The new coronavirus epidemic is still in progress. “I am sick, do you have medicine?” It is the normal thinking of the public, and when facing an infectious epidemic, the phrase will naturally evolve into “I am sick, Do you have a vaccine? “
Whether it is the AIDS drug lopinavir / ritonavir (Kelizhi) that has been included in multiple national versions of the “New Coronavirus Infected Pneumonia Diagnosis and Treatment Program” or the “candidate drugs” announced by several domestic scientific institutions “, And even a” vaccine prepared in 40 days “, the news in these days seems to gradually meet the public’s expectations for a” life-saving medicine “.
However, from the perspective of professional drug and vaccine research and development, it is very difficult to realize this expectation. It is hoped that a drug and vaccine can be born in a short time to reverse the epidemic situation of new coronavirus. The prospect is far from optimistic.
So, what exactly do you think of the “potentially working” drugs and vaccines that have emerged over the past few days?
Old Medicine New, Sea “Sieve” Medicine
“Now it is three waves. The first wave is to screen the existing old drugs with the lowest risk but the low success rate. The second wave is to see some new drugs in clinical development. The third wave is the vaccine.” Officer Chen Zhisheng’s analysis of interface news.
In addition to the fastest and most convenient way to screen existing old medicines, there is also a big reason that these medicines have been approved for marketing or have undergone at least one phase of human trials. Their safety data are known and are purely new. Compared to security risks.
This work has actually been applied in clinical diagnosis and treatment. With an interview by Wang Guangfa, a member of the national expert group, the AIDS drug lopinavir / ritonavir (Kelizhi) became popular overnight, and appeared in the national version of diagnosis and treatment. Program.
Lopinavir / ritonavir is a compound antiviral drug for AIDS treatment. According to Ding Sheng, dean of the School of Pharmacy of Tsinghua University, interface news, lopinavir / ritonavir is effective for the development of HIV targets, and the same targets are expressed in the new coronavirus.
But this does not lead to the conclusion that lopinavir / ritonavir must be effective in the treatment of new coronaviruses.
“The difference between the two is still relatively large.” Ding Sheng introduced that although the new coronavirus and HIV have the same target, the protein expression is not exactly the same, and there is only similarity between the two. Furthermore, HIV After the new coronavirus enters the human body, the infected cells are different, and the virus cycle is different. This involves how the drug enters the body and is metabolized. It has to enter different organs and tissues. Therefore, the drug simulated from in vitro experiments Metabolic results are not the same as those that enter the body. “Even if the target is 100% the same, the life cycle and the infected cells are different.”
To put it simply, although HIV also has a new type of coronavirus in common that allows lopinavir / ritonavir to function, there are still significant differences between the two, affecting lopinavir / ritonavir. Wei’s play.
In 2004, foreign researchers carried out clinical studies to study the effects of lopinavir / ritonavir on SARS virus. 41 patients with SARS were treated with lopinavir / ritonavir and ribavirin combined therapy. And followed up for 3 weeks. The clinical progress and virological results were monitored and compared with 111 historically controlled patients receiving monotherapy with ribavirin, and the results showed certain advantages.
Ding Sheng believes that this clinical trial is not very convincing based on historical data, and can be further demonstrated by real-world research. Interface News recently learned from a respiratory specialist at a well-known domestic tertiary hospital that a multicenter randomized controlled trial of lopinavir / ritonavir for the treatment of new coronaviruses is expected to be conducted nationwide. The above experts also revealed that most of the local confirmed cases received lopinavir / ritonavir treatment, but they were not all effective, and some patients who had been cured did not receive lopinavir / ritonavir treatment. The effect of the drug is currently inconclusive.
In addition, there is ambroxol hydrochloride (Musutan) such as Boehringer Ingelheim, which is thought to be able to bind to the ACE2 receptor. Therefore, it has an inhibitory effect on the new coronavirus. The ACE2 receptor is a receptor that binds the SARS virus and the new coronavirus to human cells. Interface News learned that the relevant research team is currently in contact with the hospital in Wuhan and plans to conduct a cohort study.
In addition to its effectiveness, another concern is whether these old drugs will work once the new coronavirus mutates.
Current reports show that drugs such as lopinavir / ritonavir and ambroxol hydrochloride, and even Gilead’s Ebola virus drug Remdesivir, are not a few drugs that are considered to have therapeutic potential, but they are not tangible Clinical evidence.
According to Ding Sheng, the Global Health Drug Development Center (GHDDI) currently has more than 12,000 old drugs that have passed at least the first phase of clinical research. The target where the virus acts, the next thing to do is to test the binding and interaction of the drug with the new coronavirus, to do a functional test, a cell experiment, to see if the target can affect the cell, and then to study the metabolism in the body, Absorption in the body, and finally making a priority choice, need rigorous and deep evidence of progressive progress. “
In the current urgency, time and data need to be balanced.
This is just a pre-clinical study. In the current epidemic situation, how to design a reasonable clinical trial based on real-world patients, how to collect patient information and data, etc., will still be a professional problem.
Chen Zhisheng believes that in general, screening of existing antiviral drugs has the lowest risk, but the probability of success is low.
New Medical Research? I’m afraid it’s too late
In general, in the face of a new disease, new drugs are usually developed, but in the current situation, this will be a race against time.
WuXi Biologics announced on January 29 that the company urgently promoted the development of multiple new 2019 coronavirus (2019-nCoV) neutralizing antibodies introduced through international cooperation. Preliminary research shows that these antibodies from global biotechnology companies can effectively neutralize the new corona virus. The project is expected to complete the production of the first batch of antibody samples within two months, supplying preclinical toxicology tests and preliminary human clinical trials.
Chen Zhisheng told the interface reporter that this is an antibody that was screened for the conserved sites of the new coronavirus and SARS virus from the previously reserved antibodies against SARS virus. Through the combination of antibody and virus, it is hoped that it can cause downstream reactions. Produce curative effects.
WuXi Biologics plans to complete in vitro drug efficacy tests within two weeks, conduct toxicology research in March, and then apply for emergency clinical trials (IND). In order to shorten the clinical trial time, it is planned to conduct phase 1 and 2 clinical trials at the same time, and adapt Sexual clinical trial design (adaptive trial design), one month to complete the clinical trial. Strive for conditional listing.
Adaptive clinical trial design is a clinical trial design that allows prior planning to modify one or more aspects of a trial based on accumulated data. The use of adaptive clinical trial design can accelerate the speed of drug development and make more efficient use of research and development resources. Therefore, this design has attracted attention from the pharmaceutical industry at home and abroad in recent years.
Time is too late, which is the biggest obstacle to new drug development. In Europe and the United States, the development of a new drug usually takes ten years. Although there is some urgency in the review and approval process for the current epidemic situation, as Ding Sheng said, “there is an objective law for the development of new drugs. Cannot be broken. “
By the time the drug is developed, the epidemic is likely to have ended. Chen Zhisheng admits that even in accordance with his current plan, the antibody drugs of WuXiBiology could not keep up with the most critical period of the epidemic.
In the current special situation, even if the regulatory authorities try to shorten the approval time, new drug development cannot bypass the most critical clinical trials. This requires a certain number of patients and test time to obtain accurate and effective clinical data to confirm a new drug. Before it can be launched to the market. And this is also an important part of the “objective law” in Ding Sheng’s mouth.
Another difficulty that cannot be ignored is that for the research and development of new coronavirus drugs, live viruses need to be used for research in the early stage. This requires very high laboratory requirements. Currently, only P3 and P4 laboratories can conduct research, that is, they can cooperate. There are not many institutions conducting drug research.
The vaccine is also not close to the fire.
Another public expectation is that vaccines, if new coronavirus vaccines can be developed in a timely manner, may continue to stop the spread of the epidemic.
At present, many domestic and foreign enterprises and scientific research institutions, including China CDC, Hangzhou State Key Laboratory, and Professor of the Department of Microbiology of the University of Hong Kong School of Medicine, Guo-Yong Johnson, Johnson & Johnson Microbiology, Moderna, Ai Weixin Biopharmaceuticals and other domestic and foreign enterprises have announced the launch Development of a new coronavirus vaccine.
But apparently, some of the news previously disclosed caused misunderstanding by the public.
As previously reported, Academician Li Lanjuan of the National Academy of Engineering has said that it will take at least three months for the vaccine to be successfully developed, and that the microorganism said it can be prepared in 40 days. However, in fact, Li Lanjuan also emphasized that “pass the national phase I and phase II (clinical trial) verification”, and the completion of the preparation in 40 days is only to make a vaccine sample, not to market it, or even Neither is the time to be approved for clinical trials.
In fact, as with the development of new drugs, it takes a long process from vaccine development to market, and clinical trials are still an indispensable part.
As one of the new coronavirus vaccine development companies, Zhang Lunan, director of Ai Weixin, admits to interface journalists that under normal circumstances, the vaccine is too late to be invested in this epidemic. Nowadays, the development of vaccines is largely the worst for the epidemic. Prepare for the situation.
In fact, at the time of the SARS epidemic in 2003, Kexing Biological also developed the SARS vaccine and finally completed the Phase 1 clinical trial, but the SARS epidemic had already ended at the end of Phase 1.
He introduced to Interface News that traditional vaccine development takes 1 to 2 years before clinical development and 4 to 5 years during clinical phase. The DNA vaccine technology adopted by Ai Weixin and the mRNA vaccine technology adopted by S. microbe are currently two technologies that can quickly complete the early stages of the vaccine. Zhang Lunan said that it is planned to bring Ai Weixin’s DNA vaccine to the clinic in 4 to 6 months, including early research and development for 1-2 months, and to shorten the safety evaluation to 2-3 months, and then submit the application materials and add up Very fast, it will take 4 months.
Whether it is DNA vaccine technology or mRNA vaccine technology, even if rapid synthesis and preparation are achieved, and the time for various approvals is shortened, it still cannot bypass clinical trials.
In general, the clinical trials of vaccines look at the safety in Phase 1 and the immunological response in Phase 2, that is, whether the body can produce antibodies after being injected with the vaccine, to achieve prevention, and to conduct controlled studies at Phase 3 to observe statistical differences. Among them, the number of patients enrolled in phase 3 clinical trials is often in the thousands or even more, and even the phase 2 clinical trials require hundreds of people.
At present, in order to speed up, in addition to shortening the corresponding approval time, some alternative indicators may be considered in the design of clinical protocols, such as in vitro neutralization experiments.
He said that some preliminary experimental results will be announced in the next two to three weeks. But there is no doubt that if you hope that a vaccine will be available soon, you might as well isolate yourself at home and strengthen your protection.
But it must also be pointed out that although the development of new drugs and vaccines takes a long time and far water does not quench near thirst, the current research and development is not without practical significance.
In this regard, Ding Sheng said that “the third time (a major epidemic has occurred without effective drugs and vaccines)”. He believes that after the epidemic has ended, companies will naturally have no enthusiasm for research and development. This is not the fault of pharmaceutical companies, but the research on potential drugs and vaccines for major public health epidemics should be carried out by the state.