Merck's oral specific drug Molnupiravir for the treatment of new coronary pneumonia has achieved good results, reducing hospitalization or mortality by 50%, and may be one of the decisive drugs for the treatment of new coronary pneumonia in the future

Against the new coronavirus, vaccines are an important part, but not all! For now, vaccines still cannot prevent infection 100% , so there are still many newly infected people
.
Therefore, therapeutic drugs have also become an important part of the fight against new coronary pneumonia
.

Prevent infection with new coronary pneumonia

The first non-vaccine drug for the treatment of new coronary pneumonia was Remdesivir.
Unfortunately, it is an injection and the treatment effect is not ideal
.
Injections must be used in hospitals, which will greatly limit the treatment of new crowns
.
If oral drugs are available, the treatment of new coronary pneumonia will become the norm! Just like the flu with oseltamivir, it can be treated at home
.

At present, oral drugs (mostly small molecule therapeutic drugs) for the new coronavirus have made good progress
.
There are currently at least 5 therapeutic drugs:

(1) Molnupiravir, developed by Merck;
(2) PF-07321332, Pfizer's oral 3CL protease inhibitor, this molecule has officially entered phase III clinical trials;
(3) s217622, ​​Japan Shionogi's oral 3CL protease inhibitor , Is currently undergoing Phase III clinical trials, and the official news is coming to an end
(4) Prokruline, developed by Pioneer Pharmaceuticals, is an androgen receptor antagonist;
(5) AT-527, Roche’s, and Remdesivir and Molnupiravir belongs to both RdRp inhibitors, and the current progress is also in phase III, and the results have not been disclosed
.

Recently, the first to disclose Phase III clinical data was Molnupiravir developed by Merck and Ridgeback.
The Phase III clinical trial ended early because of its excellent efficacy
.
The study targeted 775 adults with mild to moderate new coronary pneumonia .
They are considered to be at higher risk due to health problems such as obesity, diabetes or heart disease
.

diabetes

Phase III clinical interim data of Molnupiravir treatment of patients with mild to moderate new coronary pneumonia, the hospitalization or mortality rate of the Molnupiravir treatment group was 7.
3% (28/385), and the hospitalization or mortality rate of the control group was 14.
1% (53/377).
Molnupiravir reduced hospitalization or mortality by 50%, p=0.
0012
.
In terms of mortality, there were no deaths in the treatment group and 8 deaths in the control group
.

In addition, by sequencing the SARS-CoV-2 gene of subjects, it was found that Molnupiravir had the same effect on wild-type and Gamma, Delta, Mu and other mutant strains.
The mechanism of gene mutation caused by the drug is the same, which seems to be taken for granted
.

In addition, by sequencing the SARS-CoV-2 gene of subjects, it was found that Molnupiravir had the same effect on wild-type and Gamma, Delta, Mu and other mutant strains.
The mechanism of gene mutation caused by the drug is the same, which seems to be taken for granted
.

The antiviral mechanism of Molnupiravir is as follows:

The antiviral mechanism of Molnupiravir is as follows:

 

Three days after treatment, the probability of isolating replicative virus in the 800 mg group of Molnupiravir treatment was significantly lower than that in the placebo group (1.
9% vs.
16.
7%, p = 0.
02), which is a gold standard for testing virus infectivity
.
After 5 days of treatment, replication viruses could not be isolated in patients in the 400 and 800 mg groups, and replication viruses could be isolated in 11.
1% of patients in the placebo group (p = 0.
03)
.

Three days after treatment, the probability of isolating replicative virus in the 800 mg group of Molnupiravir treatment was significantly lower than that in the placebo group (1.
9% vs.
16.
7%, p = 0.
02), which is a gold standard for testing virus infectivity
.
After 5 days of treatment, replication viruses could not be isolated in patients in the 400 and 800 mg groups, and replication viruses could be isolated in 11.
1% of patients in the placebo group (p = 0.
03)
.

In fact, Molnupiravir, also known as EIDD-2801, was first developed as a candidate drug for influenza
.
As early as 2019, researchers from Georgia State University, Emory University, Washington University, and the German Federal Institute of Vaccines and Biopharmaceuticals have constructed a ribonucleoside analogue N4-hydroxycytidine (NHC).
, EIDD-1931) isopropyl ester prodrug (EIDD-2801), which showed extensive anti-influenza virus activity in cell cultures and mice, and influenza virus did not develop resistance to this prodrug
.
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.

If approved, Merck’s drug will become the first drug to be proven to treat the new crown virus infection, or it will be a major advance in the fight against the new crown pandemic
.
All new coronary therapies currently approved in the United States require intravenous injection or injection into the body
.

The progress of several other oral treatments for new coronavirus infections is as follows:

Principles and clinical progress of the four drugs

1.
Prokalamide (GT0918)-pioneering the pharmaceutical industry

1.
Prokalamide (GT0918)-pioneering the pharmaceutical industry

Prokrulide is an AR (androgen receptor androgen receptor) antagonist developed by Pioneer Pharmaceutical
.
According to related research in the pioneering pharmaceutical industry, procrulamide inhibits the function of androgen receptor, down-regulates the expression of ACE2 and TMPRSS2 from the transcription level, thereby blocking the entry of SARS-CoV-2 into host cells
.

ACE2 on the cell membrane is the receptor of the new coronavirus Covid-19, which allows the virus to enter the host cell by binding to the S1 domain of the new coronavirus spike protein (S protein)
.
The transmembrane serine protease (TMPRSS2) has a cleavage effect on the viral S protein and ACE2, making the two easier to combine, thereby promoting the virus to enter the host cell
.
Activated androgen receptor (androgen receptor, AR) can induce the expression of transmembrane serine protease (TMPRSS2)
.

Prokalamide was originally a drug for the treatment of prostate cancer.
It is said that due to accidental observations that prostate cancer patients seem to be worse than ordinary people in terms of new crown deterioration, pioneering pharmaceuticals found through experiments in February 2020 that prokalamide can Degrade ACE2 and TMPRSS2 proteins
.
At the same time, compared with other AR drugs, procrulamide can further reduce AR gene expression, so it is more likely to treat the new crown
.

 

For severely ill patients with new coronary disease, procrulamide may have another pathway that can suppress immune storm and inflammatory storm, but it has not yet been confirmed
.
In addition, the drug may have some undiscovered curative effects on the new coronavirus
.

Prokramide may have another pathway that can suppress immune storms and inflammatory storms, but it has not yet been confirmed that the drug may also have some undiscovered curative effects on the new coronavirus.

However, the results have also been widely questioned
.

However, the results have also been widely questioned
.

The most fierce fire , is the US National Academy of Medicine, Dr.
Topol Eric , he has been concerned about the new crown and has written many articles crown new research articles
.
He said that these results are so good that it is hard to believe , not to mention that in terms of new crowns , in the entire medical history , almost no other medical intervention has had such an amazing effect
.
Dr.

Topol believes , with high fatality test in the control group , almost 50% , so a comparison of the experimental drug would let P group of special effects look amazing
.

The most fierce fired is Dr.

The final phase 2 clinical trial was published in the unknown journal Front Med (Lausanne)

After the company published this conclusion, it attracted the attention of a Brazilian scholar and initiated a clinical trial initiated by the investigator (that is, a trial performed by a tripartite investigator rather than a drug developer) and reported significant results

①A trial initiated by a Brazilian researcher for severely ill patients with new coronary disease (completed)

①A trial initiated by a Brazilian researcher for severely ill patients with new coronary disease (completed)

Previously, the Brazilian researchers initiated a clinical trial on placebo severely ill patients with new coronary disease.

The Phase III global multi-center clinical trial of procluamide for the treatment of hospitalized patients with new crowns has been officially approved by the Brazilian drug regulatory agency ANVISA on September 22, local time

The Phase III global multi-center clinical trial of procluamide for the treatment of hospitalized patients with new crowns has been officially approved by the Brazilian drug regulatory agency ANVISA on September 22, local time

Registered in the United States, Phase 3 clinical trial for outpatients with mild and moderate new coronary disease (ongoing)

Research method: Compare GT0918 plus standard of care (SOC) with placebo plus SOC

Inclusion criteria: One or more mild or moderate symptoms related to COVID-19 within 5 days after the onset of symptoms

Primary endpoint: hospitalization rate within 28 days

Estimated main completion time: August 24, 2021

2.

2.

The drug was developed by Atea, and Roche acquired AT-527 rights to treat COVID-19 outside the United States with an upfront payment of US$350 million and subsequent milestone payments

On June 30, 2021, Atea Company released preliminary data on AT-527 clinical phase II double-blind treatment of hospitalized patients: 62 patients, 550 mg BID, administered for 5 days, on the second day of treatment, compared with placebo , The viral load of the AT-527 group decreased by 0.

The Phase 2 data of AT-527 currently seems inferior to Molnupiravir, but the company said it has the potential to be used as a preventive treatment after exposure in the future as a focus

From

Major clinical trial progress:

① Registered in the United States, Phase 3 clinical trial for outpatients with mild and moderate new coronary disease (ongoing)

① Registered in the United States, Phase 3 clinical trial for outpatients with mild and moderate new coronary disease (ongoing)

Research method: This study is a multi-center trial that compares the efficacy of AT-527 and placebo for light-to-medium-sized adult and adolescent patients with new coronary disease
.
Approximately 1386 subjects will be randomly assigned to the experimental group and the placebo group
.

Inclusion criteria: One or more mild or moderate symptoms related to COVID-19 within 5 days after the onset of symptoms
.

Primary and secondary endpoints: Oral 550 mg AT-527 twice a day (BID) for 5 days
.
Primary endpoint: Time to relieve or improve symptoms of COVID-19 (21.
5 hours) [Time frame: up to 29 days] Remission of new symptoms is defined as the length of time from randomization until the score remains 0 or 1 for at least 21.
5 hours; secondary Endpoint: Time to relieve or improve COVID-19 symptoms (43 hours) [Time frame: up to 29 days] Remission of new symptoms is defined as the length of time from randomization to keeping the score at 0 or 1 for at least 43 hours
.

Estimated main completion time: August 3, 2021

3.
PF-07321332-Pfizer

3.
PF-07321332-Pfizer

PF-07321332 is a 3CL protease inhibitor, which plays an important role in the life cycle of a variety of coronaviruses.
Its potential advantage is that it can have an effect on all current new coronavirus variants
.

The IC50 of PF-07321332 single-drug inhibitory activity against the new coronavirus at the molecular level is 19nM, and the EC50 of PF-07321332 single-drug inhibitory activity against the virus in human airway epithelial cells, HeLa and A549 cells that can express the ACE2 protein are 62, 99 and respectively.
56nM, showing good antiviral activity
.

Pfizer's PF-07321332 has a broad-spectrum anti-coronavirus ability, which means that its potential is great.
Although in theory the virus may still mutate and escape its mechanism of action, the actual chance of occurrence is very small
.
Pfizer also believes that the drug is expected to obtain EUA in the fourth quarter of this year during the performance call.
Pfizer currently uses the combination therapy of PF-07321332+ritonavir in clinical trials
.

Major clinical trial progress:

Registered in the United States, Phase 3 clinical trial for outpatients with mild and moderate new coronary disease (ongoing)

On September 1, Pfizer announced that it has completed the first patient in the phase 2/3 clinical trial of the new crown drug PF-07321332
.

Research method: This study is a multi-center trial comparing the efficacy of PF-07321332/ritonavir with placebo for mild and medium-sized patients with new coronary disease
.
Approximately 3000 subjects will be randomly assigned to the experimental group and the placebo group
.

Inclusion criteria: One or more mild or moderate symptoms related to COVID-19 within 5 days after the onset of symptoms
.
The total study time is up to 24 weeks
.

Primary and secondary endpoints: Primary endpoint: The proportion of participants who were hospitalized or died related to COVID-19 for any reason [time range: day 1 to day 28]
.
Secondary endpoint: incidence of adverse events (AE) and serious adverse events (SAE) of PF-07321332/ritonavir relative to placebo [time range: day 1 to day 34]; signs/symptoms of new crown Duration/Severe time [Time range: Day 1 to Day 28]

Estimated main completion time: October 5, 2021

4.
s217622 Oral 3CL protease inhibitor by Shionoyoshi Company, Japan

4.
s217622 Oral 3CL protease inhibitor by Shionoyoshi Company, Japan

Shionoyoshi is a global leader in the development of antiviral drugs such as influenza.
The well-known oseltamivir and baloxavir used to treat influenza were developed by it, and Roche was finally authorized to sell
.

The new type of coronavirus (SARS-CoV-2) has an enzyme called 3CL protease, which is essential for the proliferation of the virus, and S-217622 inhibits the growth of SARS-CoV-2 by inhibiting the 3CL protease
.
In non-clinical studies using SARS-CoV-2 to infect animals, it has been confirmed that the viral load is rapidly and significantly reduced
.
Phase 1 clinical trials started in Japan in July 2021, and phase 2/3 clinical trials for patients with mild COVID-19 or asymptomatic SARS-CoV-2 infection are currently underway
.

The new coronavirus (SARS-CoV-2) has an enzyme called 3CL protease, which is essential for the proliferation of the virus, while S-217622

In the phase 1 trial that started in July 2021, S-217622 did not show serious safety issues, and the pharmacokinetics exceeded the target blood concentration
.
In animal models, the viral load drops rapidly after treatment
.
Shionogi also announced plans to produce 1 million doses of COVID-19 therapeutics for domestic use by March 2022
.

In the phase 1 trial that started in July 2021, S-217622 did not show serious safety issues, and the pharmacokinetics exceeded the target blood concentration
.
In animal models, the viral load drops rapidly after treatment
.
Shionogi also announced plans to produce 1 million doses of COVID-19 therapeutics for domestic use by March 2022
.
In the phase 1 trial that started in July 2021, S-217622 did not show serious safety issues, and the pharmacokinetics exceeded the target blood concentration
.
In animal models, the viral load drops rapidly after treatment
.
Shionogi also announced plans to produce 1 million doses of COVID-19 therapeutics for domestic use by March 2022
.
In the phase 1 trial that started in July 2021, S-217622 did not show serious safety issues, and the pharmacokinetics exceeded the target blood concentration
.
In animal models, the viral load drops rapidly after treatment
.
Shionogi also announced plans to produce 1 million doses of COVID-19 therapeutics for domestic use by March 2022
.

Related literature:

Related literature:

Abdelnabi R, Foo CS, Kaptein SJF, Zhang X, Do TND, Langendries L, Vangeel L, Breuer J, Pang J, Williams R, Vergote V, Heylen E, Leyssen P, Dallmeier K, Coelmont L, Chatterjee AK, Mols R , Augustijns P, De Jonghe S, Jochmans D, Weynand B, Neyts J.
The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model.
EBioMedicine.
2021 Sep 24;72: 103595

The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model.

Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, Leist SR, Schäfer A, Dinnon KH 3rd, Stevens LJ, Chappell JD, Lu X, Hughes TM, George AS, Hill CS, Montgomery SA, Brown AJ, Bluemling GR, Natchus MG, Saindane M, Kolykhalov AA, Painter G, Harcourt J, Tamin A, Thornburg NJ, Swanstrom R, Denison MR, Baric RS.
An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.
Sci Transl Med.
2020 Apr 29;12(541):eabb5883

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.

Wahl A, Gralinski LE, Johnson CE, Yao W, Kovarova M, Dinnon KH 3rd, Liu H, Madden VJ, Krzystek HM, De C, White KK, Gully K, Schäfer A, Zaman T, Leist SR, Grant PO, Bluemling GR, Kolykhalov AA, Natchus MG, Askin FB, Painter G, Browne EP, Jones CD, Pickles RJ, Baric RS, Garcia JV.
SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801.
Nature.
2021 Mar; 591(7850):451-457

SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801.

Khoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R, Downs N, Walker L, Tansley-Hancock O, Greenhalf W, Woods C, Reynolds H, Marwood E, Mozgunov P, Adams E, Bullock K, Holman W, Bula MD, Gibney JL, Saunders G, Corkhill A, Hale C, Thorne K, Chiong J, Condie S, Pertinez H, Painter W, Wrixon E, Johnson L, Yeats S, Mallard K, Radford M, Fines K , Shaw V, Owen A, Lalloo DG, Jacobs M, Griffiths G.
Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.
J Antimicrob Chemother.
2021 Aug 27:dkab318

Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.

McCoy J, Goren A, Cadegiani FA, Vaño-Galván S, Kovacevic M, Situm M, Shapiro J, Sinclair R, Tosti A, Stanimirovic A, Fonseca D, Dorner E, Onety DC, Zimerman RA, Wambier CG.
Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial.
Front Med (Lausanne).
2021 Jul 19;8:668698

Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blinded Placebo-Controlled Trial.


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