On November 16, 2021, local time, Freiburg im Breisgau, Germany, made anti-coronavirus drugs in the laboratory. Pfizer said it is seeking authorization from U.S. regulators for its covid-19 oral drug, Paxlovid. (Visual China/Photo)
Entering the third year of the fight against the new crown virus, humanity still can't see the signal of the end of the epidemic, but fortunately, the latest progress of new crown drugs can give people some comfort.
On December 8, 2021, the State Food and Drug Administration (NMPA) approved the registration application of Tengsheng Huachuang Pharmaceutical Technology (Beijing) Co., Ltd. for the combination of new coronavirus neutralization antibody combination therapy drugs ampavirine monoclonal antibody injection and romimavir monoclonal antibody injection.
According to the official website of the State Food and Drug Administration, this is the first approved drug with independent intellectual property rights in China for the combination of neutralizing antibodies for the new coronavirus. The results of phase III clinical trials have shown that combination therapy can reduce the composite endpoint of hospitalization and death by 80%.
On another runway, there is also good news for small molecule drugs: in November 2021, the multinational pharmaceutical company Merck's Molnupiravir was listed in the United Kingdom, and Pfizer also announced the results of Paxlovid's Phase III clinical trial.
Neutralizing antibodies and small molecule drugs are the two main forms of NEWCC drugs. According to the incomplete statistics of the Southern Weekend reporter, there are currently six neutralizing antibody therapies and two small molecule antiviral drugs approved for marketing in different forms around the world.
However, the mutation capabilities of the new crown virus are like a sword hanging overhead, potentially cutting off the fragile connection between drugs and targets at any time, and making research and development efforts in vain.
Recently, a number of pharmaceutical companies have conducted trials around the escape ability of the Omicron strain to their own drugs. According to the Wall Street Journal reported on November 30, preliminary tests found that regeneration yuan pharmaceutical company's new coronavirus antibody mix drug was ineffective against Omicron. This is just over a year or so since the regenerative element antibody therapy was authorized for emergency use.
On December 12, Tengsheng Huachuang's parent company, Tengsheng Bo Pharmaceutical, announced that the new in vitro chimeric virus experiments and data showed that the combination therapy of ampavirus monoclonal antibody/romizumab still maintained neutralizing activity against the Omicron strain. This means that for the new strain, the new drug of Tengshengbo medicine is still effective.
It is foreseeable that Omicron will not be the end point of the new coronavirus mutation. Pharmaceutical companies need to take into account the possibility of immune escape in the product design stage. "Choosing what kind of antibodies, one or two, these prior designs are important. It takes a long time to develop a drug, and it is too late to turn around after the mutation. Tengsheng Bo Medicine replied to the Southern Weekend reporter.
New drugs are intensively listed
Compared with remdesivir, the only anti-coronavirus drug approved by the U.S. Food and Drug Administration (FDA), the clinical data of Merck Andhadmol and Pfizer Paxlovid performed well.
Interim clinical data released by Merck showed that the risk of hospitalization or death of COVID-19 patients taking Molnupiravir for 5 consecutive days was about 50% lower than that of the control group, and this figure was subsequently lowered to 30%. Medium-term clinical data from Paxlovid show that patients with mild to moderate COVID-19 who take the drug within three days of confirmed diagnosis have a reduced risk of hospitalization or death by about 89%.
Yin Lifang, deputy dean of the School of Pharmacy of China Pharmaceutical University, told Southern Weekend that the advantage of neutralizing antibodies is that they have strong specificity and small side effects. The advantages of small molecule drugs are low production costs and higher accessibility.
Both Molnupiravir and Paxlovid are administered orally. Yin Lifang said that the advantage of oral medicine is that it is highly accessible, and patients can stock up on drugs at home, while neutralizing antibody therapy requires patients to go to the hospital for injection and administration.
Yuan Shuofeng, an assistant professor in the Department of Microbiology at the University of Hong Kong, told Southern Weekend that there is a basic line in the standards recognized by the academic community: neutralizing antibodies should reduce the risk of hospitalization or death of patients by at least 70%, and small molecule drugs should be reduced by 50%. "Pfizer's Paxlovid is far beyond the standard, even comparable to the efficacy of neutralizing antibodies. Merck's Mmolupiravir final data is still clinically relevant, but Paxlovid is more competitive in terms of efficacy and safety. ”
Currently, both new drugs have submitted an Emergency Use Application (EUA) to the FDA. Once eucalyptus is passed, the drug will be used urgently without formal approval.
On December 8, AstraZeneca's long-acting antibody combinations Tixagevimab and Cilgavimab also received EUA. Unlike other neutralizing antibody drugs, this therapy is limited to pre-exposure prophylaxis. A clinical trial of 3,441 people showed a 77 percent lower risk of developing COVID-19 in subjects to the therapy.
The newly released neutralizing antibody drug, the combination of ampavirinumab/romimab, was jointly developed by Tsinghua University, Shenzhen Third People's Hospital and Tengsheng bo medicine. The results of phase III clinical trials have shown that combination therapy can reduce the composite endpoint of hospitalization and death by 80%.
Tengsheng Bo Medicine told the Southern Weekend reporter that compared with the existing small molecule drugs, tengsheng Bo medicine combination therapy has at least three advantages: the treatment window of the combination therapy is more generous and more in line with the real world clinical needs; the combination therapy drug has a long half-life, and the effective action time in the body after one injection can be as long as 9 months, which can provide a certain preventive effect; because the principle of small molecule drugs is to block viral replication, its effect on patients who have been late onset and the virus has been widely replicated is not as good as neutralizing antibody drugs.
China's first anti-covid-19 drug was approved for marketing, marking that China has the first anti-coronavirus drug that has been fully independently developed and proven to be effective through strict randomized, double-blind, and placebo-controlled studies. (Visual China/Photo)
"Old medicines and new uses" have become the only way
Like many sudden outbreaks of infectious diseases, at the beginning of the new crown pneumonia epidemic, there was no specific drug or specific treatment for the new crown virus.
The first specific therapy with high hopes is plasma for rehabilitated patients. After the new crown virus infects the human body, the immune system will produce antibodies that remain in the blood after the patient recovers. After the plasma of the recovered patient is tested for blood biosafety, virus inactivation, antiviral activity testing and other processes, the obtained special plasma can produce a certain specific effect.
In early February 2020, China Biologics carried out special plasma treatment at the First People's Hospital of Jiangxia District, Wuhan City, curing at least 10 critically ill patients. In August 2020, the U.S. FDA approved eucalyptus for the treatment of COVID-19 in the plasma of rehabilitated patients.
Neutralizing antibody therapy is a better choice than convalescent plasma preparation, difficult standardization, and short antibody time. The source of neutralizing antibody drugs also comes from the human body. The researchers obtained a batch of potentially potent antibodies from the patient's B lymphocytes, and then screened out the most effective antibodies for mass production.
From November 2020 to May 2021, regeneration yuan, eli lilly/junshi bio's neutralizing antibody therapy has passed the EUA. In February 2021, Regdanvimab, an antibody drug from South Korean pharmaceutical company Celltrion, was approved for conditional marketing in South Korea.
However, the development of neutralizing antibodies takes a long time and is difficult to solve. In the early days of the epidemic, a number of old drugs were excavated for clinical treatment. The efficacy of some of these drugs has undergone twists and turns from recognition to controversy, such as chloroquine, which was approved by EUA in the United States in March 2020 and withdrawn after 3 months.
As of now, one of the "old drugs" that has gone the furthest is remdesivir produced by Gilead. It is an inhibitor of viral RNA polymerase that blocks viral replication. In May 2020, remdesivir received EUA. Since then, despite controversial clinical data, it was officially approved by the FDA in October 2020. To this day, remdesivir is still the only COVID-19 drug to receive this recognition.
In fact, Molnupiravir and Paxlovid also belong to the "old medicine new use". According to public information, Molnupiravir was originally developed for the Ebola virus, and the development of Paxlovid can be traced back to the last SARS flu.
Yuan Shuofeng told southern weekend reporters that it may take nearly a decade to develop a small molecule drug from scratch. In the face of the severe epidemic situation, the new use of old drugs is almost the only way.
Wrestle with mutant strains
Under the microscope, the new crown virus is a small globules with a surface full of spike protein (S protein), and each S protein has about 1300 amino acids, of which more than 300 constitute the RBD region, which is the key region where the virus binds to the human ACE-2 receptor.
Ideally, antibodies can bind to the virus instead of receptors, thereby blocking the virus's invasion process. Therefore, where the binding site of the antibody and the virus is located in the RBD region, and how high the coincidence with the binding site of ACE-2, has become a reference standard in the early screening of antibodies.
Taking the screening process of ampavirinumab, which has just been listed by Tengsheng Bo Pharmaceutical, as an example, a paper published in Nature-Communications in January 2021 showed that a research team from Tsinghua University and the Third People's Hospital of Shenzhen screened a number of potential antibodies, and finally found that the neutralization effect numbered P2C-1F11 was the best, because the number of amino acids bound to RBD reached 22, of which 11 coincided with the binding site of ACE-2. "The largest bonding area means the best combination." The paper reads.
Like a carefully crafted key, neutralizing antibodies pry open the door to the virus. However, once the keyhole structure is changed, the key is in danger of becoming scrap iron.
"Mutations change the spatial structure of viral proteins, and one result is that viral proteins and proteins on human cells have improved their ability to bind to each other, which is conducive to virus invasion and increased transmission." The other side is that the binding power of antibodies and viral proteins decreases, resulting in the failure of antibodies and reducing our immunity. Lu Mengji, a professor at the Institute of Virology at the University of Essen Indy in Germany, told Southern Weekend.
From the very beginning, the fight between the mutant strain and the neutralizing antibody drug has begun. On April 16, 2021, Eli Lilly's Bamlanivimab, the world's first neutralizing antibody therapy to receive EUA, was withdrawn by the FDA for its poor response to mutant strains such as Alpha. In the public notification, the FDA said that as of mid-March, about 20 percent of mutant strains in the United States were expected to be resistant to Bamlanivimab, up from just 5 percent in January.
However, not all highly resistant variants pose a threat. Take, for example, the Epsilon strain, which is listed by WHO as a VOC (variant of concern), which has been widely transmitted in California, USA, and a paper published by a research team at the University of California, Los Angeles in June 2021 shows that Bamlanivimab's neutralizing function is completely lost. But with the advent of Delta, Epsilon quickly became marginalized, and the risk factor was reduced by two levels.
Structural biologist Wang Nianshuang told Southern Weekend that whether a mutant strain will have an advantage, the role of transmission ability to play a greater role than the immune escape. Therefore, Alpha and Delta, which have strong transmission ability and relatively weak escape ability, will quickly spread to the world, while Beta and Gamma, which have strong escape ability and weak communication ability, will eventually not spread.
On December 8, a paper by The team of Xie Xiaoliang and Yunlong Cao of Peking University published on Research Square, a preprint platform for the journal Nature, cross-compared the neutralization effects of nine monoclonal antibody drugs on five existing VOC variants (Alpha, Beta, Gamma, Delta, and Omicron): in addition to the dan-order biological antibody DXP-604, which has not yet been marketed, and GlaxoSmithKline's drug Sotorovimab (VIR-7831). All antibodies in the subject experienced different degrees of failure. Among them, the four listed antibodies of Regeneration Yuan and Eli Lilly Company have no effect. A new drug that has just been marketed, one of AstraZeneca's two antibodies is completely ineffective, and one only plays about 30% of the neutralizing effect.
Thankfully, with the exception of Bamlanivimab, the world's earliest listed company, Bamlanivimab, the remaining antibodies maintain a good neutralization capacity for the current mainstream Delta strain.
Neutralizing antibodies are designed in advance
Small molecule drugs have a better broad spectrum
"At a macro level, the virus is bound to continue to mutate. For neutralizing antibody drugs, it must also be changed. Lu Mengji told southern weekend reporters, "After the virus mutates, the binding power of the neutralizing antibody will be significantly affected, which will significantly affect the treatment efficiency." Therefore, antibodies must be reconstituted against mutant viruses. This work requires a lot of random screening, which is quite difficult overall. ”
For some small-scale pharmaceutical companies, this means unaffordable and high costs. Luo Yongqing, president of Tengsheng Bo Pharmaceutical, revealed to Southern Weekend reporters that the cost of developing a combination therapy of amphavir monoclonal antibody/romizumab is more than $1 billion, which is also the company's first commercial product. "For Tengsheng Bo Pharmaceutical, a start-up with only 3 years of establishment and only 100 personnel, the pressure and challenge brought by human, material and financial resources are enormous."
On December 12, Tengsheng Bo Pharmaceutical announced that new in vitro chimeric virus experiments and data show that the combination therapy of amphavirumab/romizumab still maintains neutralizing activity against TheOmilon strain. This result may be attributed to the "cocktail" design of the two antibody combination therapy. Luo Yongqing, president of Tengsheng Bo Pharmaceutical, once explained that when the research team screened antibodies in March 2020, the strategy was to choose a pair of antibodies to cope with the mutations that RNA viruses are prone to.
Li Ning, CEO of Junshi Biology, also stressed to the Southern Weekend reporter the importance of dealing with future mutations in the research and development stage, at least from four aspects: choose the appropriate development path, whether it is a neutralizing antibody drug or two new oral antiviral drugs are based on a clear mechanism of action; through screening to improve the anti-mutation ability of drugs, such as in the selection of antibodies, pay attention to site conservatism, affinity and other characteristics; consider combination therapy, so that a variety of drugs with different paths complement each other; accelerate the speed and efficiency of research and development.
In contrast to neutralizing antibody drugs that are struggling to race for mutant strains, small molecule drug manufacturers are signaling confidence. On December 14, Pfizer announced that preliminary in vitro test results showed that Paxlovid was able to work on the Omicron strain.
Wang Nianshuang also said that the variation produced by the Omicron strain is mainly concentrated on the S protein, while the small molecule drugs of Pfizer and Merck act on 3CL protease and RNA polymerase, respectively. At present, the targets of action of these two drugs have not changed significantly, so it is expected that both drugs will still be effective.
"The best broad spectrum, the most suitable for the whole people to use, is definitely oral medicine." Yuan Shuofeng pointed out that even if virus variation is not considered, neutralizing antibody drugs have the disadvantages of high production costs and complex dosing methods.
However, although small molecule drugs are good, their advantages of strong accessibility may in turn promote viral mutations. Lu Mengji said that if these two oral drugs are widely used, it is foreseeable that resistant strains may appear in a very short period of time, resulting in a decline in the treatment effect or even complete failure.
The reason is that patients who administer their own medication may not follow the course of treatment, or even stop the drug early. This can lead to the survival of a small number of viruses, which is equivalent to completing a natural selection process of "survival of the fittest". "So we have to be very cautious when using these two drugs clinically." Patients should adhere to the full course of medication under the guidance of a doctor until they are cured. At the same time, quarantine is strengthened to prevent continued infection of others. ”
Southern Weekend reporter Haiyang Southern Weekend intern Han Ningyu Huang Jiayu