Behind the policy support, what trapped original drugs
Written by: Our reporter Chen Xi Planning: Lin Lijun and Teng Jipu
Produced by Deep Eye Studio
Original drugs address the needs of patients who do not yet have therapeutic drugs. They are truly new drugs with great clinical value. The patients in the country are the first beneficiaries.
Original medicine is the area where the biomedical industry brings the greatest value to patients.
Recently, two posters of the American Society of Clinical Oncology and a lecture report of the American Society of Neuro-Oncology have given Nankai University Professor Chen Yue a mixed blessing.
Fortunately, Chen Yue has devoted 11 years of painstaking efforts to the original drug ACT001, which has conducted 10 clinical trials around the world. The results are gratifying. Among them, the clinical trial for relapsed glioblastoma was treated with ACT001 monotherapy. One patient obtained long-term Complete remission, and single-drug therapy for children with diffuse endogenous pontine glioma has also observed very good curative effects, which indicates that ACT001 is one step closer to the successful launch of the drug.
The worry is that the upcoming national and global multi-center clinical trials will not only require more subsidiaries and businesses in developed countries around the world, but also require a lot of financial support. The company needs to go public as soon as possible to expand its international influence. , And also provide sufficient funding guarantee for global clinical trials.
The proportion of original drugs in the true sense in my country is still very low, most of which are generic drugs
In the eyes of many people, Chen Yue is a "great god"-level figure. His blockbuster came from the fact that in 2017, the ACT001 anti-glioma drug developed by his team was approved by the U.S. Food and Drug Administration (FDA) as a rare disease drug and became one of the few in my country. One of several medicines that have obtained this qualification.
Due to the small number of patients with rare diseases, low market demand, and high research and development costs, few pharmaceutical companies have paid attention to the development of this therapeutic drug before, so these drugs are vividly called "orphan drugs."
"There is currently no specific medicine for glioma. The incidence of this malignant tumor is less than 8 per 100,000, but the 5-year survival rate is only 5%. The malignancy is very high, especially for recurrent glioblastoma, with a median survival rate. The period is only 4-6 months." Professor Li Wenbin, director of the Neurotumor Comprehensive Ward of Beijing Tiantan Hospital, Capital Medical University, lamented, because it is difficult to break through the blood-brain barrier and the immune microenvironment of the brain is not the same as the tumor microenvironment of the body. , Brain tumors have become a "forbidden zone" for targeted drugs.
At present, temozolomide, the best drug for the treatment of glioma, can only prolong the survival period of patients by about two to three months.
Chen Yue broke into such a "forbidden zone" and also made original drugs.
During his Ph.D., Chen Yue did research on the total synthesis of anti-cancer natural products and medicinal chemistry. After graduating in 2003, he joined a company in the United States that specializes in the development of new drugs using natural drugs as templates.
His research team has successively developed a number of new drugs. One of the projects code-named KOS2187 was approved by the FDA to enter global clinical trials, and was eventually acquired by Pfizer for US$250 million.
Having been in the industry for a long time, Chen Yue is well versed in what it means for a country to develop original drugs.
"For patients, original drugs solve the needs of patients who do not yet have therapeutic drugs, real new drugs with great clinical value, and patients in the country are definitely the first beneficiaries." Chen Yue said, on the other hand, there is a good Medicine, patients still have to afford it.
Otherwise, like Gleevec in the movie "I am not the god of medicine", this "magic medicine" for the treatment of chronic myelogenous leukemia was first introduced to China in 2001. The price was 23,500 yuan a box, and a box was one month. Taking the dose will cost the patient 280,000 yuan a year.
As Brad Longka, founder of the biomedical investment fund Loncar Investments, said, original medicine is the area where the biomedical industry brings the greatest value to patients.
Making one's own original drugs also means that in the future, my country will have the right to set prices, and that good original drugs can be exported to the world and can earn foreign exchange for the country.
For example, Xiu Mei Le, known as the "Global Medicine King", has a yearly sales volume of 20 billion U.S. dollars.
Conversely, importing a large number of original foreign medicines will greatly increase the burden of my country's medical insurance, and there is also the risk of being "stuck" by foreign countries at any time.
Chen Yue's industry experience also coincides with the needs of the country.
Since the 18th National Congress of the Communist Party of China, General Secretary Xi Jinping has been concerned about the health of the masses of the people and the safety of medication. He emphasized: We must always put the health of the masses of people in the first place.
He pointed out: "We must closely monitor the shortage of medicines and take effective measures to solve the supply problems of low-priced medicines,'life-saving medicines','orphan medicines' and medicines for children."
In Chen Yue's mind, it can be called (FIC, original drug) if it has obvious novelty in the three aspects of mechanism, use, and structure, or at least the mechanism of action is different.
In addition to original drugs, there are drugs with expired foreign patents, which are generic drugs.
In my country, many so-called new drugs should basically be "micro-innovations" with minor revisions. They have the same mechanism targets, and their chemical structures break through the patents of original drugs.
At present, the proportion of genuine original drugs in China is still very low, most of which are generic drugs.
The reporter inquired about the data of Yaodu and learned that as of April 2021, excluding compound drugs, there are a total of 1,001 class 1 chemical drugs in China, including 990 NME (New Molecular Entities) and only 4 FIC (First-in-class) chemical drugs. There are 700 category 1 biological drugs in China, including 662 NME and only 2 FIC biological drugs (0.29%).
From ideas to original drugs, it’s not just courage
In 2008, I accidentally saw in the journal Nature that a compound called "parthenolide" can selectively kill cancer stem cells. Chen Yue wondered whether this compound could be chemically modified to develop a targeted cancer. Stem cell medicine?
Of course he also knows how difficult it is to turn a small idea into an original medicine.
The original drug has a long R&D cycle, huge investment, low success rate, and high risk. From small molecules in drug screening to lead compounds to preclinical research, the success rate is less than one-third, and from the clinical stage to the market, the success rate is Only about one tenth.
Moreover, in European and American countries, the cost of successful research and development of a drug often reaches more than one billion U.S. dollars.
Chen Yue is not brave enough to choose original medicine.
"The combination of capital and original medicines to help the transformation of their results is common in foreign countries. This is also one of the key factors for the United States to maintain the leading position of global pharmaceutical high-tech and high-profit new drug products." Chen Yue said, although my country's life sciences There has been great progress in basic research in the fields of medicine and pharmacy. The number of high-level papers exceeds that of most developed countries, but the output rate of original drugs is still far behind that of developed countries.
The reason is that the combination of achievements and capital is not strong enough, and scientific research and industry have two layers.
On the one hand, there is insufficient connection between investment institutions and universities and scientific research units. On the other hand, most scientific research institutions and universities are almost unable to carry out standardized preclinical research that consumes huge funds.
In order to better integrate with capital, Chen Yue established the company in a standardized manner at the beginning of research and development. Therefore, in addition to his status as a university professor, he is also the founder of Tianjin Suntech Pharmaceutical Technology Co., Ltd.
However, as soon as the team started research and development, it faced the common problem of biopharmaceutical enterprise entrepreneurship-the pre-clinical early financing dilemma.
"The content of parthenolide in the experimental raw material is less than 0.1% in the chrysanthemum, which is difficult to extract and the price is high. The cheapest company quoted as high as 182,000 US dollars per kilogram. According to the exchange rate at the time, the cost per kilogram exceeded 1 million yuan. Do the experiment I can't afford it, let alone pharmaceutical." Chen Yue recalled.
The first funding came from the support of relatives and friends. Through countless experiments, the team found that the root bark of the unique Chinese plant-Magnolia can be used to extract parthenolide instead of Hangju, at a cost of only RMB 5,000 per kilogram.
This discovery not only greatly reduced the international price of parthenolide, but its preparation technology is also ahead of the international level.
But no one believes that they can make a truly original medicine.
"Before ACT001 was approved for clinical trials, in addition to some government funding for scientific and technological projects, the probability of getting investment from investment institutions was very low. At that time, financing was difficult, so we could only mobilize friends and relatives around us to invest in our original innovative drugs. In the most difficult time, Chen Yue mortgaged the only house in his family." Hao Manlin, co-founder of Tianjin Suntech Pharmaceutical Co., Ltd., who is in charge of financing, said with emotion that original creation from 0 to 1 often requires great courage. Luck, foresight and perseverance, relatively few people understand and support at the beginning, and many people wait and see. This is the inherent, essence and value of originality.
"In the early days of our original drug development, the government's supporting guidance fund gave a lot of support. However, due to the limited special funds, before the animal experiment, the largest project fund we received was a national major special project "Enterprise Original Drug Incubation". The base construction' is 6,116,700 yuan, and most of the remaining projects are less than 500,000 yuan. For the original drug project, it is a drop in the bucket. For example, the project has invested 50 million yuan in the completion of the lead compound discovery stage." Hao Manlin said.
Faced with doubts and financial pressure, they can only tighten their belts and engage in research and development, and strive to make the basic scientific research system more solid.
Chen Yue's team started with the discovery of lead compounds, and then conducted standardized preclinical studies. Under strict experimental conditions, they verified the safety and effectiveness of candidate drugs again, and commissioned qualified companies to carry out a large number of GLP safety assessments.
"GLP safety assessment needs to be completed by a nationally qualified unit. This is a legal document and a whole set of means to ensure that the preclinical safety data is reliable and accurate." Chen Yue explained.
From 2008 to 2015, for 7 years, Chen Yue's team completed all pre-clinical development, successfully improved the chemical structure of parthenolide, and applied for dozens of patents, of which ACT001 is mainly used for clinical brain tumors. forward.
Next, the team also solved a series of problems such as the scale-up production, crystal form, preparation, and metabolites of the drug.
"Original drugs only have basic scientific research literature, scientists' assumptions, and some laboratory data in the preclinical stage. There is a contradiction between the uncertainty of risks and results and the certainty of return on capital requirements." For the early stage of biopharmaceutical companies In the financing dilemma, Cheng Jie, managing director of the medical and health industry group of CITIC Securities' investment banking department, has his own views.
"At present, China's capital market has begun to embrace original drugs, and entrepreneurs in the pharmaceutical industry must first have solid laboratory data, a scientific that can withstand scrutiny, and a rigorous academic attitude; secondly, entrepreneurs must have the mindset of running a business , Let professionals do professional work, and solve the problems such as equity structure that were often encountered in the financing of early original drug companies." Cheng Jie said, through the mature capital market, mature and professional investors are cultivated, and the government is rational and professional. It is believed that the guidance of the company will gradually improve the dilemma of early pre-clinical financing.
Original drugs were coldly received, why does capital prefer to "snap up hot spots"
In 2016, as Chen Yue and his research entered the clinical stage, investors around him gradually increased, and many large investment institutions began to pay attention to their original drugs.
"Many investment institutions have decision-makers with strong financial and financial backgrounds, but the high-tech attributes of original drugs place higher requirements on investors’ multidisciplinary backgrounds, so as to prevent investment institutions from making decisions on original drug projects. Simply apply rules and regulations for data analysis.” Chen Yue said, but in many cases, in the face of original drugs, especially in developed countries such as Europe and the United States, they will inevitably be classified as high-risk investments to avoid. field.
Therefore, it is sometimes difficult to gain the trust of investors.
Investment in the field of biomedicine is extremely professional. From generic drugs to biosimilar drugs to genuine original drugs, the requirements for investors are getting higher and higher.
"There are not many such professional investors in China now, most of them are ordinary investors, they do not have the professional knowledge of the biotechnology industry." Brad Longka said.
Compared with the cold reception received by Chen Yue's original drug project, many popular target drugs are favored by capital.
Domestic pharmaceutical companies are more concentrated on the research and development of target drugs such as EGFR, PD-1/PD-L1, HER2, CD19, and VEGFR2. Among them, 60 are EFGR research and development companies, 33 are HER2, and 155 are PD-1/PD-L (including Clinical stage and listing).
The development of drugs with the same target has resulted in a situation where only a few companies can meet the market demand, but dozens of companies are competing. The inherently limited clinical resources will result in a slower progress in enrolling patients with other anti-cancer drugs.
Among them, capital played a role in fueling the flames.
"Standing on the shoulders of giants is always easier to succeed." Cheng Jie believes that due to capital's aversion to risk and the level of basic scientific research in China still needs to be improved, for these investors, investing in some mature, already profitable Capable companies are more secure.
Domestic entrepreneurs are also more inclined to develop molecules with clear mechanisms and clear targets that can be made into drugs.
This behavior of copying other people's successful cases is more like "waiting for the rabbit", but it seems that the "rabbit" is not so easy to be picked up again.
Get together to invest in popular target pharmaceutical companies. In the end, many companies competed, and corporate profit margins fell. After the drugs were launched, problems occurred in recovering R&D costs, and the virtuous circle was difficult to continue.
The consequence is that areas that might have been “high value-added and profitable” have become serious value depressions with “over-investment and product homogeneity”.
If the development of new drugs is homogeneous competition, speed is the key. Pay attention to the two "3s", that is, 3 years. The time behind the first marketed drug is not more than 3 years. The top 3 varieties exceed this range, and the clinical value is greatly reduced. , Often less than 1/10 of the original drug.
The State Food and Drug Administration has repeatedly warned against homogenous competition, and the standard for listing on the Science and Technology Innovation Board in Article 5 has repeatedly emphasized innovation.
This seems not enough to arouse everyone's enthusiasm.
In fact, getting together in developed countries in Europe and the United States may have appeared, but at present there is rarely such a high proportion of homogeneous competition in China. Tuition fees are too high and the price is too high to calm people down.
How to solve the funding dilemma and make the development of original drugs more and more smooth
Although Chen Yue's 11-year path to original drugs has been accompanied by funding difficulties for most of the time, until it has improved in recent years, some institutions have strongly supported the development of original innovative drugs.
Especially in the past year, policies that favor original drugs have followed one after another, and the state has actively introduced policies to make life easier for companies focused on innovation.
For example, through Hong Kong 18A (in accordance with Chapter 18A of the Main Board Listing Rules of the Hong Kong Stock Exchange) and the fifth set of listing standards on the Science and Technology Innovation Board, China has opened a channel for unprofitable original drug companies to list and supports the development of original drug companies with core technologies. , Especially the science and technology innovation board, with special emphasis on technological innovation.
At the same time, governments at all levels in our country have also set up a large number of investment institutions, one of their key investment directions is biomedicine.
Chen Yue believes: "These policies are of great importance to improving the transformation rate of my country's new drug achievements, promoting the introduction of my country's high-tech new drug products, thereby driving the development of my country's GDP, further satisfying the availability of medication, and improving the level of life and health protection for the whole people. significance."
"After 2015, various industry policies began to substantively point to supporting original drugs, and at the same time, in conjunction with the capital market reforms in 2018 and 2019, the capital and entrepreneurial scientists who invested in original drugs in the early stage have benefited, and the securitization process has accelerated, The shortening of the investment withdrawal cycle and the wealth effect have attracted more capital into this field." Cheng Jie said.
"The country’s policy to encourage innovation is very good. It has learned and absorbed the experience of developed countries in a short period of time, and has quickly matched the management level of developed countries. The original intention of encouraging innovation is actually understood by everyone, but it is really good. Courage, there are not many investment institutions devoted to research and excavation. When Chinese original drugs need sunshine and rain the most, they are often ignored. There are many interested institutions, and there are not many institutions that really sell." Chen Yue sighed.
Some people say that this kind of behavior is a bit like "Ye Gong is a good dragon." When it comes to the "real dragon" of original drugs, investment institutions often start hiding, then you look at me, I look at you, and wait for whoever takes the first shot, and then swarms. grab.
This has caused a waste of capital and an unbalanced distribution.
According to statistics from Yaodu, there are currently 30 biotech companies listed after the introduction of 18A in the Hong Kong Stock Listing Rules.
There are 31 companies in the biomedical sector listed on the Science and Technology Innovation Board (excluding medical device and in vitro diagnostic companies), but unfortunately few companies have successfully listed FIC or best-in-class drugs.
Hao Manlin suggested that the guidance of government policies should encourage and identify genuine innovations from the source.
In order to help investment institutions better identify the truly valuable innovations, they can try to classify the original drugs on the Chinese market.
"The grading of original drugs is more common in foreign drug management. Based on China's current national conditions, the clinical value, economic value and social value of the original drug grading model can be considered."
"At the same time, government funds take the lead to increase risk tolerance. For example, investment institutions that try to participate in government funds must invest in original innovative drugs at a quantitative index such as 50% of the funds invested in the pharmaceutical field." Hao Manlin said.
In addition, it is necessary to strengthen the scientific and professional decision-making mechanism of investment institutions.
"Investment institutions involving government industry funds must establish a scientific advisory committee composed of personnel with original innovative drug research and development experience to strictly check investment projects and focus on valuable projects for investment." Hao Manlin suggested that a full-time chief scientist should be established , To be scientifically qualitative, financial and risk control quantitative.
Cheng Jie believes that as long as the capital has a smooth exit method and reasonable returns, there will be more capital willing to invest in original drugs.
The original innovative drug can meet the unmet clinical needs, and it will certainly have a very good market prospect.