Since china's first officially approved new crown special drug Tengsheng Huachuang,lopezumab/romizumab, it has received great attention from all parties in society. According to the Statistics of Antibody Therapeutics database, as of now, there are hundreds of neutralizing antibody projects targeting the S protein of the new crown virus worldwide, of which at least 20 are in the research phase, and there are 5 neutralizing antibody therapies that have been authorized for emergency use.
With the spread of the "Omilon" virus in 88 countries around the world, patients began to see deaths, and the effectiveness of existing COVID-19 neutralizing antibody drugs has also received extraordinary attention. "Compared with the previous well-known new crown variants, from the several variants published by the World Health Organization, each has characteristics. Aumilon has some more different characteristics. The first is the large number of mutations, and mutations occur in a short period of time. On December 21, the above-mentioned ambavir monoclonal antibody / romizumab leading research and development personnel, Tsinghua University School of Medicine Professor Zhang Linqi pointed out to the 21st Century Business Herald reporter.
On the same day, Dr. Zhu Qing and others also disclosed experimental data on the "Aomi Kerong" mutant strain to the media, including the 21st Century Business Herald reporter. According to reports, the results of the ACTIV-2 Phase III clinical trial analysis of the above combination therapy (BRII-196/BRII-198 combination therapy) and the key data analysis based on the total number of patients. The data showed an 80% reduction in hospitalization/mortality in phase III clinical trials of the therapy, maintaining neutralizing activity against "Omi kerong" and other mutant strains.
Maintain good activity against Omikeron
BRII-196/BRII-198 combination therapy, jointly developed by Tengsheng Bo Pharmaceutical, Shenzhen Third People's Hospital and Tsinghua University, is the first covid-19 neutralizing antibody therapy in China.
It is worth noting that the combination therapy rapidly advanced from the initial laboratory research to the completion of international Phase 3 clinical trials and finally obtained marketing approval in China, which took less than 20 months.
Since the outbreak of the epidemic in January 2020, Zhang Zheng, director of the Research Institute of the Third People's Hospital of Shenzhen, isolated the strain, and then accelerated the screening of antibody strains; in May, the clinical phase II trial was opened; since then, it has been continuously requisitioned by the medical treatment group and the scientific research and development team of the joint prevention and control mechanism of the State Council in response to the new crown pneumonia epidemic for the clinical treatment of new crown patients; at the same time, it has also carried out multi-center clinical phase III trials overseas.
On 8 December, the BRII-196/BRII-198 combination therapy was approved by the NMPA for the treatment of adults and adolescents (12-17 years, weighing ≥40 kg) with mild and ordinary forms of COVID-19 who are associated with high-risk factors for progression to severe (including hospitalization or death). Among them, adolescents (12-17 years old, weight ≥40 kg) are conditionally approved.
According to data from the ACTIV-2 Phase III clinical trial released by the National Institutes of Health on December 5, the Phase III clinical trial of the therapy targeted patients with data on delta variants within 10 days of onset, with an 80% reduction in hospitalization/mortality. The conclusions showed that the therapy maintained neutralizing activity against "Omikejong" and other mutant strains, and the efficacy was good.
Regarding the reasons for designing a pair of antibodies instead of a single antibody, Zhu Qing, senior vice president of Tengsheng Bo Pharmaceutical and head of the biopharmaceutical department, explained to the 21st Century Business Herald reporter that from the outbreak of the epidemic last year, the design of this pair of antibodies began, considering that the new crown virus is a very new RNA respiratory virus, according to experience, its mutation rate is very high, so the use of combination therapy, the design of a pair of antibodies to target different binding sites.
The therapy builds a double defense line against the new coronavirus variant through the action of different targets and mechanisms. The new coronavirus infects human cells by binding to ACE2 on human cells, while ampavirinumab blocks the virus from binding to ACE2 at the site where the new coronavirus receptor binds directly to ACE2; romizumab blocks the reproduction of the virus with different mechanisms of action against another site in the new coronavirus receptor binding region that does not bind to ACE2.
In contrast to the mode of administration, the therapy is intravenous, with the highest drug concentration quickly reached after injection, while the highest concentration after muscle or subcutaneous injection is several times lower and takes days to a week to reach the highest concentration, which may miss the best treatment time.
In this regard, Zhang Linqi said that the administration in the form of intravenous infusion, with fast onset and high concentration, is very effective for specific groups with underlying diseases and with high risk factors for progression to severe disease, which is the focus of the treatment of this antibody drug. At the same time, based on the optimization of the antagonist, this drug not only has a fast onset of action, but also has strong stability, so it has an advantage in maintaining activity, and it will play a greater role in the early treatment of patients.
Regarding the indications, Zhu Qing pointed out that ampavirinumab/romizumab is suitable for three situations: one is a high-risk patient, the other is a patient with low immunity, and the third is that the patient is accompanied by some complications or has potential risk factors, such as diabetes, hypertension, etc.
According to Luo Yongqing, in terms of commercialization, in addition to being approved in China, the new crown drug is also submitting an emergency use authorization (EUA) application to the US Food and Drug Administration (FDA). In addition, priority will be given to countries that register and participate in international Phase III clinical trials, such as Argentina, Mexico, South Africa, etc.
Phase III clinical studies of the therapy are conducted at multiple clinical trial centers around the world, including the United States, Brazil, South Africa, Mexico, Argentina and the Philippines. Interim results of the ACTIV-2 trial phase 3 conducted by the National Institutes of Health (NIH) showed that this combination therapy had a statistically significant (unadjusted, unilateral test P->) in outpatients with COVID-19 at high risk of clinical progression compared with placebo
At present, the experimental detection data of in vitro chimeric virus show that BRII-196/BRII-198 combination therapy has no effect on nearly 10 new coronavirus variants and maintains neutralization activity: "Alpha", "Beta", "Gamma", "Delta", "Delta+", "Epsilon", "Yota", "Kappa" and "Ramda".
Image source: Tengsheng Huachuang
In addition, in addition to the therapeutic effect, Zhang Linqi also said that there is a role in the prevention of this antibody, at this stage, with the support of the Ministry of Science and Technology, academician Zhong Nanshan will carry out clinical research, especially some related studies for immunodeficient patients.
Zhang Linqi also said that at present, we still have great doubts about the future mutation of the new crown virus, and we are also monitoring and evaluating the effectiveness of antibodies at any time. At this stage, in the face of the constantly mutating new crown virus, there is no accurate answer to whether the target of amphavir maclumab/romizumab will fail.
Neutralizing antibodies and small molecule oral drugs complement each other
According to statistics, a total of 5 neutralizing antibodies or combination therapies around the world have been authorized for emergency use, namely: Casirivimab/imdevimab combination therapy of regenerative yuan, etesevimab/bamlanivimab combination therapy jointly developed by Eli Lilly/Junshi Biology, Sotorovimab jointly developed by GlaxoSmithKline and Vir Biotechnology, and BRII-196/BRII-198 combination therapy of Tengsheng Bo Pharmaceuticals AstraZeneca's AZD7442 (AZD8895/AZD1061).
5 neutralizing antibody therapies authorized for emergency use
In addition to neutralizing antibodies, there are also other new coronavirus treatment methods such as new crown vaccines and small molecule oral drugs. Here are a simple comparative analysis of neutralizing antibodies and small molecule drugs.
Regarding the nature of the two drugs, Luo Yongqing said that neutralizing antibodies are drugs that are managed from preventing infection to blocking mild infection to severe infection and death. A small molecule drug is an enzyme that inhibits viral replication.
The location of the target of the drug binding is different. Zhu Qing said that the drug target of the antibody is generally in the position where mutation is more likely, so when a viral infection occurs, the virus faces immune pressure to replicate and often mutates at the antibody recognition site; and the target location of the small molecule drug binding is generally on the enzyme, which is more conservative, so the possibility of losing activity is lower.
The mechanism of action of the two is different. Macromolecular neutralizing antibodies have both preventive and therapeutic effects, while small molecule drugs reduce the load of viral replication by inhibiting a critical step in the viral replication process. Luo Yongqing pointed out that antibody drugs can not only quickly block the binding and fusion of viruses and cells, but also build the body's immune defense line for the prevention of new crown infection. Rapidly reaching the highest blood concentration by intravenous injection to neutralize the virus has a better inhibitory effect on viruses that replicate rapidly. In addition, it also has the effect of immunomodulatory, and the time of formation of immunity is 9-12 months.
The treatment window period is different. Zhu Qing said that in clinical studies, it was found that when the human body is infected and symptoms appear within about ten days, antibody therapy is effective; while the treatment time of small molecule drugs is very short, and symptoms must be administered within three days or even as soon as symptoms appear. Otherwise, once the treatment window is missed, the efficacy of small molecules will be greatly reduced.
Compared with neutralizing antibodies, small molecule oral drugs have the advantages of convenient medication, low cost, and can be stored at room temperature, and are more likely to be favored by developing countries. But there are also some drawbacks. Zhu Qing said that at the current dose of small molecules, it takes about five days to take more pills orally. So there is a need for better oral medicines in the future. At the same time, after taking small molecule drugs, it is also easy to develop drug resistance, and the human body will not react to small molecule drugs, and it will not work.
In summary, regarding neutralizing antibodies and small molecule oral drugs, Luo Yongqing believes that the two types of drugs are not a completely competitive situation, in some cases are complementary relationships, and the two types of drugs have different use scenarios and approaches. Zhu Qing pointed out that for the new crown epidemic, whether it is vaccines, small molecule drugs or antibodies, it is actually in short supply.