Nearly two years after the emergence of the new crown epidemic, oral drugs against the new crown virus began to enter the harvest period. On November 4th, the US pharmaceutical company Merck announced that its small molecule drug Molnupiravir has been approved by the UK Food and Drug Administration, becoming the world's first oral drug approved for the treatment of mild to moderate neocorona infections in adults. Only one day later, Pfizer Pharmaceuticals of the United States disclosed the results of the clinical trial of Paxlovid, an oral drug for new crowns developed by it. Taken in the early stages of symptoms, the drug can reduce the risk of hospitalization or death of patients with new crowns by 89%. As soon as the news came out, the new crown vaccine and neutralization were on the market. The stocks of antibody and detection related sectors fell in response. After the results of Pfizer's new crown oral drug test were published, a scientist in the field of drug development wrote on the "Science" website: On our way to fight the new crown virus, there has been another turning point-we already have a vaccine, and now we have it again. The drugs that can be taken in the early stage of the disease, think about how many infectious diseases can have so many weapons!
After the COVID-19 pandemic lasted for nearly two years, doctors found that they still had few weapons: the drugs used to treat COVID-19 either did not directly deal with the COVID-19 virus and did not know the effect; either they needed injections and could only be used in medical treatment. Institutional use. However, there is no convenient, cheap, and easy-to-obtain oral medicine for people with mild or moderate infections who do not need to be hospitalized.
"Nature" magazine wrote that at first, the exploration in this area was mainly focused on searching among the existing "old medicines", and the most effective one was found to be dexamethasone. It reduces the risk of death for critically ill patients using ventilators by a third. Dexamethasone is a steroid drug designed to suppress the excessive inflammatory response of the most severely ill people. It has not been approved for use in the new crown, but it is widely used to treat the most severely ill patients with the new crown.
Wang Haoran, founder of Newland Biotech, used to work as a scientist at Novartis, an international pharmaceutical company. He told China News Weekly that many "old drugs and new applications" such as dexamethasone, hydroxychloroquine, and famotidine have been proven to have some effects. It is also used in clinical treatment, but it only shows a good effect on some patients, and it cannot be regarded as a specific medicine due to its high toxicity or unclear mechanism.
There are also some pharmaceutical companies and research teams who count the compounds in their "stocks" that may be useful for the new crown virus. Although these are not designed for the new crown, they at least make sense in terms of mechanism. So far, among these drugs currently approved by the US FDA, only Gilead’s Remdesivir requires injection. In a phase III clinical trial, the researchers found that compared with placebo, remdesivir can shorten the overall recovery time of hospitalized patients by 5 days.
About half of the COVID-19 hospitalized patients in the United States are now treated with Redecive. But some doctors say that regardless of whether patients receive the treatment, they often recover very slowly in the clinic.
Soon, doctors’ "toolbox" will have two drugs specifically developed for the new crown: orange Molnupiravir, and red and black Paxlovid with the words "COVID-19" printed on them. Both are capsules. It is very similar to the course of treatment.
On October 1, Merck announced that its oral anti-coronavirus drug Molnupiravir (Chinese translation "Monupivir") Phase III clinical trial data is optimistic. The trial enrolled 775 subjects. The enrollment conditions included patients with mild to moderate new coronary pneumonia, the onset of symptoms did not exceed 5 days at the time of enrollment, and they were all accompanied by at least one risk factor related to poor disease outcome, such as Age, obesity, diabetes, heart disease.
Interim results show that monupivir reduces the patient's risk of hospitalization or death by 50%. On the 29th day after randomization, the proportion of hospitalized deaths in patients receiving monupivir was 7.3% (28/385), compared with 14.1% (53/377) in the placebo group. During the 28 days of follow-up, no deaths were reported in the monupivir treatment group, compared with 8 deaths in the placebo group.
"The name Molnupiravir is named after Mjollnir, the ‘Thor’s Hammer’. This drug is a hammer against the new coronavirus, no matter what variant the new coronavirus will evolve." Merck’s global head of R&D introduced this. This compound is a nucleoside analog. Its mechanism of action is to combine with the RNA polymerase of the virus to introduce wrong nucleotides into the synthesized RNA molecule, causing the virus to die due to too many errors in the RNA. Based on the recommendations of the Independent Data Monitoring Committee and the results of communication with the FDA, Merck terminated the Phase III study ahead of schedule, and plans to submit an emergency use authorization (EUA) application to the FDA as soon as possible, and also to the regulatory agencies of other countries around the world as soon as possible Listing application. The United Kingdom has become the first country to approve the drug's listing, and the people it faces are elderly people over 60 or at least one high-risk group of new coronary diseases, such as obesity or heart disease.
On the second day after monupivir was approved for marketing in the UK, Pfizer reported good news about another anti-coronavirus oral drug, which was even more surprising. According to the results of Paxlovid's Phase II/III clinical interim trial, the drug can reduce the risk of hospitalization or death by 89% for high-risk adult patients with new crown infection who take the drug within 3 days of the onset of symptoms. "This is definitely a very good drug for the new crown. It is a real special drug." Wang Haoran said. Specifically, among patients who took Paxlovid medication within 3 days of onset of symptoms, 0.8% (3/389) were hospitalized without death during the 28-day observation period; 7.0% (27/385) in the placebo group were hospitalized or died, of which 7 Cases died. Among patients who took Paxlovid within 5 days of onset of symptoms, 1% (6/607) were hospitalized without death; in the placebo group, 6.7% (41/612) were hospitalized or died, of which 10 died.
The clinical trial originally planned to recruit 3,000 patients, but due to the positive results in the mid-term, the recruitment and further trials were stopped after communicating with the FDA. Currently, Pfizer is applying to the FDA for emergency use authorization. At the same time, the U.S. government has pre-ordered more than 1 million doses of Pfizer's new drug, and the United Kingdom and Australia said they have reached a supply agreement with Pfizer for 500,000 doses and 100,000 doses respectively. Pfizer’s Paxlovid is a combination drug: the small molecule PF-07321332 (hereinafter referred to as "332") and the anti-HIV drug ritonavir. The purpose of the latter is to slow down the metabolism or decomposition of "332" in the body to make it in the body Maintain a high concentration to fight the virus. The treatment process is to take two tablets of "332" plus one tablet of ritonavir at a time, twice a day for five consecutive days. Compared with monupivir, Paxlovid can be called the first specific drug for the new crown in the true sense, because the former is more like a broad-spectrum viral RNA transcriptase inhibitor, while PF-07321332 is specifically designed for Developed by the new coronavirus, its mechanism of action is to block the activity of the main protease "3CL" required for the replication of the new coronavirus.
Although there is no head-to-head comparison in the same clinical trial, the clinical results are hard not to leave an impression: Pfizer’s Paxlovid looks more effective, and the effect has reached or surpassed the neutralizing antibody. Wang Haoran said that although monupivir is relatively less effective, it has the advantages of being cheaper, easy to synthesize, having a broader antiviral spectrum, and not easy to produce drug resistance.
However, Ding Sheng, dean of Tsinghua School of Pharmacy and director of the Global Health Drug Research and Development Center, reminded that there is one more thing to pay attention to with monupivir, because of its mechanism of action, it has the risk of inducing mutations in human cells. Although this phenomenon has not been observed in Merck's trials, and a course of treatment is 5 days, the risk is lower, but it is indeed a risk that has not been fully understood.
A secretly competitive oral drug competition
After seeing the preliminary results of Pfizer's new crown specific drug, a friend asked Haoran Wang, is there any need to continue the new crown neutralizing antibody under development? Wang Haoran’s opinion is that with Pfizer and Merck’s jade in front, oral antiviral drugs and new coronavirus neutralizing antibodies with similar mechanisms can actually be suspended.
In fact, a research and development competition on the new crown oral drug has been low-key, and it did not arouse people's attention before it shined. In April of this year, the British government established an "anti-viral task force" with the goal of developing at least two anti-viral drugs this year, which people can take at home after they test positive for the new crown.
At the same time, the U.S. government has also invested US$3 billion to accelerate the discovery, development, and manufacture of anti-coronavirus drugs. The project, called the "Pandemic Antiviral Program", also intends to develop antiviral drugs for other viruses that may cause a pandemic. At least the US biotechnology companies Enanta and Pardes Biosciences, Japan's Yoshino and Novartis have all stated that they are developing oral antiviral drugs against the new coronavirus, but its progress is far behind the pharmaceutical giants Merck and Pfizer.
The FDA has previously approved some drugs specifically to deal with the new coronavirus, mainly three new coronavirus neutralizing antibodies. Last year, when Trump was treated with the new crown virus at the Walter Reid Military Medical Center, his treatment plan was Regeneron's neutralizing antibody. These neutralizing antibodies work well in early-stage patients with new crowns, and can reduce the risk of hospitalization or death by about 70% in the trial. This data is better than monupivir.
However, the treatment of neutralizing antibodies requires intravenous injection. The main reason for limiting its large-scale use is that it is very expensive. Wang Haoran roughly estimated that the average dose of a neutralizing antibody was about 1,000 micrograms. Trump took 8 grams, which is 8,000 micrograms. The cost of his early treatment with the new crown neutralizing antibody may be as high as more than 300,000 US dollars. Now due to mass production, the average price of neutralizing antibodies has dropped to about US$2,000 per dose.
In contrast, oral medications are much cheaper. Some medical and financial media wrote that monupivir is priced at about US$705 per course of treatment. Although compared with other small molecule drugs, this price is not cheap. With the widespread introduction of generic drugs in the future, the price of this drug There is still a lot of room for price reduction. Neutralizing antibodies also have a disadvantage, because they target the S protein mutation of the virus, and drug resistance is likely to appear soon, or in the case of insufficient dosage of the antibody, a new resistance mutation selected by the drug will be induced Strain. In contrast, the two new crown oral drugs have obvious advantages, that is, a wider spectrum and no fear of mutated viruses. Because the evolution of the virus's main protease is very conservative, and the probability of mutation is much smaller than that of the outer spinous S protein, Paxlovid acting on the viral protease does not care how the virus mutates; while monupivir acts on the replication process of the new coronavirus gene Among them, the mutation of the S protein mutation site will not affect it.
Merck said in a statement that it is expected to produce 10 million treatment courses of monupivir by the end of this year, and at least 20 million treatment courses will be produced by 2022. In addition, Merck has signed a non-exclusive voluntary license agreement for monupivir with Indian generic drug manufacturers to accelerate its accessibility in more than 100 low- and middle-income countries. The United States will hold a meeting on November 30 to review the safety and effectiveness data of monupivir and vote on whether to authorize its listing. Once approved, the U.S. government has pre-purchased 1.7 million at a price of approximately $1.2 billion. A course of monupivir is equivalent to approximately US$700 per course. In addition, countries that have reached an agreement to purchase the drug with Merck include at least Australia, Singapore and South Korea.
is not a day's work Just like the development of vaccines, after the SARS and MERS epidemics, both of which are coronaviruses, people’s interest in coronaviruses has greatly diminished. Pharmaceutical companies and scientists have turned to drug development for the treatment of diseases such as cancer, rheumatoid arthritis and hepatitis. Because they are more profitable. An article published in the top medical journal "The Lancet" pointed out that from 2000 to 2017, global funding for coronavirus-related research was US$500 million, accounting for 0.5% of the total expenditure on infectious diseases during the same period. Wang Haoran told China News Weekly that because the demand for the treatment of infectious diseases in developed countries is declining, the world's investment in anti-infective drug research and development is decreasing year by year. Except for Gilead, large pharmaceutical companies have not spent much energy in this field. , And shortly after he left Novartis, the company also cut off the anti-infection department. "Before the COVID-19 pandemic, big pharmaceutical companies didn't put the virus in their eyes at all."
It now appears that the fastest-running institutions in this race to find specific drugs for the new crown benefit from their long-term accumulation and investment.
Monupivir was developed by DRIVE, a non-profit organization affiliated to Emory University in Atlanta, USA. "Nucleoside drugs are difficult to make. Emory University has long-term accumulation in this area," said Ding Sheng, dean of Tsinghua School of Pharmacy. Today, in the United States, more than 90% of people living with HIV have taken at least one nucleoside reverse transcriptase inhibitor anti-HIV drug developed by Emory University scientists. After virologist and chemist George Pater jointly invented some antiviral drugs for the treatment of AIDS and hepatitis B in the industry, he joined DRIVE in 2013. The following year, he and his colleagues began a national defense-related project. It is to find a compound that can deal with Venezuelan equine encephalitis virus.
The compound the research team hopes to find can be effective against all coronaviruses. After several screenings and modifications, the compound EIDD-2801 was found, which is now Molnupiravir. In tests against Ebola, Chikungunya and influenza viruses, the "Thor's Hammer" knocked them down.
In March last year, the research team discovered that the new crown virus was also within the "range" of monupivir. In the same month, Ridgeback Biotherapeutics Corporation of the United States reached a cooperation with Emory, and Merck reached a cooperation with Ridgeback in May last year to jointly promote the clinical development of monupivir. The early chemical framework of PF-07321332, a component of Pfizer Paxlovid, was also developed during SARS. At that time, its anti-toxic ability was very good, but its water solubility and absorption were not good. It could only be administered by intravenous injection. Later, as SARS disappeared. Stopped research and development. Wang Haoran said that in the past year and a half or so, Pfizer has invested a lot of resources to make this medicine from an injection into an oral preparation with strong specificity. It only needs a very small dose to inhibit the new crown "3CL". The target of the main protease activity. He studied the preclinical data of the drug, from cell-level pharmacodynamics to the toxicology of animal experiments. "It's done very beautifully. It is a textbook-level drug development process." Senior drug researcher Derek Love lamented that less than two years after the emergence of the new coronavirus, humans have had brand new customized drugs for it. Such a speed record is very difficult to break. He said that Pfizer has a long history in the field of antiviral proteases, and the accumulation of expertise has given it a high starting point. According to the scientists involved in the development of the drug, artificial intelligence (AI) was also used in the development process. After optimizing it with AI, PF-07321332, which can be taken orally, was obtained, and the bioavailability was increased from 1.4%. It's 50%. According to relevant statistics, from January 2020 to June 2021, drug researchers have initiated thousands of studies worldwide, of which more than 650 were carried out in the United States. Janet Woodcock, currently acting as an FDA commissioner, believes that these trials compete with each other in recruiting subjects, slowing the speed of research. In addition, an analysis report co-written by her in February this year pointed out that as of November last year, only 5% of the 2,895 clinical trials in the world were rigorous enough to produce potentially useful evidence.
In Ding Sheng's view, the number of possible new crown drugs that are worth looking forward to is within five. His institution also has a new drug under development for the new crown, which is the same target as Pfizer's drug. The clinical candidate drug molecule has been selected, and the preclinical evaluation of some important indicators is better than Pfizer, but it does not have Pfizer's investment. It is currently doing pre-clinical application research and is expected to enter clinical research next year. Public reports indicate that Sinopharm Group China Biologics is currently intensively developing two new crown treatment specific drugs-new crown-specific immunoglobulin and anti-new crown virus monoclonal antibodies. Among them, the former has obtained domestic and foreign clinical trial approval documents issued by the National Food and Drug Administration and the UAE Ministry of Health and Prevention, and related clinical trials have also started.
Wang Haoran believes that few institutions can make a better oral drug for the new crown than Pfizer’s Paxlovid, because this is the accumulation of large companies for decades, and it is “burned” at a huge expense. In China, many large pharmaceutical companies are still in the "innovative imitation" stage, and there is a big gap between the R&D personnel and the knowledge accumulation. Is
a "game changer"? On the day Monupivir was officially approved in the UK, the Secretary of Health and Social Services Sayyid Javid said, “Today is a historic day for our country. For the most vulnerable infected people, this will be a game. Rule changers... They will soon be able to receive this groundbreaking treatment.” At this time, according to the average data of the last 7 days, there are about 40,000 new confirmed cases of new crown every day in the UK, which is second only to the US every day. The incidence rate is about 74,000 people. Regarding the possible impact of the new crown oral drug on the epidemic, senior drug researcher Derek Love stated on the "Science" website on November 5: The vaccine is of course significant, and it is best not to get infected at the beginning. , But there are some breakthrough infections, and worse, because of the availability of vaccines and the willingness to vaccinate, there are still too many people in the world who have not been vaccinated. For this part of the population, oral small-molecule drugs can keep the vast majority of people with new crown infections out of hospital, significantly reducing the overburden of medical systems around the world; at the same time, because they can prevent disease deterioration and death, for those who are diagnosed, It is also a great relief psychologically.
On the basis of the vaccine, together with these two drugs, Wang Haoran believes that if the standard of epidemic prevention is not particularly high, then the epidemic can basically be declared over, because almost no one will die from the new crown virus infection after becoming ill. Moreover, the two drugs of Merck and Pfizer can be used at the same time, just like the classic cocktail therapy in HIV treatment: reverse transcriptase inhibitors and protease inhibitors are combined to prevent H
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