Produced by |Tiger Sniff Medical Group.
Author |Chen Guangjing.
Edit |Wang Yipeng.
Header |Visual China.
This winter, oseltamivir, known as the "miracle drug" of influenza, has frequently appeared on the hot search.
The most recent time is that there is *** This medicine only sells for more than 20 yuan in the hospital for a box, and it sells for 320 yuan in the pharmacy;Online shopping** is also nearly 3 times higher than in hospitals.
As one of the few drugs that can fight the virus, oseltamivir has been popular for decades, and it is sold out of stock almost every year during the flu season, and it is difficult to find a drug.
Roche, a multinational pharmaceutical company, once made a lot of money around the world with this drug. In the local enterprise East Sunshine Changjiang Pharmaceutical, it once obtained more than 90% of the market share of the drug in China and became the "king of influenza drugs" of a generation. In the past three years, due to the impact of the new coronavirus epidemic, the epidemic of influenza has been suppressed, and anti-influenza virus drugs have been seriously unsalable. Data shows that by 2021, oseltamivir sales were less than one-tenth of their peak.
It wasn't until last year that East Sunshine Changjiang Pharmaceutical's oseltamivir sales began**. By the first half of this year, sales rose by 186 year-on-year4%。So, at the end of this year, can the glory of the former "king of flu medicine" be repeated?Oseltamivir, is it still worth hoarding?
The "miracle drug" of influenza is not guaranteed.
Judging from the current sales situation, the "king of flu medicine" is returning to the market. However, it seems impossible to return to the throne again.
Judging from the e-commerce data, the perennial coaxed "Kewei" (the trade name of oseltamivir produced by East Sunshine Changjiang Pharmaceutical) has reached a total of 210,000 pieces in the past two weeksRoche's "Tamiflu" (the original drug of oseltamivir) sold 50,000 pieces;Lian Yiling Pharmaceutical's Lianhua Qingwen has also sold 20,000 pieces in the past month.
But behind the hot sales, a new product is increasingly appearing in people's field of vision, this drug is mabaloxavir tablets (developed by the Japanese pharmaceutical company Shionogi, trade name: Sufuda, sold by Roche**). Also according to e-commerce data, this one costs more than 200 yuan, only 2 capsules per box, and 100,000 pieces are sold within 15 days, resulting in it often being in a state of "out of stock", and some merchants even mention ** to more than 330 yuan.
In the hospital, the main battlefield of "Kewei", there are also more and more patients, and after being diagnosed with influenza, they have obtained a prescription with mabaloxavir written on it. There are also patients who go to hospitals far away from their homes to prescribe this medicine.
Although the evaluation of mabaloxavir is mixed, after the spread and fermentation of the Internet, the signs of the rise of the "new king" of influenza seem to have appeared. This is really not good news for East Sunshine Changjiang Pharmaceutical.
Human drug development in the field of viral infections has not progressed well for a long time, with the exception of influenza. Tamiflu (the original drug of oseltamivir), which was approved in 1999, is one of them, and its sales reached $2.7 billion in the year it was launched, making it a blockbuster drug in one fell swoop.
Although after the global outbreak of avian influenza in 2005, Roche was forced by humanitarian pressure to conditionally release the oseltamivir patent, which had not yet expired the protection period at that time, it was still very profitable - in 2009, during the H1N1 epidemic, the drug sold $3 billion worldwide.
In China, in order to protect the use of drugs and avoid compulsory patent licensing, Roche has successively licensed the patents of oseltamivir to Shanghai Zhongxi Sanwei Pharmaceutical Co., Ltd., a subsidiary of Shanghai Pharmaceutical, and East Sunshine Pharmaceutical, a subsidiary of East Sunshine, which is today's East Sunshine Changjiang Pharmaceutical.
In the later competition, Kewei of East Sunshine Changjiang Pharmaceutical gradually stood out, and by the peak of 2019, it had become a large variety with annual sales of nearly 6 billion yuan, accounting for more than 90% of the market share of oseltamivir in China. East Sunshine Changjiang Pharmaceutical Co., Ltd. is also known as the "King of Influenza Medicine".
Unfortunately, the good times were short-lived. From the perspective of sales performance, after reaching its peak in 2019, due to the decline in sales of the core product "Kewei" due to the epidemic, East Sunshine Changjiang Pharmaceutical has experienced extreme changes in rapid decline and rapid development in just three years.
In 2020, the operating income of East Sunshine Changjiang Pharmaceutical Co., Ltd. was 234.8 billion yuan, down more than 60% year-on-year;In 2021, the operating income was 9100 million yuan, a drop of more than 60%, of which the income of oseltamivir is only 5500 million yuan. Since then, East Sunshine Pharmaceutical has not only changed its name to East Sunshine Changjiang Pharmaceutical, but the parent company East Sunshine has also thrown off this "burden" with a single operation and put it at 37The 2.3 billion yuan ** was sold to Guangdong East Sunshine Pharmaceutical and its Hong Kong subsidiary.
Since last year, Kewei's sales have bottomed out**. In the first half of 2022, although only 12The operating income of 9.3 billion yuan, but affected by the high incidence of influenza A in the second half of the year, the people frantically hoarded medicines, helping East Sunshine Changjiang Pharmaceutical to achieve an annual revenue of 374.5 billion yuan, nearly two-thirds of the peak. In the first half of 2023, East Sunshine Changjiang Pharmaceutical Co., Ltd. continued this momentum, with revenue of more than 3.2 billion yuan in the first half of the year, and has the momentum to return to the camp of "annual sales of 6 billion". Of these revenues, Kewei contributes nearly 90%.
At this point, the situation seems to be very good, and the "Kewei" distance is back to the peak, and it is just around the corner. But in fact, what awaits "Kewei" and its sales company is the flu medicine that has changed dramatically.
Data from: the company's annual report, Huachuang** Tiger Sniff Charting.
The flu medicine market has changed.
2021 is a turning point for the influenza virus drug market, and it is also a year for East Sunshine Changjiang Pharmaceutical and "Kewei".
In fact, in the past ten years, oseltamivir has been able to run wild in China, with annual sales from 10 million yuan to the peak of nearly 6 billion yuan, for a very important reason:After Roche made a name for oseltamivir in the prevention and treatment of influenza, oseltamivir had almost no rivals for a long time.
It can be seen from the official diagnosis and treatment guidelines that until 2020, oseltamivir faced mainly neuraminidase inhibitors such as zanamivir, hemagglutinin inhibitors such as arbidol and M2 ion channel blockers such as amantadine. These drugs cannot compete with oseltamivir in terms of principle, actual effect, and convenience of medication.
The first two oseltamivir models, including East Sunshine Changjiang Pharmaceutical's "Kewei" and Shanghai Pharmaceutical's "Orphie", were "exceptional" authorized to be listed before Roche's "Tamiflu" patent expired, occupying the leading and exclusive advantages in the market.
Originally, Shanghai Pharmaceutical was authorized earlier, but except for the peak of the epidemic, the market size of oseltamivir was not large, and Shanghai Pharmaceutical, which had a lot of approvals in hand, did not pay attention to this aspect, and its production capacity was limited, so it simply stopped production in 2016Roche has also reduced**. This has achieved the situation of the "Kewei" family dominance.
But that all changed in 2021.
In terms of generic drugs, the patent protection period of "Tamiflu" expired in 2016, and many Chinese pharmaceutical companies began to deploy this variety. Finally, on July 30, 2021, Borui Pharmaceutical's oseltamivir phosphate capsules were approved. Since then, a number of dry suspensions, capsules, and granules have been approved.
According to the database of the State Food and Drug Administration, a total of 50 pieces of information can be obtained by searching for "oseltamivir", of which there are 31 kinds of oseltamivir capsules alone. So far, oseltamivir generic drugs have become a "red ocean".
In the seventh batch of centralized procurement opened on July 13, 2022, a total of 10 oseltamivir capsules, including "Kewei", won the bid. The 75mg specification of "Kewei" was directly reduced to 0999 yuan, becoming the lowest price in the same kind of products. This is also the reason why the hospital can prescribe oseltamivir as low as more than 20 yuan.
"The bigger crisis also comes from the new drug for the flu." Also in 2021, mabaloxavir, known as "Super Tamiflu", officially entered the Chinese market four years after its first approval.
According to the "Consensus of Emergency Experts on Epidemic Diagnosis and Treatment Standards (2022)" jointly drafted by the Emergency Physician Branch of the Chinese Medical Doctor Association, the Emergency Medicine Branch of the Chinese Medical Association and other institutions, m2 ion channel blockers such as amantadine have been out, replaced by mabaloxavir, favipiravir, etcRNA polymerase inhibitors
The figure shows the replication process of the main influenza virus and the target of the drug. The life cycle of influenza virus mainly includes five processes: adsorption, entry, replication, assembly, and release. RNA polymerase inhibitors mainly prevent viral replication;Neuraminidase inhibitors mainly block the release of the virus.
From: Chinese Medical Journal
Mabaloxavir is the world's first drug that is effective against the 5-cap structure (CAP)-dependent endonuclease of influenza virus. To put it simply, it is to destroy the virus in the process of self-replication by inhibiting the endonuclease. In contrast, oseltamivir, a neuraminidase inhibitor, blocks the spread of viral replication after replicationRNA polymerase inhibitors work more early and theoretically take less time to control the virus.
This is also evidenced by the trial data. The results of the phase III clinical trial published in 2017 showed that the drug could be used in 24The fever was resolved after 5 hours, which was about 42 hours shorter than the control group5 hours. Hence the title of "Super Duffy".
Based on the data from the studies listed in the above consensus, mabaloxavir also showed a stronger advantage in reducing transmission among family members.
The price of mabaloxavir is high, and a box of two tablets can be as high as more than 350 yuan, however, it is used in a smaller amount, weighing less than 80kg, and only needs to take two tablets (20mg) at a time, and it is currently the only oral anti-influenza virus drug administered in a single dose.
When it was launched in the United States in 2020, Roche and Shionogi had already claimed that the drug could work against oseltamivir-resistant virus strains and avian influenza strains.
Although experts emphasize that the existing influenza drugs have high sensitivity to the currently circulating influenza A and B viruses and have good safety, for the "miracle drug" of influenza oseltamivir, the pressure of product iteration brought by latecomers should not be underestimated.
According to Evaluate Pharma**, by 2024, oseltamivir and mabaloxavir will be the two products with the highest market share, while the share of oseltamivir will decrease, and the market share of mabaloxavir will increase, and the gap between the two will be further narrowed.
For local companies interested in competing for the domestic market for influenza antivirals, an even worse problem is that RNA polymerase inhibitors are also rolling up. Only similar to mabaloxavir, there are 8 pipelines under development for endonucleaseThere are 5 that act on the "replicase". The product of local company Zhongsheng Pharmaceutical has entered phase 3 clinical trials, and positive results were released just in July this year.
At the beginning of this year, the generic drug of mabaloxavir developed by CSPC Pharmaceutical Group has been approved for marketing. However, because the patent of mabaloxavir will not expire until 2031, this generic drug has not really been produced and sold.
In addition, there are a large number of drugs targeting other targets of influenza viruses such as neuraminidase, hemagglutinin, and nucleoprotein, which are under development or have been marketed. It can be said that now is just the beginning, and in the future, the market competition around anti-influenza virus drugs will be more intense.
Is this medicine still stockpiled this year?
Today, in the face of influenza viruses, human beings have many means to fight it. However, it should be noted that neither oseltamivir nor mabaloxavir should be over-deified.
Judging by the data, the seasonal epidemic of influenza has only just begun.
Virology expert Chang Rongshan told Tiger Sniff that the peak of the flu epidemic has not yet arrived. He pointed out that the pattern of influenza epidemics in China is very similar to that of the United States, which is also in the northern hemisphere, which is mainly closely related to the close international travel and the fact that few people wear masks during travel.
Combined with the weekly analysis chart of influenza-like illness released by the US Centers for Disease Control and Prevention (CDC), Chang Rongshan told Tiger Sniff that since week 45, the proportion of its flu-like case reports has exceeded the baseline of 3%, which marks the beginning of a seasonal epidemic, and the trend is similar to that of the seasonal epidemic from 2022 to 2023 - 13 weeks in this year are above the baseline. Changrongshan expects this year's seasonal high incidence to continue for more than 10 weeks.
Trend chart of the influenza epidemic in the United States since 2018. This year's incidence is also higher than most historical periods.
From: CDC official website.
And the starting point of this influenza epidemic in China is very high.
In the latest weekly influenza surveillance report for week 48 (27 November to 3 December), 86%, which is higher than the level of a week ago and also higher than the same period from 2020 to 2022. 7% and 31%）；The northern region reported 74%, much higher than the same period from 2020 to 2022. 0%）。
This situation is a great challenge to the elderly and children in China. As early as October, experts from the Chinese Center for Disease Control and Prevention were already writing about the issue of influenza based on surveillance of the flu from July to August.
In the article "Risk Assessment of Public Health Emergencies of Concern in China in October 2023", the authors analyzed and judged that there will be a peak of the epidemic in autumn and winter, and the epidemic intensity is seasonal, and suggests that there may be a certain degree of medical diagnosis and treatment pressure during the epidemic, and the occurrence of severe cases and deaths cannot be ruled out.
In this regard, the author of the above article suggestsLocal centers for disease control and prevention and medical institutions should make preparations for response, and guide elderly care institutions to do a good job in prevention and controlEncourage key groups to get vaccinated against influenza, including: medical personnel, the elderly, people with chronic diseases, pregnant women, primary school students, etc；We will continue to intensify health promotion, raise public awareness of protection and health literacy, give full play to the role of non-drug interventions, and prevent multiple diseases.
During the previous epidemic of a variety of pathogens, Chang Rongshan once told Tiger Sniff that influenza was the main cause of respiratory infections this winter. This disease is preventable and controllable, and it should be taken care of.
And for the "rainy day" of influenza, stockpiling medicine should not be a lifesaver.
First of all, the lethality of these drugs against the virus is limited, and they must be taken within 48 hours to fully exert their effects.
Second, the problem of drug resistance has been a dark cloud over antivirals.
According to Jiang Yuanmin, Zhang Jiwei and others from the Institute of Chemistry, School of Pharmacy, Shandong University, the inherent high variability of influenza viruses and the pressure of drug selection can easily lead to antiviral drug resistance.
In the past few decades, when antiviral drugs targeting NA (tiger sniff note: i.e., neuraminidase) have been the mainstream of drug use, if a strain is widely circulated, new drug resistance problems are likely to emerge. For example, the 2009 pandemic of the A(H1N1)PDM09 subtype resulted in resistance to oseltamivir to this strain.
The aforementioned m2 ion channel blockers, such as amantadine, were also regarded as "miracle medicines" for influenza in the 1960s, but after more than 40 years of use, by 2009, the resistance rate to some influenza strains had reached more than 90%.
According to the information released by the National Influenza Center, since April 3, 2023, drug resistance surveillance has found that except for 4 strains of influenza A(H1N1)PDM09 subtype A(H1N1)PDM09 that are less sensitive to neuraminidase inhibitors, the rest of the A(H1N1)PDM09 subtype influenza strains are sensitive to neuraminidase inhibitors. All circulating strains of A(H3N2) and B are susceptible to neuraminidase inhibitors.
In this year's etiological surveillance, the A(H3N2) subtype dominated. This means,Oseltamivir is still effective in most people with the flu. However, in the case of heavy use of neuraminidase, the risk of virus mutation remains, which is why the relevant authorities have been monitoring the situation of neuraminidase mutation and the resistance of influenza virus strains.
Resistance to polymerase inhibitors has not yet emerged. According to the National Influenza Centre, all circulating strains of A(H1N1)PDM09, A(H3N2) and B are susceptible to these drugs. With the widespread use of the drug, the emergence of drug resistance is also a cause for concern.
Many provinces and cities in China have started free flu vaccinations for people over the age of 65.
From: Visual China.
In addition, it is important to note that all drugs will have *** With the heavy use of antiviral drugs, ** is also becoming clearer. "I had a headache that I couldn't sleep. "A flu patient who used oseltamivir told Tiger Sniff that the pain lasted for three days.
According to the article written by Pan Xiaoyan and Ling Feng of the First Affiliated Hospital of Guangxi University of Science and Technology, the common problems of oseltamivir include nausea, vomiting, diarrhea, and abdominal pain in the digestive systemHallucinations of the nervous system, gibberish, insomnia, etc.;as well as allergies, bullae, dermatitis;Wait a minute.
The authors point out that oseltamivir, as a first-line drug for influenza, has reliable efficacy, but due to possible problems with the use of the drug, and it is common in adolescents, thereforeIt is recommended to reduce the probability of irrational use of oseltamivir
Of particular note, the authors mention that oseltamivir can be used as a prophylaxis against influenza but is not preferred, "The most effective way to prevent influenza is to get a flu vaccine in a timely manner". And that's what it's easy to overlook.
In other words, instead of hoarding and abusing drugs, it is better to get vaccinated as soon as possible. This can even be said to be a lifesaver for the elderly with underlying diseases.
What's more, China's new drug R&D capabilities have been greatly improved, and the chances of a drug monopolizing the market are minimal. For the public, who have gone through several rounds of hoarding medicines, the rumors have actually gradually dissipated.
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