Nearly two years after the COVID-19 outbreak, we have finally welcomed the first oral anti-CORONAVIRUS drug.
On November 4, Beijing time, Merck (MSD) and Ridgeback Biotherapeutics announced that the company's oral antiviral small molecule drug, Molnupiravir, is listed in the United Kingdom [1] to treat adult patients with mild to moderate COVID-19.
In fact, there are already antibody drugs for the treatment of new crown pneumonia on the market abroad. One of the biggest reasons for the sensation of this drug is that it is a small molecule drug that can be taken orally, which is more helpful for large-scale epidemic control, and some even believe that this drug can change the future trend of the new crown epidemic.
How does this drug work? We already have a COVID-19 vaccine, why are drugs still necessary? How big is the impact on COVID-19?
Today, we are trying to answer these key questions.
To judge the efficacy of a drug, it is still necessary to look at the results of clinical trials.
In October 2021, Merck disclosed interim data from a phase III clinical trial of monopivir, which yielded good results and reduced the risk of hospitalization or death by 50% [2].
It is because of the good results of the interim trial that Merck plans to close its Phase III clinical trial early and begin submitting applications to the U.S. Food and Drug Administration (FDA) and regulatory agencies around the world[2] in the hope of obtaining an emergency use authorization for the drug.
From the current results, the United Kingdom has become the first country in the world to approve the drug for marketing.
Image source: Stand Cool Helo
The trial plans to enroll 1,550 people infected with COVID-19 who are mild or moderate, and the trial's interim report analyzed data from 775 of them.
The subjects were divided into 2 groups: the monupilvir treatment group and the placebo control group.
The concrete result is this:
About 14.1% of patients who received oral placebo required hospitalization, while those who received oral monupilvir were hospitalized at about 7.3%, half of the control group.
In terms of mortality, 8 patients in the placebo-controlled group unfortunately died of COVID-19 during the trial period, compared with 0 in the treatment group.
This result proves that the anti-coronavirus effect of monupipipvir is good.
As important as the therapeutic effect of drugs, there is also safety.
From the current results, the drug safety of monupilvir is good.
The overall adverse event rate in the monupilvir-treated group was 35% and the drug-related adverse event rate was 12%, while the placebo-controlled group was 40% and 11%, respectively, and the two groups were very close.
We know that COVID-19 is an RNA virus. Monupilvir can disrupt the synthesis of viral RNA, thereby killing the new coronavirus.
The process goes something like this: Monupilvir is a nucleoside analogue that binds to the virus's RNA polymerase to introduce the wrong nucleotide into the newly synthesized RNA molecule. In this way, the virus's RNA will have too many errors, and it will be killed later [3].
Does not affect.
Monupilvir is effective against many new coronavirus mutants because it acts on conserved proteins in the viral replication mechanism, that is, proteins that rarely change even if the new coronavirus mutates.
Nowadays, there are two main ideas for human research on the treatment of new crown pneumonia:
Biological macromolecules with antibodies as the mainstay;
Small molecule compound drugs that can inhibit virus invasion, replication and other links, monupilvir belongs to this category.
1. Biological macromolecule drugs
Many pharmaceutical companies at home and abroad have nearly 100 kinds of new crown neutralizing antibodies and entered the clinical research stage. Among them, 3 antibody drugs have been urgently approved by the US FDA for use.
The most famous is the new crown neutralizing antibody REGEN-COV2 of a company in the United States, which has cured former US President Trump and has been approved for listing in the United States, Japan and other countries.
(Source: Network)
In China, there are also a number of companies that are developing antibody drugs for the new crown virus. Two of these drugs have entered the clinical phase II/III stage, and it is believed that they will soon be listed at home and abroad.
2. Small molecule chemical drugs
In addition to monupipvir, there are 4 oral small molecule anti-COVID-19 drugs in foreign countries that have entered Phase III clinical trials[4]; there are also a number of domestic companies developing small molecule anti-COVID-19 drugs, and an oral drug has just entered Phase III clinical trials on October 1.
I believe that in the near future, China will be able to use a variety of oral COVID-19 drugs.
Finding an anti-CORONAVIRUS drug for human use is not easy.
At the beginning of the epidemic, scientists around the world were constantly looking for drugs to treat the new crown pneumonia, and many clinical trials were done, but many drug candidates have been shown to be ineffective.
The most typical representative is the "miracle drug" that enjoys the reputation of "the hope of the people" - remdesivir.
In October 2020, the U.S. FDA approved remdesivir for the treatment of hospitalized COVID-19 patients aged 12 years and older who weigh at least 40 kilograms and need oxygen. It is also the only small molecule drug fully approved by the agency to treat COVID-19. Unfortunately, in the course of subsequent clinical treatment, it was found that remdesivir had little effect.
Ideal antiviral drugs require broad-spectrum antiviral activity and a high resistance barrier. That is, there are many types of viruses that can be killed and are not easily tolerated.
COVID-19 neutralizing antibodies can reduce viral load, reduce symptoms, and reduce hospitalization rates, and have a good safety profile, but the disadvantages are also particularly significant:
Most of the macromolecular antibody drugs are injectable drugs, which are inconvenient for mild non-hospitalized patients to use, and there are problems such as high cost, difficulty in dealing with virus mutations, and cold chain transportation, which may be ineffective for some mutated strains and are difficult to widely use in early prevention and control.
The advantage of small molecule drug candidates is that they can be taken orally directly, generally without injection. However, many small molecule drugs have a good effect on inhibiting the virus in in vitro trials; the efficacy in in vivo clinical trials is not ideal.
Possible causes are that, in the case of routine oral administration, effective concentrations of suppressed virus are not achieved in the lungs, or that there are excessively strong, potentially toxic side effects [5].
To deal with the epidemic, it is best to "have seedlings and medicines".
The combination of COVID-19 vaccines and COVID-19 drugs can achieve a combination of prevention and treatment, and enhance our ability to respond to the NEW CROWN epidemic.
Vaccination is not equivalent to entering the "safe", or may be infected, which is expected, medically known as "breakthrough infection". In this case, antiviral drugs are needed to treat, prevent aggravation of the disease, quickly remove the new crown virus from the patient's body, and minimize the occurrence of sequelae as much as possible.
Monupilvir can be taken orally to facilitate early medication; low production costs and can be stored at room temperature; it has more advantages in large-scale popularization and promotion, and can be quickly used in high-risk groups such as close contacts, or help patients with mild diseases to quickly control their disease.
This is also one of the biggest reasons why the world's first oral anti-COVID-19 drug has caused a sensation.
Not.
Neither vaccines nor special drugs can guarantee that we will not be infected with the new crown virus.
But with these two weapons, the new crown virus is no longer so terrible for humans.
Vaccination can prevent infection to a certain extent, reduce the rate of severe illness, and special drugs can quickly cure us after infection, thus making the new crown a common disease like the "flu".
Even now that COVID-19 drugs are coming, most people still need to prevent infection, rather than treating it after infection.
At the end of the article, there is one thing I want to mention in particular:
The price of a course of monupilvir is about $700, which is equivalent to about 4482 yuan, which is not a low price for many low- and middle-income countries.
On October 27, Merck announced that it had reached an agreement with the International Medicines Patent Pool (MPP) to share patent rights to the oral COVID-19 drug monoopivir with the world as long as COVID-19 remains classified by the World Health Organization as a public health emergency of international concern: people in 105 low- and middle-income countries can access monopivir at a lower price.
As humanity faces the common covid-19 catastrophe, we are fortunate to see some human light.
bibliography
[1] Merck and Ridgeback’s Molnupiravir, an Oral COVID-19 Antiviral Medicine, Receives First Authorization in the World. 2021, November 4.
https://www.merck.com/news/merck-and-ridgebacks-molnupiravir-an-oral-covid-19-antiviral-medicine-receives-first-authorization-in-the-world/
[2] Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study. 2021, October 1.
[3] Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. 2021, November 4.
https://www.nature.com/articles/s41594-021-00651-0
[4] Unexpected win opens the way to an oral Covid antiviral, Retrieved October 1, 2021.
https://www.evaluate.com/vantage/articles/news/trial-results/unexpected-win-opens-way-oral-covid-antiviral
[5] Robert Cox, Josef Wolf, et al. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol, 2021. Jan;6(1):11-18.
Author: Luo Tianming, Zhang Xiaoyi
Editors: Zhang Xiaoyi, Zhang Jie
Typesetting: Han Ningning | Proofreader: Wu Yihe
Operations: Li Yongmin | Coordinator: Wu Wei
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