On December 8, the combination therapy of the new crown monoclonal neutralizing antibody amphavir monoclonal/romimab (formerly known as BRII-196/BRII-198 combination therapy) was approved by the China Drug Administration for the treatment of the new crown virus.
This is the first monoclonal antibody drug approved for marketing by regulatory authorities in China, and it is also the first anti-new coronavirus drug fully independently developed in China, which was developed by Tsinghua University in cooperation with the Third People's Hospital of Shenzhen and TengshengBo Pharmaceutical.
As soon as the news came out, it instantly ignited the online platform, and now, when the bullet has flown long enough and many targeted studies and discussions have settled, we may be able to understand the drug more comprehensively.
breakthrough
First and foremost, of course, is the breakthrough of "0".
Prior to this, according to the latest version of the "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Trial Eighth Revised Edition)" released by the General Office of the National Health Commission on April 14, 2021, the antiviral treatment drugs used by patients with new crown pneumonia in hospitals are treatment drugs that may have a certain effect in clinical observation studies, and the diagnosis and treatment plan specifically indicates that the current attitude towards these drugs is "trial" and needs to be "further evaluated in clinical application":
1. α- interferon: adults each time 5 million U or equivalent dose, add 2ml of sterilized injection water, 2 times a day, nebulized inhalation, the course of treatment does not exceed 10 days;
2. Ribavirin: it is recommended to apply in combination with interferon (dose ibid.) or lopinavir/ritonavir (adult 200mg/50mg/capsule, 2 capsules each time, 2 times a day), adults 500mg/time, 2 to 3 intravenous infusions per day, the course of treatment does not exceed 10 days;
3. Chloroquine phosphate: for adults aged 18 to 65 years. For those who weigh more than 50 kg, 500 mg each time, 2 times a day, the course of treatment is 7 days; those with less than 50 kg, 500 mg each time on the 1st and 2nd days, 2 times a day, 500 mg each time on the 3rd to 7 days, once a day;
4. Abidorr: adults 200mg, 3 times a day, the course of treatment does not exceed 10 days.
According to Zhang Linqi, a professor at Tsinghua University School of Medicine and director of the Global Health and Infectious Diseases Research Center, Zhang Linqi, the person responsible for the research and development of amphexab/romizumab combination therapy (hereinafter referred to as "amphelixab combination therapy"), enters the patient's body through intravenous injection, and it only takes 40 minutes to produce antibodies in the patient's body and "take effect immediately". This is very different from the efficacy of the various "trial" drugs mentioned above.
Patients targeted by the combination of ann/Y are adults and adolescents (≥ 12 years of age and weigh ≥40 kg) who test positive for the novel coronavirus and are accompanied by risk factors for progression to severe COVID-19. In addition, although the main role is mainly treatment, because the antibody can remain in the body for 9 to 12 months, it also has a certain effect on the prevention of infection.
In an interview with CCTV's "Dialogue" column, Zhong Nanshan said: "This drug is not only effective for severely ill patients, but also has relatively high antibodies after use, which has a preventive effect on patients with immunodeficiency." ”
At play in L/ROM combination therapy are neutralizing antibodies. The so-called neutralizing antibody is an active antibody that can neutralize the virus. If the new crown virus wants to invade the human body, it needs to use the spike protein on its own surface to bind to the cell, like the "key used by the thief to open the door of the house". Neutralizing antibodies can act in advance with a fragment of the viral spike protein, thereby blocking this binding and allowing the virus to fail to pry the "gate".
From the naming of this neutralizing antibody – the combination of amphavir monoclonal antibody/romizumab – it can be known that the drug uses two antibodies to the new coronavirus, namely ambalwaxab and romimab, as a combination.
In the field of neutralizing antibody drug development, the selection of combination antibodies is a common strategy. Because the target of a single neutralizing antibody is too targeted (the target is the binding site of the drug and the organism), in case the virus mutates, the target fails, which can easily lead to the failure of the drug, and the combined antibody is equivalent to double guarantee. At present, there are three kinds of combined antibodies in the neutralizing antibody drugs urgently authorized by the US Food and Drug Administration (FDA), namely Eli Lilly LY-CoV016/LY-CoV555, Regeneron REGN10933/REGN10987, and AstraZeneca AZD8895/AZD1061.
Zhang Linqi shows amphavirmab (blue pill bottle) and romizumab (red bottle)
The antibodies BRII-196 and BRII-198 used in ann/Rhodes combination therapy are carefully selected from 206 pairs of antibodies and can bind to different epitopes in the receptor binding region of the new coronavirus spike protein. Among them, the site where BRII-196 binds to the new coronavirus spike protein belongs to a highly conserved region, which can reduce the probability of mutation and escape, and the site where the other antibody BRII-198 and the new crown virus spike protein binds avoids the area that overlaps with the BRII-196 binding point, in another epitope. This combination can inhibit the new crown virus in the body very well, ensuring that it does not combine with human cells, so that the patient's condition can be significantly improved.
According to Zhang Linqi, such a federation has the effect of combining fists, even if the virus has mutated, resulting in the failure of one antibody, and another antibody to guarantee the bottom, so it can still deal effectively.
On December 5, Tengsheng Bo Pharmaceutical released the results of the key data analysis based on the total number of patients in the PHASE 3 clinical trial of the ACTIV-2 study. The data is sourced from the National Institutes of Health (NIH), and the process design and execution of Phase II and PHASE III clinical trials of Ann/Royce combination therapy are led by this institution. The entire study, conducted in multiple clinical trial centers around the world, including the United States, Brazil, South Africa, Mexico, Argentina and the Philippines, included 847 enrolled patients with rapid emergence of sars-CoV-2 variants worldwide from January to July 2021, conducted according to strict international standards for randomization, double-blindness, and placebo control. During this period, Temsex Isaac pharmaceuticals are only responsible for providing the drugs needed for the trial.
Based on the published results, the following information is available:
Compared with placebo, the combination of ann andro therapy reduced the risk of hospitalization and death by 80% in outpatient patients with COVID-19 who were clinically at high risk of severe disease, which was statistically significant.
There were no patient deaths in the treatment group within 28 days, while there were 9 deaths in the placebo group.
In terms of safety, there were fewer grade 3 or higher adverse events in the L/R group compared with the placebo group, and no serious drug-related adverse events or infusion reactions were found.
Of the four currently licensed combination therapies with neutralizing antibodies, this is the best data for phase III clinical performance.
Regeneron REGN10933/REGN10987: On September 29, 2020, The regeneration element published clinical data for 275 people in the first phase, and another 524 people on October 28. In addition to this study, Regeneration Is Also Conducting a Number of Clinical Studies. Overall clinical data show that both doses of REGN-COV2 (2.4 g and 8 g) can relieve clinical symptoms and reduce the number of outpatient visits (including hospitalization, emergency department, etc.) compared with placebo. REGN-COV2 can reduce outpatient visits by 57% (2.8% vs 6.5%) and by 72% in high-risk patients with one or more risk factors, including age >50 years, BMI >30, cardiovascular disease, metabolic disease, lung disease, chronic liver disease, chronic kidney disease, immunocompromised patients.
Eli Lilly LY-CoV016/LY-CoV555: On January 26, 2021, Eli Lilly announced on its website that the combination of Eli Lilly neutralizing antibodies bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) reduced the risk of hospitalization and death from COVID-19 by 70%, meeting the primary endpoint of the Phase III BLAZE-1 clinical trial.
AstraZeneca AZD8895/AZD1061: The results of a Phase III clinical trial published in October 2021 showed that mildly non-hospitalized patients had a 50% lower risk of severe illness or death by intramuscular injection of AZD7442 compared to placebo; a pre-analysis of participants treated within five days of developing symptoms showed that AZD7442 reduced the risk of severe illness or death by 67% compared with placebo.
Of course, whether these data are reduced by 80% or 70%, they are only the results obtained in clinical trials, and after they are actually put on the market, as the clinical data increases, the data will change, and it is possible to increase or decrease.
The test of mutant strains
With the mutation of the new crown virus, no matter what type of antibody, it will face the risk of virus immune escape. Because the site recognized by the neutralizing antibody is only a very small fragment of the spike protein. If the virus mutates at this site, the efficacy of the neutralizing antibody against the action of this site will be affected, the neutralization efficiency will be reduced, and even the neutralization ability will be completely lost. Therefore, retesting the resistance of the antibody has become a must.
An important means of testing the effects of viral mutations on existing antibody drugs or vaccines is virus experiments.
Since November this year, the variant Omicron has emerged. It is considered to be the strongest mutant strain at present, and its spike protein produces 32 mutations. So many mutations are likely to affect the site of neutralizing antibody recognition, which in turn threatens the effectiveness of monoclonal antibody drugs.
On December 23, Peking University's Xie Xiaoliang Research Group published a paper in Nature entitled "Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies", which examined the effects of Omicron mutations on nine antibody drugs authorized by regulatory authorities for emergency use.
Experiments have shown that for Omicron, the combined monoclonal antibodies of Eli Lilly, Regeneration And AstraZeneca all show different degrees of failure, and only Vir-7831 and DXP-604 can inhibit the Omicron mutant strain. Among them, the site where Vir-7831 is located belongs to the conservative site, while DXP-604 is a monoclonal antibody drug jointly developed by the domestic pharmaceutical company Danxu Biologics and the team of Xie Xiaoliang of Peking University, and is currently undergoing Phase II clinical trials in China.
The Peking University team tested the efficacy of nine monoclonal antibody drugs to neutralize different strains of the new coronavirus. The researchers extracted serum from people who had recovered from COVID-19 and those who had been vaccinated, and looked at the ability of serum in different dilution multiples to block real viruses or artificially constructed pseudoviruses infected cells. If a mutant strain needs more serum to neutralize, it means that for that mutant strain, the ability of the serum to neutralize antibodies is reduced.
In addition, the paper showed that the antibody BRII-196 in the approved combination therapy of Temsex was inactivated by Omicron, but did not show the results of another antibody, BRII-198.
On the same day, another paper published in Nature, Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2, showed that in neutralization experiments against Omicron mutant strains, only BRII-198 remained effective out of 19 of the world's representative neutralizing antibodies. The paper, written by a team of Chinese-American virologists and professors at Columbia University School of Medicine, added that because Omicron has some branches with more mutations, whether the antibody is still effective requires further testing.
In addition, the laboratory of Tsinghua University has also recently done neutralization experiments on Omicron mutant strains, and the results show that the effect of BRII-196 neutralizing Omicron has indeed decreased significantly, but BRII-198 still remains active, and the neutralization effect is even slightly higher than that of other mutant strains.
However, whether the neutralizing antibodies of the combination of anabolic/Rhodes have been validated as effective or ineffective in in vitro experiments, the results are for reference only, as these experiments were not conducted in humans. Zhang Linqi said, "The gold standard must be clinical, we need more epidemic data, more local clinical front-line doctors' research results, in order to know the virus fatality rate and transmission rate in the end, how strong the escape ability." This is the case for the entire scientific community, and it is difficult to draw conclusions until it is clinical. ”
Do we still need vaccines?
With the emergence of a variety of new crown treatment drugs at home and abroad, some people began to claim that people did not need vaccines. Compared to the reality of the situation, this is a big misunderstanding.
Taking neutralizing antibodies as an example, although antibody drugs can maintain longer activity in the human body by modification, each new variant needs to be re-measured. And Omicron has shown that because monoclonal antibodies are highly targeted, although the scope of action can be expanded by mixing, if the virus is too highly variable, the possibility of virus escape is still very large.
According to Zhang Linqi, the production cycle of neutralizing antibody drugs takes 4 to 5 months. Because the antibody is produced by fermentation of living cells in the natural growth process, on this basis, it can be purified, filtered and a series of processes to obtain drugs, and the production capacity is extremely limited.
And because of the high cost, the price of monoclonal antibody drugs is also quite high. At present, the price of similar drugs in foreign countries is 2100 US dollars / needle, which is still the government procurement price of millions of copies. Although domestic prices may be lower than foreign countries, they will still be much higher than vaccines.
According to the current virus mutation situation, with the familiarity with the virus and neutralizing antibodies, although the entire research and development process of selecting neutralizing antibodies in the laboratory will be shortened, the time required for the large-scale production stage cannot be shortened on a large scale, so the speed of virus mutation is likely to be faster than the speed of drug market research and development. In contrast, vaccination can produce many different antibodies, and even though some antibodies may be inactivated by viral mutations, some effective antibodies are generally retained.
So even if the neutralizing antibody drug allows us to have more initiative in the process of fighting the new crown pneumonia, in reality, we still can't give up the vaccine, and we need to adhere to the two-line parallel of prevention and treatment drugs. Past experience also tells us that in the fight against infectious diseases, early prevention is always the first.
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