21st Century Business Herald reporter Wu Yinggang Intern Wei Ke Beijing report Recently, a number of innovative tumor precision treatment drugs in China have been approved for new indications. On July 12, Daiichi Sankyo and AstraZeneca's ADC drug ditroluzumab for injection (ENHERTU) was approved as a single agent for the treatment of some unresectable or metastatic HER2 low expression (IHC 1+ or IHC 2+/ISH-)® adult breast cancer patients.
In addition, CStone recently announced that its selective RET inhibitor platinib capsules have been approved for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are positive for RET gene fusion; Hengrui Pharmaceutical announced that its new highly selective CDK4/6 inhibitor dalcilib isethionate tablets has a new indication, which can be combined with aromatase inhibitor as initial treatment, suitable for some patients with locally advanced or metastatic breast cancer.
According to industry media, in the first half of 2023, 20 newly approved drugs (excluding proprietary Chinese medicines and vaccines) in mainland China covered tumors, anti-infection, rare diseases and other fields, of which oncology drugs were the most, including a variety of anti-tumor targeted precision therapy drugs. However, according to the official micro-information of the National Cancer Center, in the past decade, tumor targeted therapy has made great progress and achievements in the world, and China has also achieved vigorous development in the development of anti-tumor drugs, but the domestic evidence on the overall research and development progress of anti-tumor targeted drugs is still relatively insufficient.
It is worth noting that the team of Professor Li Ning, vice president of the National Cancer Center/Cancer Hospital of the Chinese Academy of Medical Sciences, recently published a paper at JNCC, based on the national authoritative database, comprehensively revealing the broad pattern and change trend of clinical trials and approvals of targeted anti-tumor drugs in China from the beginning of 2012 to the end of 2021, and identifying the key obstacles to provide corresponding solutions and data reference for promoting the development of targeted anti-cancer drugs in mainland China.
Domestic enterprises may become pillars
The above article shows that the research and development of anti-tumor targeted drugs in mainland China is booming, and the number and proportion of trials, experimental varieties and listed drugs have increased significantly year by year, which to a certain extent shows that the implementation of personalized medicine in China is attractive to the sustainable development of the pharmaceutical market and medical system.
According to the data of the article, in the ten years from 2012 to 2021, a total of 1167 anti-tumor targeted drugs were carried out in 2632 clinical trials, accounting for 81.5% of all registered anti-tumor trials; The number and proportion of targeted drug trials showed a steady growth trend, with average growth rates of 36.0% and 6.2%, respectively.
Image source: National Cancer Center official micro-information
According to reports, the data of anti-tumor clinical trials and drugs are mainly derived from the registration information disclosure platform of the clinical trial registration database of the China Food and Drug Administration (CFDA), and the data period is from January 1, 2012 to December 31, 2021.
In fact, in recent years, precision therapy, including targeted therapy, has become more and more favored. The National Cancer Center has released information analysis that with the advancement of science and technology and the combination of professional knowledge and data of different disciplines, personalized medicine has gradually developed as an interdisciplinary field, allowing medical staff to gradually select the best treatment plan for each patient in the control and treatment of cancer.
Traditional evidence-based medicine roughly classifies tumors according to cancer site, and does not fully recognize the specificity and complexity of individual gene mutations, and the development and application of personalized medicine is essential to improve the prognosis of tumor patients.
For example, from the perspective of tumor drugs approved by the FDA, according to the data of Ping An Securities Research Report, the FDA approved the first targeted tumor drug rituximab in 1997, opening a new era of tumor treatment; From 1997 to 2005, a small number of targeted small molecules and large molecule monoclonal antibodies were on the market, and targeted drugs developed rapidly; Between 2005 and 2017, targeted drugs accounted for an increasing proportion of anti-tumor drugs approved by the FDA. Among the 14 anti-tumor drugs approved in 2015, 12 were targeted drugs, and all of them were targeted drugs approved in 2016 and 2017.
According to the analysis of AVIC Securities Research Institute, from the perspective of the research and development of anti-tumor innovative drugs, targeted therapy and immunotherapy have become the commanding heights of Chinese innovative drug companies because they target unmet clinical needs.
While the entire field of targeted tumor therapy is developing rapidly, the strength of domestic enterprises is also rapidly increasing.
The above article released by Professor Li Ning's team shows that through the study of the comparison of domestic and foreign companies, it is found that after the research and development of anti-tumor drugs has fully entered the era of precision targeted therapy, domestic enterprises have become the pillar of China.
In the past ten years, the number of targeted experimental drugs and the proportion of targeted drug clinical trials of domestic enterprises have increased rapidly, reaching an annual growth rate of 33.7% and 13.8% respectively. Relatively speaking, the total proportion of targeted drug trials initiated by foreign companies is higher than that of domestic enterprises (85.6% vs. 80.5%), but the gap between domestic enterprises and foreign companies in the proportion of drug varieties (84.4% vs. 87.0% in 2021) and the proportion of trials (87.4% vs. 88.0% in 2021) has gradually narrowed. A total of 126 immune drugs and 18 targets are currently under development, of which only one is a novel target that has not yet been approved for marketing.
Image source: National Cancer Center official micro-information
In this regard, Professor Li Ning's team analyzed in the above article that the great progress of anti-tumor targeted drugs in mainland China may be mainly due to three aspects, which can form a virtuous circle.
First, academic and industrial advances in global cancer drug research and development have driven the development of China and beyond; Secondly, China's pharmaceutical innovation ecosystem has gradually improved, which is greatly related to the acceleration brought about by a series of reforms since 2015, attracting more investment from domestic and foreign enterprises and driving the sustainable development of enterprises. In addition, the huge potential of personalized medicine to improve healthcare has triggered the attention and investment of policymakers in more efficient and sustainable healthcare systems around the world, including China.
Therefore, taking the high-quality development of domestic enterprises as the starting point to promote the development of China's pharmaceutical R&D is the key to the development of targeted anti-tumor drugs in the next decade, especially the key to its innovative drug development.
R&D models must change
At the same time of rapid development, Professor Li Ning's team also pointed out in the article that based on the rapid follow-up model, China's targeted anti-cancer drugs have made significant development, but the drugs on the market are not the first of their kind.
Almost all of the targets under development in China already have products on the market, and domestic companies are significantly less globalized than foreign companies. This means that Chinese companies will still not be able to contribute first-class targeted anti-tumor new drugs to the world in the short term. In the new era of China's integration into the globalization of R&D, China's R&D model must be transformed from "me-better" to "first-in-class", from the perspective of innovation ability, innovation internal and external forces, and innovation ecology.
Zhu Xun, a member of the National New Drug Advisory Committee, once told the 21st Century Business Herald on this issue that the real original innovative drug, the first must be the first in the world, the second must be internationally recognized, and the third should have sufficient market share and certain sales in the international market.
But at present, not only me-too drugs have entered the white-hot competition, first-in-class and me-better products are facing great challenges.
According to Zhu Xun's analysis, for first-in-class, its failure rate is very high, from clinical to approval and marketing, the global success rate does not exceed 8%; For me-better drugs, although the first-in-class is not necessarily best-in-class, but because the cost of R&D new drug investment has increased significantly, the cost of surpassing the product after listing is too large, so the company will continue to optimize in the early stage, most of the new drugs have been listed for 85 points, and it will be very difficult for other companies to do me-better in the future. There is a big difference between a 60-point drug and an 80-point drug, but there is not much difference between an 85-point and a 90-point drug.
In addition to the issue of drug initiative, Professor Li Ning's team also emphasized in the article that China's human genetic resources play an indispensable role in the sustainable development of precision medicine research. They are particularly prominent in oncology research and multi-center research, and China has continuously strengthened legislation and ethics, and initially established a relatively complete legal system and ethical standards from the collection of biological resources to export.
R&D institutions generally believe that China's control of human genetic resources is relatively strict compared to the United States. The United States regulates and regulates the transfer of human genetic resource materials in scientific research projects through the development of standard biological material transfer agreements. The external transfer of Chinese GRs is also managed by the government, but the export requirements for samples are stricter and the process is time-consuming.
The transfer of Chinese GRs also needs to be approved by the government, and the export of samples should go through strict application procedures, including ethical approval, research approval, administrative authorization, etc. Only legitimate domestic entities can export resources, so the overall layout at the national level should be strengthened to promote the development of targeted and personalized medicines.
On this issue, Professor Li Ning's team pointed out in the article that on the one hand, given the fundamental importance of clinical genomics in cancer, R&D organizations should advocate regulations and policies that encourage genomics activities and related international activities. On the other hand, a national resource strategic protection platform should be jointly established to standardize the safe storage and sharing of sample data to ensure that patient privacy and data security are protected. In addition, incentives and public-private partnership frameworks should be established to facilitate access by academia and industry stakeholders to biological samples and data for research purposes, which is also critical for sustainable R&D of innovatively targeted anti-tumor drugs in China.
It is understood that as early as 1986, Nobel Prize winner Delbecco proposed that to solve the tumor problem, we must first understand the genome.
Yang Huanming, an academician of the Chinese Academy of Sciences, also said that the genomics of tumors now mainly focuses on gene mutations, translocations and chromosomal structural changes, etc., which is of great significance for elucidating the molecular mechanism of tumors and realizing tumor prevention, early diagnosis and precision treatment.
For example, tumor prevention, by detecting changes in the tumor genome, can predict the risk of tumors with genetic predisposition in the family to achieve the purpose of preventing tumors; Early diagnosis of tumors, through the sequencing of free DNA in body fluids or secretions, obtain the genomic information of tumors, and achieve the purpose of early tumor screening; Precision treatment of tumors, for patients who have been diagnosed with tumors, by detecting changes in the genome of tumor cells and tumor microenvironment, learning about changes in molecular signaling pathways, and formulating personalized treatment plans for patients.
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