China Business Daily (reporter Ma Jiawen / photo) On December 8, the first domestic anti-new crown virus special drug was approved by the State Food and Drug Administration for emergency listing. Compared with vaccines, new crown antiviral drugs have attracted more attention.
Combination therapy drugs for covid-19 neutralizing antibodies that patients need
A question: How effective are the new crown antiviral drugs
Where is the "special effect" of the first domestic anti-new crown virus special drug? On December 8, the State Food and Drug Administration (NMPA) approved the listing application of Tengsheng Huachuang Pharmaceutical Technology (Beijing) Co., Ltd. (hereinafter referred to as Tengsheng Huachuang) for the combination therapy of neutralizing antibodies for the new coronavirus. The therapy includes ampavirinumab injection (BRII-196) and romizumab injection (BRII-198), which can be used in combination to treat mild and ordinary adults and adolescents (12-17 years, weighing ≥40 kg) with a high risk factor for progression to severe (including hospitalization or death) with covid-19.
At the beginning of last year, Tengsheng Bo Pharmaceutical Biotechnology Co., Ltd. (hereinafter referred to as Tengsheng Bo Pharmaceutical), Tsinghua University and the Third People's Hospital of Shenzhen jointly established Tengsheng Huachuang to jointly develop antibody drugs for the new crown virus. "The combination of amphavir monoclonal antibody/romizumab reduces the risk of hospitalization and death in COVID-19 outpatients at high risk of clinical progression by 80%." Luo Yongqing, CEO of Tengsheng Huachuang, told China Business Daily that 837 patients infected with the new crown virus in four continents and six countries were divided into a combination therapy group using ampavirinumab/romizumab and a placebo (saline) group for control, using randomized, double-blind control for experimental testing. As of the 28-day end point, there were zero deaths in the treatment group and nine deaths in the placebo group. In the treatment group, hospitalization and mortality were significantly reduced, both in patients who started treatment early (within 5 days of symptom onset) or late in life (within 6 to 10 days of symptom onset).
How do specific drugs work? The new crown virus enters the human body, binds to human cells and replicates in large quantities, infecting other normal cells in the human body. Neutralizing antibody therapy is the injection of drugs into the human body, mimicking the antibodies produced by the human immune system, and binding to the new crown virus, so that the virus loses the ability to bind to human cells.
Antibody drugs have been successfully used to treat AIDS, Ebola and other diseases. Luo Yongqing said that the antibodies selected this time were isolated from the serum of the recovered patients, and the two antibodies with the strongest binding ability and antiviral ability were the two antibodies. At the same time, the epitopes of the two antibodies binding viral spike glycoproteins are different, which can avoid potential future resistance, that is, escape caused by mutations in the virus, and it is not easy to develop drug resistance. Bioengineering genetically engineered the pair of antibodies to give them a longer half-life. Typically, antibodies produced by the body have a half-life of about 21 days, and can have a half-life of up to 76 days after modification. This means that the antibody remains in the blood for a longer period of time and the effective concentration is longer.
"The blood concentration of amphavir monoclonal antibody/romizumab inhibits 90% of viral growth by 300 times, that is, after 9 months of injection, it can still inhibit 90% of viral growth by 40 times." Protect the body for up to 9 months, or even 12 months. Luo Yongqing said.
Second question: After the appearance of "Ami Kerong", did the special drug still work?
In experimental tests, the safety record of combination therapy with antibodies for the new coronavirus neutralization is zero deaths, but are there any side effects in patients after use? Zhang Yao, chief medical officer of Tengsheng Huachuang, told China Business Daily reporter: "During the experimental test, the overall incidence of adverse reactions above the third level was 3.8%. The most common serious adverse effect was the exacerbation of COVID-19-related pneumonia in patients. In fact, a randomized, double-blind form was used during the experimental test, so the subjects did not know what was injected, and patients who injected normal saline reported more adverse reactions than patients who took the drug. Based on this, we believe that the use of antibodies is very safe. ”
Luo Yongqing said that the combination of amphavir monoclonal/romizumab reduced the risk of hospitalization and death in COVID-19 outpatients at high risk of clinical progression by 80%.
It is worth noting that neutralizing antibodies may be more susceptible to viral mutations. Shi Rui, a postdoctoral fellow at the Institute of Microbiology of the Chinese Academy of Sciences, believes that preventing the failure of neutralizing antibody drugs due to viral mutations is a difficult point in the preclinical development of new crown antiviral drugs. Most of the neutralizing antibody drugs have a single site (mostly the receptor binding domain of the S protein on the surface of the virus), and if the key amino acid site of the receptor binding domain mutates during the passage of the virus, the neutralizing antibody drug may face failure.
Before the approval of the first domestic anti-new crown virus special drug, the new crown "super" mutant strain "Omicron" has just been discovered. Studies have shown that the combination of ampavirinumab/romizumab is effective against virus variants such as "alpha", "beta", "gamma", "epsilon", "delta", "delta+", "ramda" and "mu", so is it effective against "Omilon"?
Luo Yongqing said: "When the neutralizing antibody combination therapy drug was clinically conducted from January to July this year, it was the time when the mutant strain was widespread in the world. From the earliest 'alpha' 'beta' to 'delta' and other viral variants, the neutralizing antibody amphavir maclonumab/romimab can remain active. We currently have four laboratories around the world conducting experiments to determine whether Omilkejong has an effect on ambavirumab/romimvir monoclonal antibody combination therapy, and the results will be seen in the next two weeks or so, and I am confident in the effectiveness of the drug. ”
Three questions: Will special drugs become "sky-high drugs" in the future?
Li Ankang, chief financial officer of Tengsheng Bo Pharmaceutical, told the China Business Daily reporter that the current price of the new coronavirus neutralizing antibody combination therapy drug required by a patient is 2100 US dollars in the United States, including two 50 ml amphavir monoclonal antibodies and two 50 ml romizumab. The dose used is "1 g + 1 g", which is based on the concentration of the drug distributed in the body to calculate a dose that is sufficient to produce aggressive power against the virus.
Cold chain transportation, production technology, cost of use... Will the high price become a major "label" after the advent of the first domestic anti-coronavirus special drug? Taking Eli Lilly's new crown monoclonal antibody Bamlanivimab as an example, the CEO of Eli Lilly has publicly stated that the pricing of Bamlanivimab monopharmaceutical will be $1250 per bottle per course in developed countries, and will adopt a tiered pricing model according to the country's ability to pay.
Li Ankang said: "The pricing of the new crown virus neutralizing antibody combination therapy drugs in the Chinese market has not yet been finalized, and has been communicating and communicating with relevant state departments, and the subsequent pricing will be decided after further research according to the amount of government orders and drug supply." In addition, according to the current demand, the supply of pharmaceutical production capacity is sufficient. At present, we have entrusted the production of drugs to WuXi Biologics, which ranks in the top three in the world and has huge production capacity, so we are not worried about production capacity. In the future, when the scale of production is expanded, the cost will be reduced. If future production increases, there should be room for further reduction in drug prices. ”
It is worth mentioning that even with the new crown special drug, the vaccine is still indispensable. Luo Yongqing said that the new crown vaccine is active immunization, but some people may have different levels of antibodies after vaccination. The treatment of covid-19 drugs complements the new crown vaccine. In addition, in terms of prevention, the new crown special drug may be more suitable for those who are still low in antibody levels after vaccination, as well as some people with cancer, hypertension and other diseases and people with low immunity.
"In terms of the prevention of the new crown virus, neutralizing antibody drugs can only be a supplement to vaccines. Because even in large-scale production, the cost of neutralizing antibody drugs cannot be lower than that of vaccines. Therefore, for large-scale prevention, the first choice is vaccine. Lee Saidang Kang.
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There is a market of nearly 100 billion yuan behind the new crown special drugs
Industrial Securities Research Report pointed out that the commercial market space for new crown neutralizing antibody drugs can reach 6.9 billion US dollars to 14.6 billion US dollars (about 44.8 billion yuan - 94.9 billion yuan). According to relevant statistics, there are currently 217 therapeutic antibody projects for the new crown virus in the global development stage, of which three groups of antibody therapies have been granted urgent authorizations for the treatment of patients infected with the new crown virus; 79 antibody projects are in clinical trials (Phase I./II./III.); 66 antibody projects are in the early detection stage, of which 60 antibody projects are in the preclinical stage; at least 29 countries and 291 companies/institutions are developing antibody therapies for the new crown virus.
Up to now, on the track of the new crown virus special drug, Eli Lilly, Regeneration Yuan, and GlaxoSmithKline's new crown neutralization antibody therapy have been authorized for emergency use by the US Food and Drug Administration (FDA). According to the financial report, in the third quarter of this year, the sales of regenerative new crown antibody drugs were $804 million; Eli Lilly expects to complete the transportation of about 200,000 doses of new crown neutralizing antibody drugs in the third quarter of this year, and the remaining drugs will be completed in the fourth quarter. The deal brought in about $330 million in revenue in the second half of the year. After Eli Lilly, Regeneration Yuan, and GlaxoSmithKline, Tengsheng Bo Pharmaceutical also submitted an emergency use authorization application to the US FDA. It is worth noting that the American regeneration yuan said at the end of November this year that after preliminary tests, the combination therapy with antibodies lost its efficacy against the Aumecreon variant. Eli Lilly has also previously said that the company is testing the effect of neutralizing antibody therapy on new variants, but will not speculate on the final result.
In September this year, Tengsheng Bo Pharmaceutical also announced that it would invest 100 million US dollars to promote the commercialization of drugs. Li Ankang said frankly that the new crown virus neutralizing antibody combination therapy drug is the company's first product to enter commercialization, which will definitely bring further cash flow support to the company, and can also bring better support to the company's subsequent research and development and other product line development. At present, the company's research and development investment in the new crown virus neutralizing antibody combination therapy drug is very large, follow-up investment is also increasing, as for the drug, when the company can make a profit depends on the development of the future market.
"We are actively discussing with the relevant units and hope that the drugs can be used on patients as soon as possible." Prior to submitting the application, we had donated a large number of drugs for the treatment of patients. Once on the market, we will continue to benefit patients in a commercial manner, and we hope to accelerate this process." Luo Yongqing said.