Image source @ Visual China
Wen | city boundaries, the author | Zeng Jiayi, Editor | Liao Ying
In 2001, an anti-cancer miracle drug came out, which not only opened the history of human targeted anti-cancer drugs, but also became the starting point for three Young Chinese people to start a business. This miracle drug was later successfully released by the movie "I am not a medicine god", which is the "Gleevec" (imatinib mesylate) developed by pharmaceutical giant Novartis.
The listing of Gleevec has been called a turning point in the history of cancer drug research and development.
At that time, Wang Yinxiang was doing postdoctoral work at Yale University in the United States, and his research topic was just related to this. At a party that year, Wang Yinxiang met Zhang Xiaodong, a ph.D. in chemistry at the University of Maryland, and discussed the possibility of developing an anti-cancer drug targeting epidermal growth factor receptor (EGFR) kinase, which is the technical route they have continued ever since.
Discussing starting a business together, Wang Yinxiang pulled his doctoral classmate Ding Lieming in the United States, and in 2003, the "Three Musketeers of Beida" Wang Yinxiang, Zhang Xiaodong, and Ding Lieming, the founded Beida Pharmaceutical was officially born.
After 8 years of hard work, Beida Pharmaceutical finally succeeded in creating its core product in 2011 - the first small molecule targeted anti-lung cancer drug "Exetinib" (trade name: Kemena), and China has its own Gleevec.
Yu Minhong once said that the relationship between the real "Chinese partners" is far more complicated than in the movie, and the relationship between the "Three Musketeers" of Beida Pharmaceutical is even more complicated.
01, behind the anti-cancer miracle drug
In 2020, the revenue contribution of exetinib was 1.813 billion yuan, accounting for 96.9%. But after it entered the collection, it has been marked as a "cabbage price", and it also faces fierce competition from pharmaceutical companies such as AstraZeneca and Chia Tai Tianqing.
It is worth noting that in the just-issued 2021 financial report, Beida Pharmaceutical did not announce the annual sales figures of exetinib as always, only mentioning that its sales exceeded 1 billion yuan for 6 consecutive years.
The star products of the past have gradually "faded", how did Beda Pharmaceutical and its exetinib step by step come to today?
Unlike Microchip Bio's Lu Xianping, who held high to be a "First-in-class first-class" from the beginning, Beida Pharmaceutical started with me too (tracking imitation) drugs.
Specifically, generic drugs are completely copied from others, and me too is to innovate on the results of other people's research, avoiding the patents of others to develop new drugs with the same effect, even in the patent period does not need to be authorized. This is a way to research domestic new drugs, and it is also a shortcut to imitation (Fast follow)-up to innovation (First-in-class).
Fast follow includes me too, me better/best in class, and more. In addition to Beta Pharmaceutical's extinib, such as Hengrui Pharmaceutical's Apatinib and Junshi Bio's PD-1 monoclonal antibody drug, are also me-too is known as a typical benchmark for domestic innovation.
In 2003, Beida Pharmaceutical was born in Zhejiang.
When Beida Pharmaceutical was founded, Zhang Xiaodong became one of the founding shareholders of Beta Pharma Inc. (Beta Pharma Inc.), an Innovative Pharmaceutical Company registered in the United States, with the patented synthesis technology of EGFR tyrosine kinase. Unexpectedly, there is a big hidden danger left here, which we will mention in detail later.
Wang Yinxiang and Ding Lieming had similar experiences. Born in 1962, Ding Lieming is three years older than Wang Yinxiang, both of them had worked in the local health and epidemic prevention station before entering the university, and then Ding Lieming was admitted to Zhejiang University, and Wang Yinxiang entered the Hebei Staff Medical College (now Hebei University Medical College), and after completing the master's degree in China, the two intersected during their doctoral studies at the University of Arkansas Medical College in the early 1990s.
During his doctoral studies in the United States, compared with Ding Lieming's clinical medical doctorate in the department of pathology, Wang Yinxiang's scientist temperament was more prominent, and he studied a doctorate in biochemistry and molecular biology, and then entered the Department of Molecular Biophysics and Biochemistry of Yale University for postdoctoral studies.
After nearly 10 years, in 2011, the drug ektinib hydrochloride developed by Beida Pharmaceutical for the treatment of lung cancer was approved for listing by the State Food and Drug Administration, and Kemena became the first small molecule targeted anti-cancer innovative drug with completely independent intellectual property rights in China, and it was called "the first original small molecule targeted anti-tumor drug in China" by the international medical journal "The Lancet", "opening a new era of anti-tumor drug research and development in China, which is a very successful and perfect innovation case".
But as the pioneers of China's first generation of "me too", Ding Lieming, Zhang Xiaodong and Wang Yinxiang did not continue the myth of Exetinib.
02, falling apart to breaking up
A pharmaceutical investor said: "Beta Pharmaceutical's exetinib is a product of a specific historical period, not an original drug in the true sense from the mechanism to the target to the molecular structure, but the benchmarking drug AstraZeneca's small molecule-targeted drug gefitinib (Iressa)." ”
Exetinib is primarily used in the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer with sensitive mutations in the epidermal growth factor receptor (EGFR) gene. The incidence and mortality of lung cancer ranks first among malignant tumors in mainland China. Data show that in 2020, more than 820,000 people in China had new lung cancer, and more than 710,000 people died of lung cancer.
Compared with the traditional chemotherapy for malignant tumors, which is good or bad, drug targeted therapy is mainly aimed at a target or several targets in malignant tumor cells for targeted attack, so as to achieve the effect of accurately inhibiting the proliferation of tumor cells.
Before exetinib, the domestic lung cancer targeted drug market was dominated by foreign pharmaceutical giants. Like most anti-cancer drugs, imported drugs are very expensive, such as taking gefitinib, the cost of a month is about 16,000 yuan, and after the listing of Exetinib in Beida Pharmaceutical, the monthly treatment cost can be reduced by about 1/3.
Not only that, behind the highly sought after by capital in Beida Pharmaceutical, it is still from exetinib. Since exetinib was approved for listing in 2011, its revenue has achieved "rocket-like" growth, and in 2016, it achieved revenue of more than 1 billion yuan for the first time, becoming one of the few star anti-cancer drug products with sales of more than 1 billion yuan in China, and its cumulative sales have exceeded 10 billion yuan.
However, under the scenery of great success in capital markets and commercialization, Beida Pharmaceutical has ushered in an important turning point. Just nine months after the company's listing, on August 17, 2017, Wang Yinxiang, who is also the founder, resigned as a director and president of the company for personal reasons.
Not only that, in 2017, Wang Yinxiang left with director Du Ying and vice president and financial director Xu Sulan, chief scientist Hu Shaojing, chief medical officer Tian Fengfen, supervisor Hu Yunyan and seven others. Some of these people chose to start a business with Wang Yinxiang.
It turned out that as early as 2015, Wang Yinxiang founded an innovative pharmaceutical company focusing on "First-in-class" - Jiakesi. In Wang Yinxiang's view, "innovative drugs are very difficult, but China's time node has arrived, and it is necessary to do global innovative drugs." ”
2015 is not only the year to open the medical reform, but also the node for capital to enter. This year, BeiGene, Junshi Biological, Hengrui Pharmaceutical, and Cinda Biologics have successively gained capital pursuit, and China's innovative drugs have entered a new stage.
At that time, Beida Pharmaceutical still chose to do "me-too", so after exetinib was its self-developed product, other products relied on "buying, buying and buying".
If Ding Lieming and Wang Yinxiang are just ideologically incompatible, then what is involved with Zhang Xiaodong is the interests of real money and silver.
In April 2016, Belda received clinical approval for the third-generation EGFR drug BPI-7711, which can be regarded as an upgraded version of exetinib. This has attracted the attention of Beida Pharmaceuticals.
Because there is no conclusion in the case of Beida Pharmaceutical suing Beida for "breach of trust", Beida withdrew the lawsuit in 2021.
Beida Pharmaceutical, which originally held high the "leading small molecule targeted drugs in China", failed to make further efforts after the founders fell apart, but also let it grasp the advantages of a generation of EGFR. In the domestic market today, AstraZeneca, Hexion Pharmaceutical and Ellis have three generations of EGFR products on the market.
But for Betta Pharmaceuticals, what is invisible is the real risk.
03. Drop the first echelon
Especially in the face of the expiration of the patent for the core drug ektinib in 2023, it has made it worse for Beida Pharmaceutical, which has already experienced a decline in performance.
As a pharmaceutical investor said: "Beida Pharmaceutical started early and rushed to a late set, and now it has long been far away from the first echelon of innovation ability." ”
In the view of this investor, Beida Pharmaceutical only relies on the words of exetinib + ensartinib at present, in fact, there is not much room for imagination, and there will be growth but it will not explode.
According to the market data of Frost & Sullivan, in 2018, the market share of the third generation of China's EGFR-TKI drug market has reached 38%, the market share of the first generation of drugs is 57%, and the market share of the second generation of drugs is only 5%.
After the collection in 2019, the product prices of AstraZeneca, Chia Tai Tianqing and Qilu Pharmaceutical have dropped to 54.7 yuan / piece, 45 yuan / tablet and 25.7 yuan / piece respectively, while The extinib of Beida Pharmaceutical is 64 yuan / piece.
Jicai can be said to be the "touchstone" of a pharmaceutical company's innovation, but for Beida Pharmaceutical, the innovation of its follow-up products is the magic weapon to ensure that it does not fall behind.
Ensartinib (trade name: Bemena), a new domestic class 1 drug for the treatment of advanced non-small cell lung cancer with ALK mutations, is the product originally obtained by Beida Pharmaceutical through holding Xcovery; its similar competitors are roche and Pfizer and Novartis.
Bevacizumab injection (trade name: Be'andantine), which was approved for listing in 2021, was developed by Beda Pharmaceutical in cooperation with Beijing Tianguangshi Biotechnology Co., Ltd. With the expiration of Roche's original drug patent, there are more and more biosimilars of bevacizumab, and bevacizumab biosimilars of 8 companies in China, including Hengrui Pharmaceutical and Innovent Biologics, have been approved for listing.
That is to say, it is not easy for these two products to create the glory of exetinib, and it is necessary to know that extinib was born in the context of a blank space of domestic innovative drugs, and its initial market space and the imagination given by the capital market can be imagined.
If it is successfully listed in Hong Kong stocks, Beida Pharmaceutical will have sufficient funds to do research and development, but from the perspective of the company's talent innovation, since Mao Li, who became the chief medical officer in 2021, this position has been vacant for more than a year. As the company's "soul figure" Ding Lieming, he is not like Wang Yinxiang who is a medical research background.
In the field of pharmaceutical innovation, the gathering and dispersion of scientific research talents is not a new thing, and there are many "pharmaceutical masters" who can create a biopharmaceutical listed company after leaving, such as Fang Jianmin of Rongchang Biology, Yu Dechao of Cinda Biology, Du Ying of Zaiding Pharmaceutical, and Chen Bo of Junshi Biology. Their departure has a great impact on the original company.
As one pharmaceutical investor put it: "The requirements for 'vision' or judgment in the me-too era are very low, which is not the same as the requirements for real innovation today." ”
For Beida Pharmaceutical, which has experienced the disintegration of the "Three Musketeers" and the loss of core talents, it is even more painful in this regard, and it is more urgent to need fresh blood.