 1, 2021 that its oral antiviral drug Molnupiravir has reduced the hospitalization rate or death risk of patients with mild to moderate COVID by approximately 50%

Merck plans to seek emergency use authorization in the United States and submit sales applications to other drug regulatory agencies around the world

 This is the most suitable time

Considering that the United States has the best medical resources in the world, including well-trained doctors and the most advanced medical equipment in the world, this is indeed distressing and shocking

why?

The key factor is that selfishness pretends to be a love of freedom

During the American Revolutionary War, Patrick Henry’s famous battle slogan was "Either give me freedom or give me death!" Today, I suspect that this battle slogan may be "Give me freedom, give me death!" because it is super 99% Covid-related deaths were not vaccinated

But we still have to put aside the political realm and return to the scientific level for professional analysis

1.

In the 1990s, inspired by the drug lamivudine (Epivir), chemistry professor Dennis Liotta and virologist Raymond Schinazi discovered emtricitabine (Emit riva), an HIV nucleoside reverse transcriptase inhibitor

 

It is worth noting that more than 90% of HIV-infected people receiving treatment in the United States take drugs containing lamivudine or emtricitabine

 

Professor Liotta and Schinazi once again used Pharmasett's sofosbuvir for gold panning, which is an inhibitor of anti-hepatitis C virus NS5B polymerase

 

As one of the founders, Professor Schinazi holds 4.

 

 

In 2013, Emory University established the Emory Institute for Drug Discovery (EIDD), with GlaxoSmithKline veteran George Painter as the chief executive officer Official
.
In 2014, they discovered through screening that n-hydroxycytidine (NHC, EIDD-1931) is an antiviral drug
.

However, the polarity of EIDD-1931 is too large to penetrate the cell membrane
.
To improve bioavailability, they used an old trick in drug design: creating prodrugs
.
The hydroxyl group is converted to the corresponding isobutyric acid to produce EIDD-2801, which is converted to Molnupiravir when appropriate
.

 

 

When Painter and his collaborators began testing EIDD-2801, they were surprised to find that the drug showed broad-spectrum activity against many RNA viruses, including influenza, hepatitis C, Ebola, Chikungunya, and equine.
Brain
.
Inflammation and coronaviruses, such as SARS-CoV-1 and Middle East Respiratory Syndrome
.

For example, EIDD-2801 shows a significant therapeutic effect on ferrets infected with influenza virus (an animal commonly used to study human respiratory viruses)
.

 

In 2015, the Emory team contacted researchers at Vanderbilt University to verify whether EIDD-2801 can fight the coronavirus through research, and he did it
.

 

COVID-19 pneumonia appeared in early 2020, and the focus of the medical and scientific communities quickly shifted to the evaluation of EIDD-2801 as a global large-scale drug reuse treatment method
.
In March 2020, Emory University authorized Ridgeback, a small biotherapy technology company in Miami, to conduct human research
.

 

Ironically, many people believe that Molnupiravir is too toxic to be used as a drug because of its mutagenic properties
.
In April 2020, Rick Bright, the director of the U.
S.
Biomedical Advanced Research and Development Agency (BARDA), who was fired by Trump, complained, "Ridgeback Biotherapeutics ignores Rick Bright’s complaints.
, To put pressure on him to provide funds for the production of EIDD-2801
.
"Its safety is worrying
.

 

In May 2020, Ridgeback Biotherapeutics Co.
, Ltd.
and Merck & Co.
started a clinical trial of EIDD-2801
.
Merck gave it a code name: MK-4482, which later became Molnupiravir, and began phase II/III clinical trials in October 2020
.

 

Currently, Merck is forced to terminate the clinical trial of Molnupiravir
.
The drug is safe and effective for treating patients with mild to moderate COVID-19, but it reduces hospitalization and mortality
.
However, it is unethical to continue to give placebos to patients participating in the trial
.
Merck now uses Molnupiravir for test subjects
.

 

Merck will now issue an emergency use application to the FDA
.
Hope the approval is coming soon!

 

2.
Molnupiravir's mechanism of action

Molnupiravir's mechanism of action is well known: Just like Gilead’s Remdesivir, Molnupiravir kills the coronavirus by blocking the synthesis of RNA polymerase (RdRp)
.

After oral administration, Molnupiravir is easily metabolized by plasma esterase into the active drug EIDD-1931
.
It can exist in two forms: one form is similar to cytidine, which forms a single bond between carbon and N-OH; the other form is similar to uridine, which forms a double bond between carbon and n-hydroxyl
.

These two forms are called tautomers, and the transition between them can cause mismatches in the transcription process
.
Therefore, when the virus grows in the presence of EIDD-1931, its RNA-dependent RNA polymerase reads the compound in the form of uridine instead of cytidine, thereby replacing uridine with cytidine
.

In short, EIDD-1931 works by interfering with the synthesis of RNA
.
In the process of viral RNA synthesis, the addition of this molecule will cause subsequent misreading of base pairs, leading to a high mutation rate, and ultimately to the death of the genome
.

Because the drug forces the coronavirus to make many mistakes when it replicates, the virus cannot be synthesized
.
Therefore, some people worry that it is mutagenic and has potential risks to humans
.
However, Merck’s comprehensive tests have shown that high-dose drugs will not produce mutagenic effects in animals, and Phase 3 clinical trials have not found that they have mutagenic effects in humans
.

Now, Merck has proven that Molnupiravir is safe and effective, and it has changed the way we fight the coronavirus
.

First of all, it is an oral medicine, which is more convenient than remdesivir and neutralizing antibodies
.
Second, Molnupiravir can fight a variety of viruses, which means it can also be used to treat other viral infections
.
The third and most interesting feature is that Molnupiravir appears to have a high resistance barrier
.

Usually a drug will force the virus to rapidly develop a mutant that is not affected by the drug, and then make the drug useless
.
In laboratory tests, despite the "expected" mutations, Molnupiravir was not found to promote drug resistance in animals, which means that Molnupiravir is effective against all variants, including the Delta mutant strain
.

3.
In the future, there will be antiviral drugs from Pfizer and Roche

Pfizer's PF-07321332 followed closely, and Phase II/III clinical trials began in early September 2021
.
Unlike Molnupiravir, PF-07321332 inhibits the 3CL protease of coronavirus
.
It is speculated that PF-07321332 is also a CYP3A4 substrate, so it can be combined with AbbVie's ritonavir to increase oral availability
.

At the same time, Atea Pharmaceuticals cooperated with Roche to develop At -27
.
Like Remdesivir, AT-27 can inhibit the production of RNA-dependent RNA polymerase
.
But it also has certain activity on viral non-structural protein 12 (nsp12) polymerase
.
AT-27 is in a farther position in the development process
.

In any case, the success of Molnupiravir is good news that the world desperately needs
.
I hope that through the combination of vaccines and oral antiviral drugs, the invisible enemy of the coronavirus will be defeated in the near future
.

Science will win!

Slow resistance, low production cost

-The success of Malnupravir is another victory for nucleoside antiviral drugs

Malnupravir is expected to become the first oral anti-coronavirus drug approved for marketing, which is another verification and victory of nucleoside antiviral drugs
.
In the treatment of many major viruses such as HIV, HBV, HCV and other diseases, nucleoside antiviral drugs are undoubtedly the most important class of antiviral drugs
.

Generally speaking, viral polymerases are less prone to mutations than viral surface proteins
.
The binding site of nucleoside antiviral drugs is the active area of ​​polymerase, so nucleoside antiviral drugs are not so easy to develop resistance
.
Slowness, which is why Redecive and Malnupravir still have high inhibitory activity against various mutant strains such as Delta, Gamma and Mu
.

Compared with Remdesivir (Remdesivir, Remdesivir), another important advantage of Malnupravir is its simpler structure, no complex phospholipid prodrug part (Protide), and simpler synthetic route
.
It can be delivered via cheap cytosine
.
A simple amino conversion is obtained, which is convenient for rapid mass production and lower production cost
.

Given that the COVID-19 disease may continue to mutate in the future and new RNA viruses may trigger new epidemics, the deployment of broad-spectrum anti-RNA virus drugs in advance for potential RNA viruses is an important strategy
.

Due to the structural similarity of RNA virus replication key polymerase (RdRp), the development of broad-spectrum anti-RNA virus drugs is very feasible
.

The correct clinical research protocol is the key to the success of Molnupiravir Phase III

From the online information, the special highlight of the clinical trial design of Molnupiravir is: the entry standard is laboratory-confirmed mild to moderate COVID-19, and there is at least one risk factor related to the severity of the disease (such as obesity,> 60 years old)
.
Age, diabetes and heart disease), and symptoms appeared within 5 days before randomization
.

The main efficacy indicator is the percentage of hospitalizations and/or deaths within 29 days after randomization
.
This is the real clinical benefit
.

1.
Remdesivir research review

Looking back at the clinical study of Redecivir in China a year ago, the study was divided into two groups: mild and severe
.
Compared with the Molnupiravir clinical study, the selection criteria of the key group of the redevir clinical study is the main evaluation index for the phase III clinical study of Molnupiravir
.

From a clinical point of view, in the severe stage, the use of antiviral drugs is already too late
.
The main evaluation index of the Redecive mild group is the clinical recovery time
.
However, the length of clinical recovery time is not important
.
Whether it is serious or causes hospitalization is the key
.

According to information obtained on the Internet, preclinical studies have shown that Molnupiravir has higher in vitro anti-coronavirus activity than remdesivir, and it is still effective against remdesivir-resistant coronaviruses
.
Its IC50 for the new coronavirus SARS-CoV-2 in the Vero cell line is 0.
3uM, which is stronger than the 0.
77uM of Remdesivir
.

Although Molnupiravir is more effective than remdesivir, this does not mean that remdesivir is ineffective
.
If safety permits, increasing the dose of remdesivir is sufficient
.

The purpose of clinical research is to reflect the efficacy of the product under the premise of ensuring the safety of subjects through reasonable design
.

In the design of the Molnupiravir project, Merck completely got rid of the influence of the previous Remdesivir project, which is also the key to the success of the Molnupiravir research
.

2.
Factor analysis of the success of Molnupiravir Phase III clinical trial

First, the Molnupiravir study selected the right subjects
.
For viral infections such as COVID-19 pneumonia, antiviral treatment must be carried out in time
.
This is similar to antiviral treatment for influenza
.

Molnupiravir selected subjects who developed symptoms within 5 days
.
Once the initial antiviral window is missed, the symptoms of COVID-19 pneumonia are mainly caused by the body's immune response, and have nothing to do with whether there is a virus in the patient's body
.

At the same time, considering the low hospitalization rate and mortality of healthy young people due to new coronavirus infection, subjects with basic diseases such as old age and obesity are selected
.

Among them, the hospitalization rate and mortality rate after the new coronary pneumonia infection are relatively high
.

Choosing such subjects can reduce the sample size
.
From the results of the phase III study, of the 377 patients in the placebo group, 45 were hospitalized, 8 died, and the mortality rate was 2.
12%
.
This mortality rate is also higher than that of healthy young people
.

Secondly, the Molnupiravir study is also very cautious in the selection of the main evaluation indicators
.
First of all, hospitalization and mortality are the clinical benefits and direct evidence of the efficacy of Molnupiravir
.

At the same time, the Molnupiravir study did not use mortality alone as the main evaluation index
.
Due to the low mortality rate, the sample size calculated from the mortality rate will be relatively large
.

For example, if the death rate of the control group is estimated to be 2.
12%, the death rate of the test group needs to be controlled at 0.
3% to obtain a sample size of 1550
.
This is undoubtedly a challenge
.
This research adopts adaptive design method to design
.

Due to the consumption of value, the mortality rate needs to be controlled at a low level
.
From the test results, there were 385 patients in the experimental group and 0 deaths; in the placebo group, there were 377 patients and 8 deaths
.
This result is very lucky
.

If 1 of the 385 patients in the experimental group died, there would still be a significant difference between the two treatment groups, but once there were 2 deaths, the P value was greater than 0.
05, and the interim analysis would fail
.

Therefore, the combined calculation of hospitalization rate and mortality increases the overall certainty of the study
.

According to the interim analysis data, 28 of the 385 patients in the experimental group died in hospital, and 53 of the 377 patients in the placebo group died in hospital
.

Even if the experimental group adds 8 hospitalized patients, that is, 36 cases, a significant difference can still be obtained
.
Therefore, this design is a relatively safe design
.

Third, adopt the Adaptive Design method, and use the interim analysis results for the report
.
The ad hoc analysis of Adaptive Design itself consumes a kind of value
.
If there is no significant difference in the results of the interim analysis, the final analysis will face greater challenges
.

In addition, as mentioned earlier, Adaptive Design itself will also lead to an increase in the total sample size
.
This is the risk of adaptive design
.
However, Merck's R&D personnel made the right decision through risk analysis, which greatly advanced the approval of the drug
.

Molnupiravir compound patent or until 2038

Similar to Remdesivir, Molnupiravir is also based on a known nucleoside antiviral compound
.
Emory University discovered that EIDD1931 compounds can be used as broad-spectrum antiviral drugs to prevent the replication of a variety of RNA viruses, including influenza virus, SARS and Middle East respiratory syndrome virus, Ebola virus and respiratory syncytial virus
.

However, unlike Remdesivir, although Gilead has applied for a compound patent, the patent for the use of the COVID-19 virus is first listed by Wuhan University
.
Emory University has made a low-key priority application in 2020, and filed a PCT international patent application in February 2021
.

Patent for using Molnupiravir to suppress new coronavirus

The latest application of Molnupiravir to inhibit new coronavirus.
Patent Publication Number: WO2021159044A1, Title of Invention: n4-hydroxycytidine and its derivatives and related antiviral uses (n4-hydroxycytidine and its derivatives and related antiviral uses) one A pharmaceutical composition for the treatment of COVID-19 pneumonia infection, the active ingredient of which is a compound of formula XXI

The example verifies that EIDD-1931 and its isobutyric acid prodrug EIDD-2801 (ie Molnupiravir compound) inhibit the activity of the new coronavirus
.

The patent application date is February 7, 2021
.
Based on three US priority patents, they were filed on February 7, March 11, and March 25, 2020
.

(Source: Internet, reference only)