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Text | "Finance" reporter Xin Ying Lingxin
Edit | Wang Xiao
On March 27, 2022, Pfizer's new crown oral drug Paxlovid (nematvir tablets / ritonavir tablets) was priced at 2300 yuan a box, which can be taken continuously for five days, that is, a course of treatment. Slightly lower than it was previously priced in the United States, a course of treatment is about $530 (about 3367 yuan).
Oral medication has long been seen as the last piece of the puzzle against covid-19. Paxlovid, which was urgently approved to enter the Chinese market in February, has been included in the Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Trial Version 9) (hereinafter referred to as the "Diagnosis and Treatment Plan"), which is suitable for adults and adolescents of mild and ordinary types within five days of onset and accompanied by the progression of severe high-risk factors.
The first batch of 21,000 boxes of Paxlovid in China have been distributed to Jilin, Shanghai, Guangdong, Zhejiang and other places for use, and have successively entered the provincial medical insurance directory. Knowing the price of Pfizer's drug in China, virologist Chang Rongshan directly called "very expensive", "It is not a new drug, and the price of raw materials produced is not high." The cost of new use of old drugs is mainly clinical trials, and these costs should be amortized over a period of five years or more."
But as an exclusive covid-19 drug, Paxlovid is difficult to reduce prices in the short term, and the only thing that can really shake its global pricing system is new competitors.
Although Pfizer announced in late 2021 that Paxlovid had reached a voluntary licensing agreement with the Un-backed public health organization Drug Patent Pool (MPP), which means that generic drug manufacturers in a large number of low-income countries can obtain Pfizer's COVID-19 oral drug license, although the Chinese market is not among them. Chinese Medicine (600056. SH) is responsible for Paxlovid's commercial operations in the Chinese mainland market.
According to the incomplete statistics of "Finance and Economics Big Health", there are currently 17 small molecule new crown drugs in China in emergency research and development, of which the oral drugs of Junshi Biology, Pioneering Pharmaceutical and Real Biology have entered the clinical phase III trial.
A domestic new crown drug research and development person believes that once domestically listed, the pricing of a course of treatment may be around 500 yuan, floating up and down 200 yuan, "the new crown oral drug as a new drug has just been listed, considering the research and development cost pricing is slightly higher." This predicted price refers to the pricing of oral anti-influenza virus drugs, and when the domestic imitation of Tamiflu is listed, the price is about 300 yuan for five days.
In addition to the possible decline in drug prices, the challenge for new crown pharmaceutical companies is how much market capacity is there under the constantly mutating new crown virus? Can it make the next Duffy?
To be the next "Duffy", Omi kerong is the dodge
Shenzhen Third People's Hospital is the only designated hospital for COVID-19 in the region, and the hospital has procured 1,000 copies of Pfizer's COVID-19 drug. "Now it is mainly used for patients who may develop severe diseases, such as tumors, diabetes, and physical obesity." Lu Hongzhou, president of the hospital, revealed that the drug has shown an effect, but it will take time to issue a systematic assessment.
For elderly, high-risk patients with underlying diseases, it is still a more economical option to use Paxlovid at an early stage to prevent it from developing severe disease. According to Chang Rongshan, gamma globulin, thymus peptide and other drugs that enhance human immunity are also more effective in the treatment of new crown pneumonia, but the total drug cost may be higher than the 2300-person Paxlovid. Among them, the human albumin is 650 yuan per stick, two sticks at a time, which needs to be used for a long time, and the total cost may be as high as tens of thousands of yuan.
The problem is that the replacement of other epidemic strains by Amikeron and the factor of universal vaccination have greatly reduced the proportion of patients who are likely to develop severe illness, and the use of Paxlovid has become less urgent.
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Lu Hongzhou once said in an interview with "Finance and Economics Great Health" that the symptoms of patients admitted to the hospital during the current round of local epidemic in Shenzhen were mainly concentrated in the upper respiratory tract and rarely violated the lungs. This is related to the characteristics of the Omiljun strain and the widespread vaccination of vaccines.
At present, the main epidemic strain in China is Omikerong, and 1.4 billion people have been vaccinated 3.2 billion doses.
Jiao Yahui, director of the Medical Administration Bureau of the National Health commission, introduced at the press conference of the joint prevention and control mechanism of the State Council held on March 19 that from the perspective of disease, mild and asymptomatic infected people are the mainstay, accounting for more than 95%.
In January, a paper published on the medical paper preprint website MedRxiv analyzed that between November 30, 2021 and January 1, 2022, about 80,000 people infected with the new crown virus were hospitalized in Southern California, and only 1,721 people were hospitalized. The study followed up 280,000 Omilon cases and 88 hospitalized patients, respectively, with less than half the hospitalization rate of delta case follow-up patients.
Even if hospitalized, patients with COVID-19 caused by Omi kerong may not need long-term medication. Data from the aforementioned study showed that the median length of hospital stay was about 1.5 days, which was 3.4 days less than the Delta case.
As of 24:00 on March 26, there were 27,567 confirmed cases nationwide, including 53 severe cases. "In this round of outbreaks caused by the Omiljun strain, some patients do not need such drugs. Because their symptoms are generally mild, even asymptomatic infected people. At present, these (COVID-19 oral) drugs are not cheap and are not necessary from an economic point of view. A staff member of a domestic hospital designated for the treatment of new crown pneumonia analyzed the "Financial Health".
The upside for Paxlovid is that there is currently a neutralizing antibody COVID-19 drug approved for the latest Protocol. This is a macromolecular injection, but it has not yet entered clinical use, "the production and supply preparations are still in progress." "This drug comes from Tengsheng Bo Pharmaceutical, whose related responsible shao, has no pricing and time plan to enter the clinic.
Pfizer's CEO had expected to produce 120 million paxlovids by the end of 2022, with sales totaling $63.48 billion. Pacific Securities noted in its report that if expectations are to materialize, Paxlovid will be the drug with the highest sales in history.
The opportunity for domestic drugs? Alleviate side effects or be a breakthrough
In Hong Kong, China, where the outbreak broke out, Pfizer's COVID-19 drug has been widely used since March 16. However, from the current feedback from local regulators and experts, Paxlovid is still far from Duffy.
At the beginning of paxlovid's listing, Hui Shuchang, Chair Professor of Respiratory System at the University of Chinese in Hong Kong and a member of the Government Expert Advisory Panel, introduced that its scope of application was mild patients within five days of onset. About a week later, the HaB changed the guidelines to the elderly over 60 years old, and those under 60 years old considered whether to give a prescription based on whether to be vaccinated or have high risk factors, thus greatly reducing the applicable patient base.
Chui Chun-ming, president of the Hong Kong Hospital Pharmacists Association, reminded that Pfizer's drug is "in conflict" with many drugs, such as a cholesterol-lowering drug, if taken with this drug, it may cause muscle pain or even rhabdomyolysis, which is an adverse reaction that may be life-threatening. In addition, the drug has nephrotoxicity, and it is not recommended for people with severe liver or renal insufficiency, "so you must be very careful when prescribing this drug."
The "Diagnosis and Treatment Plan" states that the instructions should be read in detail before use, and should not be combined with drugs such as piperidine and ranolazine that are highly dependent on CYP3A for clearance and whose plasma concentrations increase can lead to serious and / or life-threatening adverse reactions.
Paxlovid is a combination of two drugs, nematvir tablets i.e. 3CL protease inhibitors PF-07321332 and ritonavir (Ritonavir). Among them, 3CL protease is a key enzyme that inhibits viral replication. The above-mentioned new crown oral drug research and development enterprises introduced that ritonavir tablets themselves are anti-AIDS drugs, there are some liver damage or adverse reactions to nerve symptoms, which as a new crown drug has a problem is that it will soon be decomposed by enzymes in the body, in order to make the drug effect continue to play, so the joint use of ritonavir tablets can inhibit these enzymes. However, there are also some drugs that lower blood pressure and blood lipids that need to be metabolized by enzymes, so long-term use will accumulate toxic side effects.
Nucleoside analogues have cumulative toxicity to the liver, and The dose of Paxlovid is also large, "which also determines that it cannot be used for a long time, and each patient can only use one course of treatment for five days." Chang Rongshan believes that this drug cannot block the replication of the virus, but can only suppress it. If such drugs are used on a large scale, they may help to screen strains that are more likely to avoid drug attacks.
Tamiflu's safety performance is more reassuring than Paxlovid's, which became a "miracle drug" with annual sales of $3 billion during the 2009 H1N1 influenza pandemic. Public data show that although Tamiflu may cause side effects such as dizziness and vomiting, the incidence rate is only 1% different from that of placebo.
Paxlovid's domestic "follow-up" should try to eliminate the same problem as it, of course, it is also an opportunity to "overtake", "Some domestic companies are trying to avoid some side effects of combined drugs in the same technical route as Pfizer." The above-mentioned new crown oral drug research and development enterprises said.
How close are potential competitors?
In the face of many potential competitors, the popularity of vaccines, the reduction of patient symptoms and other status quo, Chinese pharmaceutical companies have to continue to develop new crown drugs, and must make adjustments.
"Now that there are many mild and asymptomatic patients in Aomi Kerong, it is a great challenge for enterprises to change the clinical indicators of severe disease and case fatality rate." The above-mentioned new crown oral drug research and development enterprises said that the company is also actively communicating with the State Food and Drug Administration (CDE) and striving to adjust the trial plan according to the new clinical situation.
At the end of 2021, Pioneering Pharmaceuticals announced the results of an interim analysis of a global multicenter phase III clinical trial of its new crown oral drug pkrutamine, which showed that it was "not statistically significant due to the small number of events". The trial began in March 2021 with mild and moderate COVID-19 patients, with the proportion of hospitalized patients within 28 days as the primary clinical endpoint. Pioneering Pharmaceuticals explained that the trial was enrolled in the whole population, and the popularity of vaccines and the hospitalization rate of NEW CROWN patients in the United States were extremely low, and they were also partially affected by the milder symptoms caused by Omi kerong.
In another clinical trial in China, Brazil and Southeast Asia, which also targeted mild and moderate diseases, pioneering pharmaceuticals raised the entry threshold and included high-risk patients; it also extended the trial endpoints to hospitalization rates, subjects requiring oxygen, and composite indicators of mortality, etc., "more abundant than the design of the previous single clinical endpoint." COVID-19 is a dynamically changing disease, so clinical trial design also needs to keep pace with the times. Tong Youzhi, founder of Pioneering Pharmaceuticals, introduced at the performance communication meeting that this update has been communicated with CDE and agreed.
Pioneering Pharmaceutical told Caijing Health that the above-mentioned trials, which had announced interim analysis at the end of 2021, will release the final analysis data in the near future. "It will tell us the results of the effectiveness of pkrutamine in the treatment of COVID-19, based on data on efficacy and safety, to advance the commercialization of the product." Tong Youzhi said.
Among domestic oral drugs, the fastest progress before this is Junshi Bio (688180. SH, 1877.HK), an oral nucleoside anti-SARS-CoV-2 drug VV116, developed in collaboration with Suzhou Wangshan Wangshui Biomedical Co., Ltd. (hereinafter referred to as "Wangshan Wangshui"), has been approved in Uzbekistan at the end of 2021 for the treatment of patients with moderate to severe COVID-19.
In the Chinese market, its phase III clinical trials of global multicentre have just recently started. On March 16, Junshi Bio announced that it initiated an international multicenter, randomized, double-blind, controlled Phase III clinical study for the treatment of moderate to severe COVID-19, with the primary endpoint being the percentage of participants who progressed to (critical) severe COVID-19 or all-cause deaths as of day 29. The study has completed the enrollment and administration of the first patient.
In addition, for mild and moderate covid-19 infection phase II/III global multiple center clinical research, has completed the first patient enrollment and administration in the Shanghai Public Health Clinical Center, Junshi Bio revealed to the "Finance and Economics Health" that the study is expected to enroll about 2,000 patients, the target patient recruitment targets in addition to China, will be mainly distributed overseas, surrounding areas such as East Asia, Eastern Europe, Southeast Asia, etc., other regions such as South America, North America.
The research and development progress of real organisms has attracted much attention from local governments. Pingdingshan Municipal Government official micro-release, on February 28, Zhang Leiming, secretary of the municipal party committee, mentioned at the meeting that the new drug "azifedine" developed by the real biological company will soon be listed as a special anti-new crown pneumonia drug.
However, Pfizer-verified 3CL is the most popular technical route for new crown drugs at present. Just on January 14, with drugs from Medner and other companies on the market, Genting ShinYao announced that it has obtained an exclusive global license for a group of 3CL protease inhibitors developed by the Singapore Centre for Experimental Drug Discovery (EDDC) to treat COVID-19.
Junshi also announced that he would join the "race" around 3CL. On January 26, the Wangshan Wangshui Cooperation was announced to participate in the competition for oral anti-COVID-19 drugs targeting 3CL proteases.
Simcere Pharmaceuticals also has R&D progress flowing online. However, the relevant person in charge of Simcere Pharmaceutical told Financial Health that it has not yet been approved for IND (New Drug Clinical Trial Application), but on March 25, the chairman of Simcere Pharmaceutical responded at the investor meeting on when to enter clinical research, "There will be results in the near future".
Chang Rongshan analysis, Paxlovid is currently the most effective target for the enzyme 3CL, and a synergist is also used in the drug design, and the drugs currently under research can not PK with it in this regard.
At present, the domestic new crown oral drug 3CL drugs are all in the pre-clinical stage, and the leader in the first half of the year may be able to enter the clinical trial stage. The above-mentioned new crown oral drug research and development enterprises expect that domestic 3CL inhibitors new crown oral drugs may be listed as soon as the end of 2023.
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