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On November 4, local time, the UK Drug and Health Products Regulatory Authority (MHRA) approved the world's first oral drug for anti-coronavirus (hereinafter referred to as monupiravir) to be launched in the country.

According to the MHRA announcement, the drug will be used for mild to moderate COVID-19 patients over the age of 18 or with a high risk of severe illness. The so-called "high risk" means that they have at least one risk factor that is prone to severe illness, such as obesity/overweight, advanced age (>60 years old), diabetes or cardiovascular disease, etc.

The drug needs to be taken orally twice a day, 4 pills each time, and 5 days of taking is one course of treatment. Studies have shown that if the drug is taken within 5 days of positive COVID-19 tests and symptoms appear, the patient's risk of hospitalization or death will be reduced by half.

Effective for all variants

Monopirvir was jointly developed by Merck and Ridgeback Biotechnology.

According to the "In-depth Interpretation | The first oral drug for the new coronavirus is here, what impact will it have on the epidemic?" (click the title to learn more), it is active against a variety of RNA viruses, including the new coronavirus, and can cause the virus to produce erroneous mutations, thereby interfering with the virus's replication and achieving antiviral effects.

According to the MHRA announcement, monupivir was approved for marketing in the country, mainly based on the fact that on October 1 this year, Merck released the interim analysis results of the third phase of clinical study move-out. The study originally planned to recruit 1,550 unvaccinated COVID-19 patients. Due to the gratifying previous data, the study terminated recruitment early.

This interim analysis showed two positive results:

First, the risk of hospitalization and death in the medication group is halved.

29 days after 775 subjects were randomized, the hospitalization or mortality rates of the monupivir group and the control group were 7.3% (28/385) and 14.1% (53/377) respectively (p=0.0012). A total of 8 subjects died, all in the control group. Based on this, the researchers believed that monupivir could reduce the chance of progressing to severe illness or death in mild and moderate patients by 50%, and reduce the mortality rate to 0%.

Second, it is effective for infection with mutant strains.

About 40% of the subjects received viral sequencing. The results showed that monupivir showed consistent efficacy in the variant strains delta, gamma and mu.

"Genotoxicity" question not answered

"Based on the move-out analysis, the safety of the monupivir group and the control group is comparable, and there is no statistical difference in the chance of adverse drug events." Albert Shaw, an infectious disease expert at Yale University School of Medicine, posted that it was launched in one month after the third phase of the analysis was released, and the long-term safety issues of the drug could not be answered.

The process of artificially increasing the rate of virus mutation until it can no longer replicate and eventually disappear is called a lethal mutation. Like monupivir, a person who permanently changes its genetic information by inserting an error code into the viral RNA is called a mutagenic agent. In May this year, the American Journal of Infectious Diseases published a study by the University of North Carolina that mutagenic agents may have a teratogenic effect on human genes. This may induce cancer, may also affect fetal development and increase the incidence of birth defects.

Rick, former head of the U.S. Biomedical Advanced Research and Development Administration (Barda), said that in an animal drug experiment similar to monupivir, his offspring was found to have no teeth or partially missing skulls at birth. In April 2020, due to concerns about mutagenicity, Rick, who was still in office, refused to fund the research and development of monupivir.

British MHRA said that the above-mentioned "genotoxicity" problem has been widely studied and has not been found to pose a risk to humans. Animal experiments did not find that monupivir is genetically mutagenetic or toxic, so it was able to enter the third phase of clinical practice.

But Jaimie    meyer, an infectious disease expert at Yale University School of Medicine, pointed out that the move-out study did not include women who were pregnant, breastfeeding or pregnant. Both men and women were required to take contraceptive measures and could not have unprotected sexual behavior within one week after taking the medication. "The long-term safety issues will be particularly important when the drug goes from clinical trials to the market."

China's self-developed drugs are attracting attention and may be used for severe treatment

According to the information of the "Wall Street Journal" Institute of Knowledge, in addition to monupivir, China's Kaituo Pharmaceutical's ar (androgen receptor) antagonist prikluamide, Roche's RNA polymerase inhibitor At-527, and Pfizer's 3cl protease inhibitor PF-07321332, are all oral drugs for anti-new coronavirus. Previous data show that these three drugs generally have obvious effects on non-hospitalized mild and moderate patients, and can quickly reduce viral load and reduce the possibility of severe disease.

It is said that these three drugs are also expected to disclose interim data for the third period this year. According to convention, after this data is released, the research and development party can apply for "emergency use authorization". Once approved, the drug can be legally launched in the corresponding region.

Among them, Kaituo Pharmaceutical's A-antagonist Purkluam has attracted much attention. Data shows that Purkluamide downregulates ACE2 and TMPRSS2 expression from the transcriptional level by inhibiting androgen receptor function, thereby blocking the entry of the new coronavirus into host cells.

Tong You, founder of Kaituo Pharmaceutical, said that prkluamide may be expected to become a therapeutic drug for the entire disease cycle of mild, medium and severe COVID-19 patients. Preliminary data from the Phase 3 clinical trial of severe patients conducted in Brazil showed that after taking prkluamide, the risk of death of severe patients decreased by 92%, and the median hospitalization time of patients was 5 days; while the control group was 14 days. Analysis said that it may inhibit immune storms and inflammatory storms, which is different from other drugs under development.

Kaituo Pharmaceutical recently issued an announcement stating that the Phase 3 global multi-center clinical trial of prkluamide for the treatment of hospitalized patients has completed its first patient enrollment and administration in the United States on October 1. The trial has been launched in medical centers in 14 countries including China, the Philippines and Brazil.

Can oral medication end the epidemic?

Monupivir was approved and is regarded as a "new dawn of anti-epidemic". Its oral administration will greatly improve patient compliance and convenience. Home isolation treatment can also reduce the workload of hospitals and help avoid medical runs.

But some comments pointed out that this may lead to a new round of epidemics.

First of all, timely and effective distribution of drugs is a problem.

The applicable population of monupivir is relatively limited. In addition to mild to moderate symptoms and at least one high-risk factor, the earlier the drug is used, the better the effect. MHRA recommends that the drug should be taken as soon as possible within 5 days after the positive test occurs.

This time point is particularly important. Earlier clinical studies on patients with new coronavirus in Wuhan showed that the average time for infected people to develop from initial mild symptoms to dyspnea is 5 days.

However, in most countries, virus testing is not a "compulsory behavior". People conduct self-checking at home based on their own situation. This may cause patients to miss the best time to use the medicine.

Secondly, when patients with mild and moderate symptoms are treated at home, their mobility may increase or lead to more spread of the virus.

Doctors prescribe this drug to eligible patients, and patients do not need to be hospitalized and quarantined. In July, India released data on monupivir, saying that the treatment course is 5 days and the observation time is 28 days, and 78.3% of mild patients turn negative nucleic acid. This means that for a period of time, positive patients may spread the virus while they are free to move. Newly infected patients will also prescribe medicine, free to move, and spread the virus.

n) Reports that antiviral oral medications may be "game changers". But in the early stages of drug supply, this was just a "game" for a few countries.

Merck said it will produce 10 million courses of monupivir by the end of this year.

So far, the US government has ordered US$1.2 billion, or about 1.7 million courses of medication. At the same time, at least eight countries or regions in the Asia-Pacific region including New Zealand, Australia and South Korea have signed agreements or are negotiating procurement. Among them, Australia has confirmed to purchase 300,000 courses of medication.

As of October, the UK has purchased 480,000 courses of related drugs. The UK government and the UK National Health Service (NHS) will confirm how to configure and use them within the course. Independent drug analyst Penny ward told the British Medical Journal that according to the current average daily rate of more than 40,000 new infections in the UK, it will be used up soon.

"What we are most worried about is that, like the distribution of COVID-19 vaccines, wealthy countries have gained far more than their population share. And low- and middle-income countries are once again at a disadvantage," cnn said.

On October 27, Merck and its partner Ridgeback announced that it had reached a treatment license agreement with the United Nations to abandon patents in 105 low- and middle-income countries around the world to allow them to produce generic drugs.

Merck also said it plans to adopt a tiered pricing strategy for developing countries. According to a draft document disclosed by Reuters, the World Health Organization is working to get treatment for low-income countries at $10 per course of treatment.

On September 30, the Affiliated Hospital of Jining Medical College "exposed his family's scandal" on its official website, informing the 30 doctors of the hospital that had academic misconduct such as falsification of papers, and issued corresponding punishments.

The "medical community" found that most of the doctors involved were deputy chief physicians, involving multiple departments such as cardiology, oncology, anorectal surgery, etc. Among them, 21 corresponding authors (first authors) canceled the qualification for promotion of professional titles for three years on the basis of withdrawal, and canceled the application for science and technology awards, scientific and technological talent titles and graduate supervisors within 5 years; another 9 co-authors reported criticism in the hospital.

On the afternoon of October 21, the Affiliated Hospital of Jining Medical College held a special meeting on scientific research integrity education for all staff. Vice President Ban Bo said: "The scientific and technological documents signed by this unit and I will be comprehensively sorted out, and the scientific and technological documents published have been compared and inspected one by one since January 1, 2016."

It is reported that the Affiliated Hospital of Jining Medical College is not the first hospital in the local area to conduct self-examination, self-correction and self-exposed hospitals.

On September 7 this year, Jining First People's Hospital took the initiative to inform eight doctors of tampering with data, fabricating research processes, and improperly signing academic misconduct, and announced the relevant punishment results: all four people were disqualified from applying for scientific research projects within five years and promoted (hiring) for one year of high school professional and technical positions.

On October 28, the hospital issued two consecutive notices, proactively informing 14 doctors of academic misconduct such as data tampering and improper signatures in publishing papers, and imposed corresponding penalties.

Shortly after the self-inspection notice was issued, the website of the National Health Commission forwarded the above two "academic misconduct and paper fraud". It is worth noting that on June 3 this year, the Science and Technology Education Department of the National Health Commission issued eight consecutive notices related to scientific research integrity, reiterating the need to strengthen the construction of medical research integrity.

8 related notices were issued on June 3rd

Among them, two old documents, "Notice on the Publication of the "Five Unauthorized" Academic Papers" and "Medical Research Integrity and Related Conduct Codes" jointly issued by the Ministry of Education, the Ministry of Science and Technology, the Health and Family Planning Commission and other departments, were reissued, requiring all units to establish an investigation and handling mechanism for academic misconduct and conduct self-inspection.

This is related to the frequent occurrence of academic misconduct in the medical field. Since this year, the National Health Commission has reported the results of investigation and handling of many medical research integrity cases, which has caused heated discussions in society, such as:

On June 8, the Science and Technology Education Company of the National Health Commission announced the investigation and handling results of seven institutional medical research integrity cases, mentioning 8 public tertiary hospitals and 17 doctors across the country, including the Central Hospital of Songjiang District, Shanghai.

On September 2, the National Health Commission website announced the investigation and handling results of 12 institutional medical research integrity cases. The papers involved mainly involve the purchase and sale of papers, forging and tampering with research data, charts and other academic misconduct, and a total of 51 people were dealt with.

The "Notice on Medical Research Integrity and Related Conduct Codes" issued by the National Health Commission, the Ministry of Science and Technology, and the State Administration of Traditional Chinese Medicine previously stipulates that "medical research institutions should take the initiative to investigate and deal with scientific research misconduct in their institutions." The "Rules for Investigation and Handling of Scientific Research Integrity Cases (Trial)" also clearly states that scientific research breach of trust is led by the first corresponding author unit.

In addition, according to the "Notice on Carrying out Special Education and Rectification Activities for the Construction of Integrity and Work Style in Medical Research" (Guowei Science and Education Letter [2021] No. 193), many places across the country are deploying special activities and conducting self-inspection and rectification of institutions and individuals.

On November 3, Chongqing Medical University issued a statement saying that Professor Huang Ailong of the school led the emergency research team of the new coronavirus and found three super antibodies with broad-spectrum neutralization activity against various mutant strains of the new coronavirus. The antibodies also showed strong neutralization ability to the Delta strain, which is currently highly contagious. The research results were published online in the top international journal Nature Communications on November 2.

It is understood that the three antibodies screened can be manufactured through genetic engineering and can achieve large-scale production. At present, Chongqing Medical University is jointly developing related drugs with internationally renowned antiviral drug experts, and is expected to enter clinical research early next year.

On October 4, the Discipline Inspection and Supervision Commission of Zhongwei Municipal Commission for Discipline Inspection and Supervision of Ningxia Hui Autonomous Region reported a typical case of violating the discipline of epidemic prevention and control. On July 31, Li Mingchen, then director of the Haiyuan County Transportation Bureau, was identified as a second close contact and was transferred to the centralized medical observation point in Haixing Development Zone for isolation and observation.

On August 2 and on August 6, Li Mingchen arranged for his friend to deliver liquor to his room through Yang Yanren, a staff member of the centralized medical observation point. On the evening of August 8, Li Mingchen refused to cooperate with the centralized medical observation point after drinking, and insulted and beat medical staff and staff, causing adverse social impact. In September 2021, Li Mingchen was given a serious warning within the party and removed from his position as a senior party official and director of the Transportation Bureau; Yang Yanren was given a government warning.
Chapter completed!