Oral COVID-19 medication: effective!

Merck announced on October 1, 2021 that the oral antiviral drug Molnupiravir co-developed with Ridgeback is safe and effective for the treatment of COVID-19

Because the results exceeded expectations, the study was terminated early

The news quickly ignited a frenzy, which was not only quickly forwarded by the major media, but also caused a frenzy in the stock market

Main results of phase 3 clinical trials

The interim analysis of the Phase 3 MOVe-OUT clinical trial announced this time is a multicenter randomized controlled trial

Subjects are laboratory-confirmed as mild to moderate COVID-19, have at least one risk factor related to serious diseases (such as obesity, age> 60 years, diabetes, and heart disease), and have symptoms within 5 days before randomization

The study recruited subjects from around the world, of which Latin American population accounted for 55%, European population accounted for 23%, and African population accounted for 15%

The main efficacy indicator is the percentage of hospitalizations and/or deaths within 29 days after randomization

Among the evaluated cases, mutants such as Delta, Gamma, and Mu accounted for 80% of the infected cases

Main results:

• Among patients taking Molnupiravir, 7.

  
  

• During the 29-day observation period, a total of 8 subjects died, all in the placebo group

  
  

• There were no significant differences in any adverse events (35% vs.

  
  

This phase 3 clinical trial initially planned to enroll 1,550 patients

Merck is currently applying for an emergency use authorization (EUA) from the FDA

Merck expects to produce 10 million treatment courses by the end of 2021

In addition, Merck has signed agreements with a number of generic drug companies to accelerate the supply of Molnupiravir in low-income and middle-income countries

The basis of Molnupiravir's success

The antiviral drug Molnupiravir (EIDD-2801) is an antiviral small molecule (RdRp inhibitor)

Preclinical studies

As early as March 2020, Baric, a well-known coronavirus expert at the University of North Carolina who reported the bat coronavirus SHC014 with Shi Zhengli, uploaded a very important article on bioRxiv, reporting that his newly synthesized compound NHC is killing the new coronavirus.
Virus
.
In terms of viruses, it is more active in vitro than remdesivir, and the coronavirus that is resistant to remdesivir is still effective
.

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
.

EIDD-2801 is a biological prodrug of NHC (beta-4-hydroxycytosine-5'-isopropyl ester)
.
EIDD-2801 can reduce weight loss and inhibit pulmonary hemorrhage in mice infected with SARS coronavirus
.
Coronavirus replicates in lung tissue
.
At the same time, it improves lung function and reduces acute lung injury and alveolar disease
.

Phase 2 clinical trial results

On June 21, 2021, a clinical trial led by the University of North Carolina (UNC) was uploaded on MeDRIXV.
Three days after treatment, patients treated with EID-2801 (Molnupiravir) isolated replicated viruses in 800 mg The probability was significantly lower than that of the placebo group (1.
9% vs.
16.
7%, P=0.
02), which is the gold standard for detecting viral infectivity
.

After 5 days of treatment, the replicated virus could not be isolated in the patients in the 400 mg and 800 mg treatment groups, and the replicated virus could be isolated in 11.
1% of the patients in the placebo group (p=0.
03)
.

Further confirm the molecular mechanism of action

On August 11, 2021, the Max Planck Institute published a good article in the journal Nature SME, reporting the molecular mechanism of action of the potentially highly effective antiviral drug Molnupiravir
.

This study describes the mechanism by which Molnupiravir induces mutations in viral RNA replication
.
The active form of Molnupiravir is β-D-N4-hydroxycytidine (NHC)-triphosphate
.
Viral RdRp will mistakenly use NHC triphosphate instead of cytidine triphosphate or uridine triphosphate as a catalytic substrate
.

NHC can cause large amounts of A and G in viral RNA replication, leading to mutations in RNA products
.
The structural analysis of the RdRp-RNA complex containing the mutant product shows that NHC can form a stable base pair with G or a in the active center of RdRp, which explains how the drug evades proofreading and synthesizes mutant RNA
.

This two-step mutagenesis mechanism may be applicable to a variety of viral polymerases, so Molnupiravir may have broad-spectrum anti-RNA virus activity
.

Follow-up impact

In the early stages of infection, the virus replicates rapidly, and the host's immune system has not had enough time to establish an immune defense.
Therefore, the best time for antiviral therapy to block the virus is a few days before the infection
.

Molnupiravir is an oral capsule designed for outpatients in the early stage of the disease, so the number of beneficiaries will be greatly increased
.

In this regard, Dr.
Fauci, the White House's chief medical adviser, made an "impressive" comment today
.

In the treatment of early and mild COVID-19, the three approved drugs are all monoclonal antibodies, all of which are injections, and usually require hospitalization, which severely limits their clinical applications
.

Another antiviral drug used to be "the hope of the people".
The remdesivir developed by Gilead is also an injection drug.
Therefore, it cannot be used in outpatient clinics early and can only be used for severely ill patients who are hospitalized.
In addition, more and more A lot of evidence shows that Remdesivir is not effective for patients with severe COVID-19
.

Gilead also tried to develop remdesivir inhalation, but on July 30, 2021, the company announced that it would stop clinical trials of remdesivir inhalation
.
At present, the hope for early treatment of COVID-19 oral antiviral preparations lies in Molnupiravir
.

The final clinical trial of Merck's antiviral drug Molnupiravir has shown positive results far exceeding market expectations, and has greatly satisfied the most important and earliest clinical problems that have been resolved
.

As former Director of the U.
S.
Food and Drug Administration Scott Gottlieb said:

"This is an amazing result.
I mean, this is a profound game rule change.
There is an oral pill that has this effect
.
"

Sure enough, on the one hand, Merck's stock price soared, and even the US stock market, especially the stock price of travel companies, such as Disney, also rose sharply after hearing the news
.
This means that people value the important role of Molnupiravir in returning to normal life as soon as possible
.

At the same time, the great success of oral antiviral drugs has also become a bomb thrown at vaccine and monoclonal antibody companies
.
The shares of the new vaccine company Novavax and the emerging anti-viral monoclonal antibody company Vir even fell 23%
.

(Merck & Co.
)

(Disney)

(Vaccine company Novavax)

(Mab Company Vir)

However, as a treatment option after infection, antiviral drugs cannot actually replace vaccines as a pre-infection prevention method
.
In other words, humans are still inseparable from vaccines, and vaccination is still the basis for preventing COVID-19 infection
.
Therefore, the stock prices of vaccine companies gradually rebounded after a sharp decline
.

But oral antiviral drugs will obviously replace part of the use of antiviral monoclonal antibodies
.

However, we also need to see that the current oral antiviral drugs can only reduce critical illness/mortality by 50%
.
In other words, 7.
3% of infected people still suffer from severe illness or death after oral antiviral treatment, which still cannot meet human needs
.

This means that looking for more effective antiviral drugs and antiviral drugs combined with monoclonal antibodies is still a need for the treatment of COVID-19
.

As early as February 4, 2020, when we were discussing the treatment of COVID-19 pneumonia by Remdesivir, we mentioned that ultra-early antiviral therapy + monoclonal antibody combination therapy is an ideal method for the treatment of COVID-19 pneumonia
.

While oral antiviral drugs have made breakthroughs, approved monoclonal antibodies are also studying outpatient intramuscular injections to treat COVID-19, and some progress has been made
.

Due to the positive effects of the oral antiviral drug Molnupiravir in clinical trials, people have even more reason to look forward to getting rid of the trouble of the new coronavirus as soon as possible and returning to normal life
.

(Source: Internet, for reference only)