Entering The Global Market: Chinese Biomedical Enterprises Are Facing The Challenge Of Innovation

? ? ? Not long ago, ryzneuta ?（ F-627) for the treatment of chemotherapy-induced neutropenia (CIN) was officially accepted by the U.S. Food and Drug Administration (FDA). This means that Yiyi biological innovative medicine has stepped further. It is reported that Yiyi biological is also the first Chinese biopharmaceutical company in China that has completed the global phase I to III clinical trials completely relying on its own team, and has submitted the bla (biological product license application) to the US FDA as the main body of application, and has been officially accepted.

? ? ? In addition to Yiyi bio, many pharmaceutical companies have also targeted the clinical practice in the United States. For example, recently, the indication for CIN of Wanchun biological punabilin has been given priority review by FDA; Prior to this, Junshi bio has also submitted to FDA a rolling BLA for the treatment of recurrent or metastatic nasopharyngeal carcinoma (NPC). With the development of China's biomedical industry in recent years, many domestic innovative enterprises are actively planning the overseas market, starting from the clinical application to go out to sea in various forms. Before that, Baiji Shenzhou authorized Novartis PD-1 part of the overseas market rights and interests, and gakos's products in research were authorized to Aberdeen, etc. According to the statistics of China Bio, a consulting agency, in 2020, there will be 271 cross-border transactions between Chinese pharmaceutical enterprises and overseas pharmaceutical enterprises, an increase of 300% compared with 2015.

? ? According to Liu Jubo, chief executive officer of Yiyi bio, it is "natural for Chinese Biomedical enterprises to go out to sea. On the one hand, the biomedical industry has achieved a certain stage of development; on the other hand, pharmaceutical enterprises need to explore a broader market.

According to some data, China's prescription drug market will be about 1.2 trillion yuan in 2020, while the global market will be more than 900 billion US dollars (about 5.85 trillion yuan). China's prescription drug market will occupy a relatively low proportion in the global market. In addition, Roche's annual sales of prescription drugs exceed 300 billion yuan, while the leading pharmaceutical companies in A-share market have an annual sales of more than 20 billion yuan, less than 1 / 10 of Roche's. The difference in sales scale comes from overseas markets.

A board chairman of a listed pharmaceutical company pointed out to the reporter of 21st century economic report that the number of innovative drugs in the Chinese market has increased in recent years, but there are not many truly global innovations. Many of them are gathered in the existing track. At present, there are more than 70 clinical trials of PD-1 in China, but the clinical trials of car-t cell therapy targeting CD19 is twice as much as that of PD-1.

In Liu Jubo's view, China's pharmaceutical industry is changing from imitation to innovation, including fast follow, such as Cinda pharmaceutical, and then to license in, such as the success of zaiding pharmaceutical, and the success of cdmo (a kind of drug R & D and production outsourcing service), such as YaoMing Kant. However, the core is still that the enterprises should have their own R & D capabilities, Finally, sustainable development can be achieved, reaching the global market. Xinda pharmaceutical and zaiding pharmaceutical are also doing independent research and development“ Regardless of the choice of the first easy after the difficult, or the first difficult after the easy, a variety of modes, but ultimately independent innovation and R & D has become the general direction of the same goal by different paths. "

The field of innovative medicine in China is in a transitional stage from imitation to brand-new. People's vision

Innovative drugs are never expected to be seen, and are highly sought after

Since the deepening of medical reform in 2015, encouraging innovation has become an important direction of reform. In the view of the industry, innovative drugs usher in the best era. Liu Jubo analyzed that national policies and capital are the main driving forces.

In recent years, a number of policies have been introduced to promote the development of innovative drugs, such as accelerating the review and approval of innovative drugs; Join ICH to promote international mutual recognition of clinical results; The system of drug marketing license holder should be introduced; The negotiation and dynamic adjustment of medical insurance catalogue will accelerate the rapid volume of innovative drugs after they are put into the market.

Under the background of policy support, the attractiveness of investment return of innovative drugs is increasing, capital has entered the board one after another, and the transactions of license in and license out projects of innovative drugs are gradually frequent.

"Great changes have taken place in China's pharmaceutical industry in the past 10 years. Innovative drugs are not expected to be seen. Now pharmaceutical companies are flocking to do innovative drugs. It's not just because everyone's awareness has improved, but because of the combined effect of sales environment, medical insurance environment and approval environment. " Liu Jubo told the 21st century economic reporter that the policy has a great impact on the development of China's pharmaceutical industry.

As one of the first batch of new drug registration people in China, Tang Yanmin, a partner of Qiming venture capital, has experienced the whole development process of China's new drug approval environment and witnessed the changes of the whole Chinese pharmaceutical environment.

"This is the golden time for the development of innovative drugs in China. In terms of the number of talents, the degree to which the regulatory level of the regulatory authorities is close to that of the United States and Europe, especially in terms of the review time, it used to take an average of three years for an innovative drug to get a clinical approval, but now it only takes three months. In these aspects, China has made great progress, laying a very good foundation for the rise of innovative drugs in China as a whole. " Tang Yanmin pointed out to the 21st century economic reporter.

According to the analysis of Southwest Securities Research Report, China's innovative medicine field is in the transition stage from imitation to brand-new, so we should seize the opportunity to dig for gold. At present, China's pharmaceutical industry is in the era of rapid follow-up of international innovative drugs.

Tang Yanmin explained that "fast follow" means that the original drug may not have been approved, and there are some uncertainties in the research and development, but this target basically has patent medicine, which is very likely. Enterprises start to follow up quickly when they see some clinical effects.

In fact, in human cells, only 15% of the targets are easy to be made into drugs. These targets have been almost done in the past hundred years. Now, the remaining 80% of the targets are difficult to prepare drugs, which is becoming more and more difficult.

For this reason, many domestic innovative enterprises choose fast follow, and the strategy is gradually accelerating, and the time gap between domestic and foreign research is further narrowed. The follow-up time point has quietly moved from the listed drugs to phase III, phase II, and even the preclinical stage. The number of competitors has also expanded from several previous companies to more than a dozen or even dozens.

For example, in terms of claudin 18.2 target, only Astellas Pharma is in phase III in the world, but there are nearly 20 local pharmaceutical enterprises in China, including meiyake, tianguangshi and Chuangsheng, which have entered phase I. A similar condition was found in PD-L1 / TGF- β、 On the trop 2-adc track.

The vast majority of these new mechanism drugs made in China have not entered the clinical practice, or have stagnated soon after entering the clinical practice, and gradually marginalized with the passage of time. Occasionally listed, it has not been widely recognized in clinical practice, nor has it been widely recognized by domestic and foreign industrial peers.

Fierce competition has also slowed down the pace of some pharmaceutical enterprises. For example, since this year, baiaotai has announced to stop the clinical development of three ADC drugs. According to the 2020 annual report released by balotex, the three drugs cost 340 million yuan in R & D investment.

Pressure from the rapid introduction of foreign new drugs

Previously, Wang Lei, executive vice president of AstraZeneca global and President of international business and China, said in an interview with 21st century economic reporter that the track congestion is very normal. Chinese enterprises have successfully entered the world through cruel competition, which will become the vitality of enterprises. Maybe in the future, Chinese innovative pharmaceutical products can benefit the whole world at reasonable prices.

How to survive, this is also the answer that Chinese pharmaceutical enterprises are looking for. In recent years, many enterprises have focused on the global market.

In fact, the competitors of Chinese enterprises are not only Chinese pharmaceutical enterprises, but also global competitors. Liu Jubo explained that China and the world were separated. It would take 7-8 years for all new drugs to enter China after they were listed in the United States, but now this time has been basically reduced to 1-2 years. As long as the drugs listed in the United States, only two years will enter China. This has also brought competitive pressure to China's innovative drugs.

"The demand difference between the Chinese market and the United States and other international markets has been very small. If we only locate in the Chinese market, the investment will not be much reduced, but the income will be greatly reduced, which is quite different from the investment return rate of positioning the global market, especially in the field of innovative drugs; On the contrary, if we invest the same cost to sell the global market, we can get high profits, and we can invest it in the next stage of R & D, which will form a virtuous circle, and the enterprises will become stronger and stronger. China alone will eventually form a vicious circle. " Liu told the 21st century economic reporter.

In fact, from the perspective of market size statistics, the world has a broader market than China. According to iqvia statistics, China's domestic prescription drug market will be about 1.2 trillion yuan (including generic drugs) in 2020; According to the statistics of evaluate, the global prescription drug market will reach 904 billion US dollars in 2020, about 5.8 trillion yuan, and 1.4 trillion US dollars in 2026.

The macro development environment of the country also determines the enterprise strategy. Liu Jubo said that in the early days, few companies that only made innovative drugs survived. Even if they could succeed, the original model was to invite tenders after new drugs were put on the market. They could not sell products in the first four years, but could enter the medical insurance three years after they were on the market; In contrast, generic drugs can be included in medical insurance in one year.

However, under the background of national procurement with quantity, the profits of generic drugs are becoming very thin. Pharmaceutical enterprises have to innovate to enable their sustainable development. Then they find that it is not enough to innovate only in China. Because of the competition from multinational pharmaceutical enterprises such as the United States, Chinese enterprises must also do the international market.

In countries with large market demand, it has become a common mode for pharmaceutical enterprises to enhance sales capacity with the help of partners. Liu Jubo said that Yiyi biological's f-627 will also find partners in China, the United States and Japan. For this drug, Liu said he was very confident, because there are few similar products in China, and the first market is very large, so it will not enter the market for a long time.

It is understood that f-627 is the world's first third-generation G-CSF (recombinant human granulocyte colony stimulating factor Fc fusion protein) product independently developed by Yiyi biological with its own team, which is used to treat chemotherapy-induced neutropenia (CIN).

As the first domestic new biological drug to complete global phase I to III clinical trials abroad, according to the information previously disclosed, the global development plan of f-627 covers 10 clinical trials, and has recruited more than 1200 patients in many countries and regions including the United States, the European Union, Australia and China. So far, f-627 phase III clinical trials (nct03252431 and nct02872103) have been successfully completed and have reached the primary and secondary endpoints. F-627 has also shown significant and lasting patient clinical benefits in the trial. As a new structure, it provides a unique and natural long-term treatment scheme, which is expected to replace the PEGylated G-CSF therapy in the current market.

Independent research and development is the only way for Chinese Pharmaceutical Enterprises

At the same time, Liu Jubo also stressed that innovative drugs must be real innovative drugs, not pseudo innovation.

"If we copy the products listed in the United States and sell them in China after a little modification, this mode is not good for Chinese enterprises, because it creates a false environment and the innovation ability of Chinese Biopharmaceutical Enterprises will never be trained. In the field of biopharmaceuticals, if China's pharmaceutical enterprises do not enhance innovation, they will never catch up with the United States. "

In Liu Jubo's view, in order to achieve sustainable development, we need to really innovate, whether it is fast follow mode or licencein mode, and finally we should really do our own R & D innovation.

License in is a kind of product introduction mode, that is, introducing the research results of foreign pharmaceutical enterprises, which can make the importing party not be limited by the existing R & D ability. Through the way of license in, the products can almost synchronize with foreign advanced products, enter the Chinese market at the first time, and establish the first mover advantage.

However, some opponents think that it is a kind of speculation, which is not conducive to the research and development of local innovative pharmaceutical enterprises. As many pharmaceutical companies enter the license in track with higher and higher trading volume, whether they can earn back the cost has become a problem.

Not long ago, license in has also become the focus. Under the new rules, there are some pure license in project companies, and it is not easy for the industry to pass the examination of the science and technology innovation board.

Tang Yanmin thinks that what the CSRC resents is some cases of rapid wealth creation. In particular, the fund takes out a sum of money to find two people, buy two products, and immediately save a company, which quickly changes from zero to tens of billions of market value. This is not conducive to real innovation“ Everybody's going to make quick money, and it's not sustainable. "

In Tang Yanmin's opinion, which mode to choose depends entirely on the core competence of the core team“ Strictly speaking, license in is not a model, but an enterprise case. For example, zaiding chose license in because Du Ying, the core soul of zaiding, was born in BD. she has been doing BD in large foreign enterprises, and has a lot of network and resources, which can effectively promote relevant progress. "

According to Dr. Wang Zhiwei, senior vice president of Baiji Shenzhou, being able to do a good job in license in just shows that its R & D strength is also very strong“ Only if we have strong R & D ability can we understand other people's products and do clinical and development follow-up. "

Wang Yinxiang, chairman of gakos, believes that the way each enterprise chooses depends on its own development. For example, we mainly do independent research and development, rely on in-house ability, and use allosteric inhibitors, mainly aiming at difficult drug targets.

"Yi Yi bio's model is to do the most difficult work first and insist on doing all clinical stages. If the first phase is sold out, the success of the new drug has nothing to do with the enterprise, because the money has already been earned. However, the enterprise is unable to understand how to do phase II and phase III in the United States, how to go on the market, and whether the manufacturer can obtain the GMP audit of FDA through this drug. " Liu Jubo said that Yi bio chooses this difficult way, but it can make enterprises grow faster.

According to reports, the acceptance of the BLA submission represents that Yi Yi will soon accept the FDA's review of Chinese factories, and is expected to become the first Chinese biopharmaceutical company to obtain FDA GMP certification, and the follow-up commercialization process is also in preparation.

However, in Liu Jubo's view, no matter what form it is, whether it is easy to do first or difficult to do first, it will eventually go on the road of independent research and development, which will also be the road of sustainable development of Chinese Biomedical enterprises, and there will be more new global Chinese Biopharmaceuticals in the future（ Wei Xiao, an intern, also contributed to this paper.)

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