Securities Times reporter Chen Lixiang
A few days ago, the news that BeiGene's global Phase III clinical "head-to-head" study of zanubrutinib achieved the superiority of progression-free survival (PFS) caused quite a stir in the pharmaceutical industry.
This is my country's first self-developed new anti-cancer drug approved in the United States. This time, it achieved a "complete victory" in the global clinical trial of "head-to-head" international first-line therapeutic drugs, bringing warmth to a group of innovative drugs that are planning to go overseas.
After nearly ten years of development, the continuous advancement of pharmaceutical reform, and the support of the capital market, my country's pharmaceutical industry has begun to emerge in the global market, the R&D and innovation capabilities of pharmaceutical companies have been continuously improved, and the number of domestic innovative drug IND (new drug clinical research approval) applications has continued to rise. .
More and more local pharmaceutical companies are no longer limited to the domestic market, but are actively participating in global competition, trying to "go global" with their self-developed innovative drugs.
A number of industry insiders told the Securities Times reporter that with the continuous increase in policies, the iterative upgrade of new pharmaceutical research and development technologies, and the evolution of the global commercialization pattern, internationalization is the only way for local top pharmaceutical companies, and now is the time to promote innovative drugs overseas. good time.
However, it is not easy for domestic innovative drugs to successfully go overseas. The cost is high and there is not much successful experience to refer to. It is necessary to be familiar with the rules and requirements of overseas listing, establish a clear global R&D strategy as soon as possible, and always pay attention to the research and development progress of similar drugs around the world. , Choose the appropriate mode of going to sea to stand out.
unstoppable
In the past few years, thanks to the introduction of a series of policies such as the reform of pharmaceutical policies, the steady advancement of drug review reform, and the revision of drug registration management measures, historical problems such as insufficient innovation capability and slow review progress in the pharmaceutical industry have been resolved.
Coupled with the launch of the Science and Technology Innovation Board and the registration system, and the support of the capital market for innovative pharmaceutical companies, the innovation and transformation of pharmaceutical companies have been strongly promoted.
In the past two years, the research and development of domestic innovative drugs has gradually entered the harvest period.
The data shows that the number of IND applications for innovative drugs has been increasing year by year. In the field of oncology, since 2019, the number of core clinical trials of domestic innovative drugs has surpassed that of the United States, and will reach 123 in 2020.
It is worth noting that the number of first IND applications has increased sharply. From 2010 to 2020, a total of 1,636 innovative drugs submitted IND applications for the first time, of which 86% were from 689 local Chinese companies.
In 2021, the number of applications for domestic chemical drugs and domestic biological drugs will exceed 200, a record high.
This series of figures shows the rapid development of the domestic innovative drug research and development industry, which has provided a large number of candidate drugs for going overseas.
At the same time, in order to cope with the "involution" of the industry brought about by policies such as stricter control of medical insurance fees, leading pharmaceutical companies have begun to boldly "go out" and actively participate in international competition. Domestic innovative drugs have ushered in a golden period.
Statistics show that since the beginning of this year, more than 50 Chinese innovative pharmaceutical companies have been vigorously promoting their "going overseas" business.
According to the relevant reports of Yikai Capital, according to incomplete statistics, since 2017, 6 to 8 innovative drug products in my country have submitted drug marketing applications to the FDA (US Food and Drug Administration) every year; in 2021, domestic pharmaceutical companies License-out (External license of a certain technology or patent) The total transaction amount reached 13.3 billion US dollars.
"In the short term, there is no opportunity for innovative drugs to go overseas, because the FDA's review standards remain unchanged for most of the time. Anytime there are drugs that meet the standards, they can be considered overseas. But in the long run, the entire pharmaceutical From the perspective of the industry's technological iteration and commercialization competition pattern, innovative drugs have the best time to go overseas." Zhang Fei (pseudonym), a senior pharmaceutical industry investor, analyzed the reporter.
At the technical level, new drugs around the world are currently undergoing a new technological change, which brings opportunities for my country's innovative drugs to overtake the curve: the research and development of macromolecular monoclonal antibodies represented by PD-1 has become saturated, and the competition is increasing. Intense, the emergence of double-antibody and even tertiary-antibody drug research and development also reflects the intensification of industry competition. Such drugs will face high clinical costs and more stringent audits when going overseas.
At present, the research and development of innovative drugs has entered the era of gene and cell therapy. The improvement of nucleic acid transmitter preparation technology and the maturity of allogeneic cellular immunity technology will strongly boost the development of the entire industry and provide Chinese innovative drug companies with a good opportunity to go overseas. .
In terms of the commercialization competition pattern, the timing of going overseas needs to be global.
For example, among PD-1 drugs, K drug has first-mover advantages and technical advantages, but it still leaves room for latecomers to catch up or even overtake; while Daiichi Sankyo's ADC drug DS-8201 is used in breast cancer and other indications The significant efficacy of the drug will greatly increase the cost of catching up for latecomers, and directly lead to the suspension of multiple clinical phase II and III research and development of other drugs.
Therefore, the competition pattern of the entire industry and the progress of drugs under research by overseas companies also provide directions for Chinese pharmaceutical companies to choose the timing of innovative drugs to go overseas.
Breakthroughs in independent overseas travel
At present, there are two main modes for domestic innovative drugs to go overseas—independent going overseas and license-out.
The core of the former's going overseas is to solve "unmet clinical needs". There are very few successful people, but once they are successful, they can bring huge returns to the company; the latter's cooperation model can more effectively accelerate the launch of drugs and become the choice of more pharmaceutical companies. .
Going overseas independently is a major problem for innovative pharmaceutical companies, which requires solid technical accumulation and strong financial support.
Zhang Fei said that it is not easy for innovative drugs to be listed in European and American countries. The biggest difficulty is the clinical trial link, which tests the financial strength of pharmaceutical companies and the ability to design clinical trial plans.
"If the drug has a competitor, it needs to do a comparative experiment with the competitor that has already been listed, and it is necessary to buy the competitor's drug. Generally speaking, when a new drug is undergoing clinical trials in the United States, the cost of a patient is often It started with $200,000 to $300,000." Zhang Fei said.
It is undeniable that no matter in terms of R&D investment, output efficiency or operating profit, there is still a big gap between local pharmaceutical companies and European and American pharmaceutical giants, and they cannot blindly internationalize.
Going overseas for new drugs has very strict requirements on the comprehensive strength of pharmaceutical companies. Even star products of listed companies such as Chi-Med’s surufatinib and Innovent’s sintilimab are still struggling to “break through”. The road to "going to sea" is long and difficult, and there are only a handful of successful people.
Despite this, there are still many leading pharmaceutical companies that choose to challenge themselves to go overseas, including BeiGene, Kanghong Pharmaceutical, Wanchun Pharmaceutical, Kintor Pharmaceutical, Innovent Bio, Junshi Bio, Chi-Huang Pharmaceutical, Yifan Pharmaceutical, etc. .
However, in the past few years, it has not been smooth for innovative drugs to go overseas on their own. The reasons for the common obstacles include the lack of international multi-center clinical trial data representing the patient population in the United States, the blockade of on-site inspections or overseas trials due to the new coronary pneumonia epidemic, and the lack of efficacy of the subjects. Expected and so on.
BeiGene's core self-developed product, BTK inhibitor Baiyueze® (zanubrutinib), is the first innovative drug to be successfully launched independently. It is one of the few cases where domestic innovative drugs have successfully gone overseas independently.
In 2021, zanubrutinib will achieve sales of 700 million yuan in the US market.
In the first half of 2022 alone, its sales in the United States reached 1.015 billion yuan, an increase of 504.5% compared with the same period last year.
In the final analysis of the global Phase 3 head-to-head ALPINE trial, zanubrutinib achieved PFS superiority results compared to Ibrutinib (ibrutinib), thus becoming the world's first and only patient in chronic lymphocytic lymphocytes. In leukemia (CLL), "head-to-head" versus ibrutinib, a BTK inhibitor that achieved superiority in PFS.
The Southwest Securities Research Report stated that the success of zanubrutinib, differentiated products, strong capital and a strong overseas team are hard conditions.
Junshi Bio is one of the first Chinese innovative pharmaceutical companies to establish a laboratory in the United States.
In 2021, Junshi Bio will have nearly 10 clinical trial applications for innovative drugs approved, 3 of which are reported by China and the United States.
Up to now, 7 drugs have been approved by the US FDA for clinical trials.
Among them, Toripalimab injection (Tuoyi®) is the first domestically produced monoclonal antibody drug targeting PD-1 approved for marketing in my country. ) has conducted more than 30 company-initiated clinical studies covering more than 15 indications.
"Since China joined ICH, the overall level of clinical research and drug development of domestic pharmaceutical companies has risen to a higher level, approaching that of Western countries. We all conduct drug development under the same review system and quality standards, whether it is early preclinical Both data and clinical research data can be accepted by ICH members (that is, most countries in the world)." The relevant person in charge of Junshi Biology told reporters, "In this context, for pharmaceutical companies, 'going out' is actually a A resource integration and reuse is a natural choice.”
License-out becomes mainstream
The license-out model means that the company conducts early drug research and development, then authorizes the project to other pharmaceutical companies for later clinical research and development and marketing, obtains clinical results at various stages according to the milestone model, and takes a certain percentage of sales after commercialization.
Compared with independent research and development, domestic license out transactions tend to be hot.
This is because pharmaceutical companies cooperate with overseas pharmaceutical companies through License out, which can not only achieve complementary advantages on the research and development side, reduce the risk of new drug research and development, but also use the sales network of large international pharmaceutical companies on the sales side to make domestic innovative drugs faster. Enter the international market.
"The common practice now is to conduct preliminary research and first-phase clinical studies in China, and then take the report to a global academic conference to preach, seek financial and technical support, and promote the clinical process of new drugs." Zhang Fei analyzed, At present, there are not many domestic companies that have the technology to develop new drugs and have large funds to support a new drug for clinical trials. Large sums of money are often very difficult. If the Legend Bio model is adopted, it is a more feasible way to cooperate with multinational pharmaceutical companies in R&D and share profits.”
Legend Bio is a subsidiary of GenScript Biotechnology, a Hong Kong-listed company.
In 2017, Legend Bio announced that it had reached a cooperation agreement with Janssen (Janssen) to jointly develop, produce and commercialize the BCMA-targeting CAR-T therapy LCAR-B38M, which was officially approved by the U.S. FDA in February this year. It has become the first innovative cell therapy product in China to successfully go overseas.
In June of this year, Legend Bio disclosed in the first quarter that its milestone revenue in the current period had reached $40.8 million.
In the past two years, the number of license-out transactions has shown explosive growth, and the transaction value has increased significantly. In the past two years, many transactions have exceeded 2 billion US dollars. transactions, Rongchang Bio’s ADC drug and Seattle Gene’s $2.4 billion authorization, etc.
According to statistics, since 2017, license out transactions have become increasingly popular. As of May this year, there have been 149 domestic related transaction projects.
In terms of target distribution, PD-1 is the most popular target, followed by BCMA, VEGF, HER2, CD19 and other popular targets.
More and more local innovative pharmaceutical companies are joining the team.
According to incomplete statistics, 27 pharmaceutical companies have entered overseas markets through License out, of which Luye Pharma has completed 10 transactions, mainly the commercial authorization of Ristigmine transdermal patches in many countries around the world.
Henlius, Bio-Tech and Innovent completed 8, 7 and 5 authorizations respectively, and the commercialization of biosimilars is progressing rapidly.
With their rich pipelines and innovative targets, Hengrui Medicine and BeiGene, etc., tend to cooperate on the R&D side to promote the overseas layout of their products.
The Southwest Securities Research Report pointed out that, on the whole, License out has gradually entered the deep water area, from the early commercial authorization to the in-depth integration of R&D and commercialization, and comprehensively accelerates the emergence of domestic innovative drugs on the international stage.
The successful license out has brought considerable returns to pharmaceutical companies.
For example, last year Junshi Biosciences cooperated with the Institute of Microbiology of the Chinese Academy of Sciences and Eli Lilly and Lilly, and it was one of the first neutralizing antibodies in my country to participate in the global anti-epidemic.
From 2020 to 2021, JS016's overseas R&D and commercialization-related technology licenses and franchises will bring Junshi Bio's revenue of nearly 3 billion yuan.
The industry's hotly discussed "shortcuts" to success
"In recent years, my country's pharmaceutical industry has developed rapidly, and many fields have reached the world's leading level, especially in cutting-edge fields such as stem cells, immune cells, genetic technology, regenerative medicine, and precision medicine." Hainan Boao Medical Technology Co., Ltd. Deng Zhidong, general manager of the company, told reporters that domestic innovative drug research and development have achieved fruitful results and have the strength to participate in international competition.
However, domestic innovative drugs will still face many difficulties when going overseas, such as timing of going overseas, specific markets for going overseas, differentiated positioning of overseas products, overseas clinical trials, overseas drug application approval, international business management, international market competition, quality and cost control, Technical confidentiality management, policy and legal risks, etc.
The first step for a pharmaceutical company to successfully go overseas is to fully understand the FDA's review process and review focus.
Deng Zhidong said that there are some differences in the review and application mechanism, review principles, and re-evaluation mechanism of new drug approvals between China and the United States.
For example, in terms of the review and application mechanism, the FDA adopts the "direct declaration, first-level review" mechanism, while my country adopts the "multiple declaration, second-level review" review mechanism; in terms of review principles, FDA's technical requirements for IND It is relatively loose, and the system of "wide entry and strict exit" is implemented, especially after the clinical phase II, the elimination rate is relatively high, while my country adopts the "strict entry and strict exit" system, and the withdrawal is mainly concentrated in the clinical research application stage.
"Summarizing our experience, I believe that for innovative pharmaceutical companies to successfully go overseas, a forward-looking global strategy and layout is crucial." The relevant person in charge of BeiGene told reporters that there are two major elements that deserve attention: one It is the ability of enterprises to globalize, especially whether they can design and execute high-quality multi-center clinical trials according to international standards. Judging from some recent signals from overseas regulatory agencies, the importance of international multi-center clinical trials has been continuously emphasized. It has become a choice that new drugs must make when going overseas; second, whether innovative drugs can "go global" ultimately depends on whether the internal science and R&D strength are solid. On the one hand, in the drug discovery stage, whether they can develop truly differentiated drugs. Drug molecules, on the other hand, can better control the quality of global clinical trials, improve development efficiency and reduce costs through the capabilities of internal teams.
"It is necessary to establish a clear R&D strategy as soon as possible. If the goal of a company is to make innovative drugs that can successfully go global, it must start planning in advance from the early stage of drug development, and formulate R&D plans for the globalization of products, including molecular screening. Evaluation from target selection or differentiation potential, etc.” The relevant person in charge of BeiGene introduced that on the whole, global team building and R&D planning are very important. Treatment status, etc., formulate clinical plans and registration strategies, and comprehensively evaluate whether the product itself meets the requirements of global application, thereby determining the company's future global R&D plan and layout.
The communication between the drug administration affairs team and the drug regulatory agency also plays an important role in drug development and registration applications. "Through communication, the drug regulatory agency will provide guidance on the direction and strategy of drug research and development to avoid detours." , BeiGene has established a global R&D team of more than 3,300 people, covering dozens of countries such as China, the United States, Europe, and Australia.
The relevant person in charge of Junshi Biotech also expressed the same view to the reporter: "There are two key points for local innovative drugs to go overseas - the first point is 'new', the product or treatment plan is unique, It is truly new and can meet the unmet clinical needs; the second point is 'early', from the first day of product establishment, preparations for overseas start, running through pre-clinical, clinical, CMC, production and other links. A lot of things belong to 'opening the bow without turning back the arrow', and it will be difficult to make up for it later."
The relevant person in charge of Junshi Bio also told reporters that for local companies, "going overseas" is indeed a big challenge. If you want to successfully go overseas, you must have the following capabilities: First, you must have high-quality innovative products that global patients need; The second is to have an international R&D team; the third is to have strong external partner support; the fourth is to fully understand the local review and approval and medical insurance policies; the fifth is to have the ability to build a high-quality commercial model.
"The satisfaction of the above conditions is actually a gradual process, and it takes a certain amount of time to accumulate experience. You can start by finding an international partner to help the company properly accelerate the process. The size of the partner is second, and the most important thing is whether it is suitable." he added.