Sankei reported that under the epidemic |, data and rationality are still needed after the wave of emotions

Duan Jingyuan/Wen

The spread of the epidemic is still continuing, and the announcement of the new mutant strain Omicron has also cast a layer of uncertainty over the direction of the epidemic.

"Whether the newly announced strains are likely to become dominant strains and cause a new round of pandemics mainly depends on the spread capacity of the mutated strains, that is, infectivity, and immune escape, as well as the pathogenicity of the virus, whether it causes severe illness or death, and whether it has the potential and whether it can eventually be achieved is two more issues," Jin Dongyan, a professor at the School of Biomedical Sciences of the University of Hong Kong and an expert in virology, pointed out to Caijing. In his view, Omicron has more mutations in the spike protein, but whether it will cause stronger contagiousness and pathogenicity is too early to draw conclusions, and it still needs to be observed and more researched.

On the first day of October, Merck announced phase 3 data on oral antivirals for patients with mild to moderate COVID-19, showing positive mid-period analysis results. The good news "turned out", and the sound of small molecule drugs or pushing the epidemic into influenza began to appear. On the same day, Merck Rose by double digits and closed up 8%, while at the other end of the world, the US and Hong Kong stock markets reacted first, and A shares also responded just after the opening of the holiday - the stock prices of new crown neutralizing antibodies and vaccine companies fell together.

In the short period of time, the overseas market in the Pfizer small molecule followed by the release of data, the domestic development of pharmaceutical and other research and treatment of new crown small molecule drugs enterprise voices also continued, the market in the same period of feedback positive signals. But with the recent update of Merck data, the efficiency decline, Merck stock price fell sharply, while vaccine stocks Moderna and BioNTech stocks rose rapidly.

In the secondary market, "small molecule drugs" and "vaccines, neutralizing antibodies" seem to be placed on opposite sides, "one end will rise, the other will fall". In fact, the trend of the epidemic and the release of various information on drugs have been amplified by the secondary market.

Returning to the virus and technology itself, excessive pessimism or blind optimism is not beneficial, and it seems wiser to rationally look at the changes in the virus and preventive treatment measures. At this stage, vaccines, neutralizing antibodies and small molecule drugs are still complementary, and more to solve the needs of different populations at different stages of pre-treatment.

The release of the data has triggered a market frenzy, and the multiple problems of small molecule drugs still need to be solved

Coinciding with the eleventh holiday in China, Merck released the clinical research data of the small molecule therapeutic drug Molnupiravir, and in the Phase 3 study of mild or moderate COVID-19 patients, positive mid-term analysis results were obtained, reducing the risk of hospitalization or death by about 50% compared with placebo.

With the release of trial data by Merck, voices about oral drugs can push the epidemic to influenza began to appear, the US and Hong Kong stock markets took the lead in giving a positive response, and A shares also responded just after the opening of the holiday. But rather than saying that the market's performance is based on "superior" test data, it seems to be the public's expectation and "voice" for the end of the epidemic.

The heat of the secondary market undoubtedly needs to be set off by the efficacy of medicine. "If more specific drugs are proved to be safe and effective, this will undoubtedly give the public a more layer of confidence, and the availability of drugs in the early stages of infection can reduce the rate of severe illness and mortality, and at the same time avoid becoming a source of transmission after open social activities," said Tong Youzhi, founder, chairman and CEO of Pioneering Pharmaceuticals. Pioneering pharmaceutical treatment of the new crown drug pkrutamine is a rapid progress in the development of small molecule drugs in the world, and three phase III international multicenter clinical trials for patients with mild and severe covid-19 are currently being carried out globally.

Pkrutamine, like small molecule drugs such as Merck, Pfizer and Gilead, has been conducted in the company's previous research and development pipeline, and has been explored as a treatment for COVID-19 since the covid-19 pandemic.

According to public information, Merck's Molnupiravir was developed as early as 2003 to treat other viruses that also use RNA as genetic material and require RdRp for RNA replication, such as hepatitis C virus. Pfizer has also publicly revealed that its PAXLOVID infrastructure came from 2002 to 2003, and 3CL protease inhibitors were found in response to the SARS virus, but they could not be made into oral dosage forms at that time. Pukrutamine is a new generation of androgen receptor (AR) anti-antagonists and degradants, is a rapid progress in the development of pharmaceutical research and development pipeline, the previous clinical trials are for prostate cancer and breast cancer, for prostate cancer treatment in China for phase III clinical and in the United States to complete phase II clinical, for breast cancer treatment in China for Phase Ic clinical trials.

During the epidemic, small molecule drugs have been favored by the industry, and clinical trial data have not been released until now.

In this regard, Tong Youzhi explained to the financial network that this is due to the comprehensive effect of small molecule drugs in clinical use, especially when administering drugs at high concentrations, different organs and different tissues may cause the activation of a major target and multiple secondary targets, so small molecule drugs must first ensure drug safety, need a longer test cycle to explore safety and safety windows, after slow climbing, collect more test data.

A variety of small molecule drugs are screened out from the previous clinical pipeline, after the early safety and safe dose data accumulation, can enter the verification stage of drug activity and effectiveness faster, accelerate the progress of the trial, but also to complete the SMALL MOLECULE drug CMC process and quality control related verification work, "small molecule drugs The whole development cycle is very long", Tong Youzhi said.

On the other hand, the mechanism of action of small molecule antiviral drugs determines that there is stronger stability in response to strain variation. According to Tong Youzhi's explanation, the target of small molecule drugs is not the spike protein of the virus, but the host cells infected by the virus, and the effectiveness of the drug will not be greatly changed because of the mutation of the virus.

As Zhu Zhaoming, an analyst at Haitong Securities, pointed out to the financial network, because small molecule oral drugs are more convenient than injection drugs, and the price is cheaper, and the accessibility to patients is higher, which also enables infected people to use drugs in a timely manner to stop the development of the disease and the spread of the virus in an early stage, thereby reducing the mortality rate of severe disease and reducing the number of infected people.

However, it should be further pointed out that according to the information released by Merck and Pfizer, in real cases, it is necessary to start treatment within no more than 3 days or 5 days from the time when symptoms appear. According to Tong Youzhi's explanation to the financial network, if the disease has been more serious, the virus has fully replicated and spread in the human body, the danger of the disease is no longer only from the virus itself, but the over-activation of the human immune system, the emergence of an immune storm, may kill not only the virus, but more importantly, endanger the normal function of the human body. "So in the beginning, with the sharp rise of the virus, if the virus can be controlled as soon as possible, reproduction can be prevented, using foreign drugs and human autoimmune suppression virus, it is possible to achieve a rapid cure."

This means that patients need to be diagnosed accurately and in a timely manner, drugs need to be given to patients within the right time window (such as early in the development of the disease), and the progress of the patient's disease needs to be closely monitored for further management. This undoubtedly puts forward higher requirements for timely diagnosis and improvement of drug accessibility.

"For small molecule drugs to treat the new crown, if they are approved for marketing as prescription drugs, their market share and therapeutic effect will be limited, and the rapid accumulation of clinical data and the approval of marketing as OTC products may be the most important point for small molecule drugs in the future." Zhu Zhaoming pointed out to Caijing Network, "On the other hand, expanding the treatment plan for people with higher risk exposure earlier, such as high-risk exposure, may also be of significance for the commercialization of small molecule drugs in the future."

There is also the problem of drug resistance in front of small molecule drugs. Similar to HIV drugs, resistance to antiviral drugs tends to be a thorny issue. "Even if small molecule drugs are more readily available for purchase and use, frequent administration of multiple infections can lead to resistance." Jin Dongyan pointed out to the financial network.

Not only that, but on November 26, Merck updated its analysis to reduce the combined risk of hospitalization and death by 30 percent, down from 50 percent initially reported. "If the effectiveness of many small molecule drugs is not ideal, then joint use will be a direction that can be explored, but if there is a drug with a significantly better effect, it can be used alone," Tong Youzhi told Caijing.

It is worth mentioning that the information released by the current development of the pharmaceutical industry shows that pkrutamine is effective for patients with mild and severe diseases of the new crown. The reason behind this, Tong Youzhi said, when used for the treatment of severe patients, in addition to inhibiting viral infection of host cells, pkrutamine can also inhibit the secretion of inflammatory factors caused by the new crown by regulating the patient's immunity and inflammation-related signaling pathways, preventing the occurrence of cytokine storms, thereby alleviating the body's immune inflammatory response and tissue damage in the body, and then effectively improving the symptoms of patients with severe new crown infection.

With the virus pandemic, the "vaccine + drug" dual response mechanism is more effective

"The biggest uncertainty about the future development of the epidemic is the mutation of the virus. If the mutation of the virus causes the failure of existing vaccines and drugs, it will take more time to re-develop them, and the control of the epidemic will become a protracted battle. Du Xiangyang, chief analyst of Southwest Securities Pharmaceutical, told Caijing. If the virus no longer has subversive mutations, and the vaccination rate can reach the ideal state of 70% in the world, then the dual response of 'vaccine + drug' can be completely controlled. ”

"In past experience, vaccines are the most effective preventive measures and means during the virus pandemic," Jin Dongyan pointed out. According to the currently published case data, Du Xiangyang pointed out that at present, only from the mutation site of the Omicron mutation strain, there are more mutations in the S protein and RBD region than the Delta strain, which means that Omicron shows a certain degree of immune escape, but it needs to continue to be observed." In order to further ensure the effect of population immunity brought about by the vaccine, whether to replace the original strain, or to form a mechanism like the influenza vaccine to change the strain fixation mechanism, is still being widely discussed and determined.

What is the question answered now? It's how we should be exempted. Whether it is an inactivated vaccine or an mRNA vaccine, after completing a full course of vaccination, after half a year, the function of cellular immunity is still there, but the function of humoral immunity is significantly reduced, on this basis, how to achieve strengthening, so that immune function is stronger. "Zhong Nanshan, an academician of the Chinese Academy of Engineering, said at the Greater Bay Area (Shenzhen) Vaccine Summit a few days ago." But we're still collecting data, we're still watching dynamically, and it's not possible to draw conclusions anytime soon. ”

"The existing COVID-19 vaccines on the market, based on the current technology platform, replacing the strain is something that can be done very quickly." Jin Dongyan told the financial network, "For the version of the new strain, usually only a small number of changes need to be made to the existing vaccine version, so once the relevant companies get the strain, they can quickly develop a new vaccine, even faster than the estimated time." It is reported that a number of new crown vaccine companies such as domestic Kexing have released news that if necessary, the vaccine can be adjusted for the strain, and even in a very short period of time.

Wang Bin, founder of Aidi Weixin, also told Caijing That last year, Aidi Weixin and Inovio cooperated, and it took only two and a half months to push the new coronavirus DNA for the original strain into clinical trials. "This is still at the height of the epidemic, many R & D and production facilities are not available," Wang Bin said, "now if you need to update the vaccine against the mutant strain, the time will be faster." ”

The replacement of the strain of the NEW CROWN vaccine is something that can be done quickly, and the reason why Delta has not been implemented is not that it cannot be done, but because there is no consensus between regulators and academics on whether Delta is necessary to use a vaccine specific to the variant. In Jin Dongyan's view, it is necessary for regulators to set down a mechanism, when to change vaccines according to what standards, and to clarify this mechanism.

What is more widely discussed and being studied is how to construct more effective vaccine combinations and explore the immune and protective efficacy of homologous or sequential vaccinations to enhance the immunity and protective efficacy of the needle.

According to a set of data released by Chile, for people who have completed two inactivated vaccinations, another booster injection, whether homologous or sequential, can improve the effectiveness of immunization. According to incomplete statistics and combing, Chile has carried out a number of trials, involving three different trials, including continuing to receive the same vaccine after receiving 2 doses of inactivated COVID-19 vaccine, strengthening injection of AstraZeneca adenovirus vector vaccine and Pfizer mRNA vaccine.

In addition, in China, the research carried out by Zhang Wenhong, director of the Department of Infectious Diseases of Huashan Hospital Affiliated to Fudan University in Shanghai, is aimed at receiving a recombinant protein subunit vaccine reinforced injection after two inactivated vaccines; Zhu Fengcai, deputy director of the Jiangsu Provincial Center for Disease Control and Prevention and WHO new crown vaccine priority review expert, is also studying the "mixed beating" of the reinforced needle, which is six months after the two-shot inactivated vaccine immunization, with CanSino's adenovirus vector vaccine as the reinforcing needle.

According to Wang Bin, in August this year, the new crown DNA candidate vaccine (INO-4800/pGX9501) was approved to carry out clinical trials with inactivated vaccines to explore sequential immunization strategies. The inactivated vaccine in combination immunization test with the NEW CROWN DNA vaccine is CoronaVac developed by Beijing Kexing.

In fact, compared to the "active immunity" produced by vaccination, neutralizing antibodies have also been clinically shown to have a certain degree of preventive effect.

"After injecting neutralizing antibodies, the antibodies will form protection in their bodies, and once there is a virus invasion, they will block it, and do not let the virus enter the host cell for reproduction, which can be understood as passive immunity." Li Ning, CEO of Junshi Biotech, told Caijing That Junshi Bio's JS016 was approved by EUA for "post-exposure prevention", which is a typical preventive function. This indication targets high-risk populations, including those who are not fully vaccinated or are not expected to produce an adequate immune response after full vaccination, and who have been exposed to COVID-19 infection or in an institutional setting at high risk of exposure.

With the continuous emergence of the new crown variant, and the transmission rate is increasing, the speed of transmission is accelerating, the prevention and control of the virus is challenging, and there is an urgent need for effective measures to cope with the changes.

Du Xiangyang and Zhu Zhaoming both told the financial network in the interview that wide vaccination is the most important way to prevent the spread of the virus, and special drugs are a powerful supplement on the basis of vaccination.

"Vaccines and drugs complement each other, but there is no overlap in the population of users," Wang Bin pointed out. He believes that the new crown vaccine is a preventive vaccine for healthy people, and the goal is not to get sick and not to die. Drugs are used only after the patient enters the hospital, and the two are different application scenarios and markets, complementing each other.

"With a vaccine, there will be a population protection rate, which means that under the protection rate of the vaccine, more people are safe against the virus." Patients who are not protected from the onset of the disease will go to the hospital for treatment, at this time, the drug can play a therapeutic role in the patient. Therefore, vaccines and drugs should be used together, so that better prevention and treatment effects can be achieved. Wang Bin said.

Li Ning pointed out to the financial network that according to experience, a drug can not do all-round, "as our understanding of the disease and the development of treatment methods are getting deeper and deeper, the choice of therapy may undergo a gradual substitution, or may form a set of complementary combination punches." ”

How to understand the trend of the epidemic and epidemic prevention measures? "What is the premise for controlling the outbreak and returning to normalcy? It is to reduce the case fatality rate, the new crown virus can eventually go to the direction of influenza, and the transmission force and pathogenic rate can be reduced," Academician Zhong Nanshan pointed out publicly a few days ago. Effective vaccines, coupled with drugs, can significantly reduce the health threat of new crown pneumonia to the human body, and the health risks of new crown virus are largely "flu".

A number of experts have told the financial network in the interview, first of all, it is very clear that the vaccine is the basis for forming a national immune barrier, in the process of establishing the barrier, for the population that has not yet had time to complete the vaccine injection, or can not produce sufficient antibodies after injection, antibody drugs can provide prevention. For breakthrough infections, where previous vaccinations have been given or received antibody/small molecule drugs after infection, the risk of hospitalization and death to progression to severe illness is correspondingly reduced. If the new crown flu is flu, then it can also be considered the end of the epidemic.