Professor Lu Wei: The development of China's innovative medicine from the perspective of PI

Guide: How to improve the speed of research and development of innovative drugs in China?may, on May 10 this year, Amel® has become the second three-generation EGFR-TKI target new drug in the world after the Ohitini ®, and the first independent research and development of EGFR-TKI innovative drugLeadingPI, the lead researcher in the clinical research of Amela ®, and Professor Lu Wei, director of the oncology department of Shanghai Jiaotong University's affiliated thoracic hospital, spoke highly of the drug: "The clinical research of Amel® is of landmark significance to the development of new drugs in ChinaIt basically alleviates the dependence of patients with advanced lung cancer on imported drugs in China, and brings new choices and hopes for patients with advanced lung cancer"
until that, athirds' three-generation EGFR-TKI inhibitor, Ochtinib, was a unique ® in the global lung cancer treatment marketAccording to AstraZeneca's financial results, Ohitini ® full-year sales of $3.189 billion in 2019, with sales in China at a time when sales have been at a high levelHow canslow down chinese people's dependence on imported drugs? How to improve the speed of research and development of innovative drugs in China? How to narrow the gap in drug efficacy at home and abroad? Facing a series of problems, Professor Lu believes that the root cause of the problem lies in the weak basic research strength of our country and the lack of transformational medicineProfessor Lu Wei,,director of theOncology Department of Shanghai Jiaost Hospital, Shanghai Jiaotong University,three factors that have choked the throat of China's drug innovation andlooking back over the past two decades, cancer treatment technology from surgery, radiotherapy, chemotherapy to today's targeted treatment, immunotherapyPeople no longer talk about cancer color change, some cancers are moving towards chronic diseaseIn May, Nature Reviews Drug Discovery published a review entitled "Cancer Cell Therapy: Prospects for Clinical Trials", which mentions the country's rise in immunotherapy and similar in the number of immunotherapy drugs developed in the United States China's immunotherapy development seems to be a prosperous, but the real emergence of innovative drugs are few, what is the throat of China's innovative drug development? In Professor Lu's view, there are three main factors restricting the development of immunotherapy in the field of lung cancer: drug resistance mechanism is not well understood
before the advent of EGFR-TKI drugs, lung cancer patients are mainly treated by surgery or chemotherapy, these treatment methods have large side effects, short survival With the in-depth understanding of lung cancer, it has been found that the occurrence of tumors is related to the development of the driving gene, and more than 40% of Chinese lung cancer patients are non-small cell lung cancer (NSCLC) patients with The Mutation of the EGFR gene Therefore, by targeting drugs to effectively suppress tumor-driven genes can inhibit and delay tumor progression, improve the survival of patients with non-small cell lung cancer, and soon set off a wave of EGFR inhibitor research and development boom, EGFR-TKI drugs were born However, tackling the challenge of non-small cell lung cancer is not easy, and drug resistance is one of the major challenges Patients with the EGFR gene mutation developed resistance 1 year after receiving targeted drug therapy with first/second generation EGFR-TKI The proportion of patients with drug resistance is as high as 60-70%, forcing scientists to launch a third-generation EGFR-TKI drug EGFR-TKI resistance mechanism is a complex problem, the most common is the eGFR pathway has a secondary mutation, in which the T790M mutation accounts for half of the drug-resistant patients However, t790M mutations are not the only variables that produce resistance, such as MET amplification, HER2 amplification, PI3K/AKT pathway activation and other bypasses or downstream pathway activation are also important causes of drug resistance In addition, uncertainties such as tissue or phenotype transformation and pharmacology contribute to the development of EGFR-TKI resistance in patients "At present, our understanding of immuno-drug resistance mechanism is still in a very lackofed state, we do not have a comprehensive system of immune resistance, lung cancer has not established immune typing, which is undoubtedly a challenge for the development of new drugs." Professor Lu said frankly immune markers cannot be established
when drug resistance becomes an inevitable problem in EGFR-TKI treatment, treatment strategies, in addition to the use of a new generation of EGFR inhibitors, clinical trials will more often try to combine drug-using options, including EGFR-TKI combined anti-angiogenesis drugs, immunocheckpoint inhibitors and diphosphate nucleosome polyenzyme (PARP) inhibitors "One of the dilemmas we face now is that there are a lot of combination therapies, but it's not clear which combination therapy is best for patients," Some combination therapy also has a certain degree of blindness, on the whole or the principle of trial and error Professor Lu explained that clinicians had hoped that the selection of PD-1 would be more precise, but the immune markers of PD-1 were not ideal Therefore, the development of immunomarkers has also become a major factor restricting the precise treatment of immunotherapy drugs in Professor Lu's view, the theory of immunity should have its own type, according to different types, according to different treatment strategies In fact, immune distype is not determined in lung cancer Little is known about the immune microenvironment The classifications of "immune exemption", "immune inflammation type" and "immune desert type" in people's mouths are still in the experimental hypothesis stage "There are many biomarkers from different immune latitude predictions to biomarkers, so when immune species are not established, it's hard to talk about precision therapy for immunity, " said Professor Lu "
target development is difficult
in the 2020 latest version of the NCCN lung cancer guidelines, such as EGFR, ALK, ROS1, BRAF, KRAS, NTRK, PD-L1 and other traditional targets are listed, but also we also see a number of emerging targets, such as MET, RET rearrangement, HER2 mutation, TMB and so on , however, finding a target is only the first step, and ultimately designing a therapeutic drug will have to go through a lot In the case of KRAS, although its role in cancer was identified more than 60 years ago, it was once shrouded in the "drugless" spell because the surface of the KRAS protein did not have a typical inhibition site Although awareness of KRAS has improved in recent years, we have not yet developed a drug that can inhibit KRAS mutations There are many more targets like this, says Prof Lu Target development is still a long way off if you want to do the precise treatment of lung cancer the gap between China's clinical trial level and the international mentioned that China's new drug clinical trial level and foreign countries still have a small gap, Professor Lu Wei does not agree with yijun's view: "I think the level of clinical trials is not the main problem restricting the development of new drugs in China." Why can't we make the first-in-class innovation? I've been saying that when China doesn't have many Nobel laureates, doesn't China have a real era of new drug innovation? "
" our biggest gap is still in basic research, in the mechanism we have not yet figured out, the real sense of new drug innovation is impossible to talk about Professor Lu Wei cited PD-1 inhibitors as examples, in recent years, a total of 6 PD-1 products in China were approved and entered the commercialization stage, of which 4 are domestic, namely, Junshi Bio's Toi ®, Cinda Bio's Dabershu ®, Hengrui Pharmaceutical's Erica ® and Baizi Shenzhou's Baizean ® The prosperity of the market gives the Chinese people the illusion that the gap between PD-1 inhibitors and foreign products in China is not very large However, Professor Lu pointed out that most of the domestic PD-1 clinical research trials today are based on chemotherapy, lacking the courage to match the head-to-head with international standards In Professor Lu's view, after more than 20 years of development, the level of clinical trials in China, especially the level of clinical trials of cancer drugs has been significantly improved As a senior Leading PI, Professor Lu has experienced three stages of the development of clinical trials of lung cancer in China and feels the continuous improvement of the level of clinical research in China 1999-2009, this period, China officially under the gCP (Drug Clinical TrialS Quality Management Practice) principles under the guidance of the standard clinical trials, in this stage we are more to learn how to integrate with the world, domestic clinical trials have no say Professor Lu called the period "a rush." after a decade of catching up, our clinical trials are at the same level as the international community in many ways Between 2009 and 2019, many international multicenter clinical trials were led by Chinese scholars At the same time, the results of many clinical trials in China began to be published in top international journals Although the mainstream of research at this time is still developed countries such as the United States, at least we have a say in clinical trials with Chinese characteristics Professor Lu called the decade a "tidal event" starting from 2019, with the continuous strength of China's national strength, China's pharmaceutical industry has also been developed rapidly, especially after decades of experience in clinical trials, China will have more and more drugs to go abroad, to the international China's clinical trials are from "catch the tide", "tide" to "lead the tide." why many people and yijun, feel that China's clinical trial level and foreign still have no small gap? Professor Lu's answer is: Because of the uneven development of various regions of China, the length of time to start clinical trials varies from place to place, and the level of clinical trials is uneven In fact, in recent years, china's clinical trials in the quality and quantity have been significantly improved According to the 2019 China Cancer Clinical TrialS Blue Book, 338 new cancer clinical trials will be added in China in 2019, with 310 new drugs In addition, the head aggregation effect of tumor clinical trials in China is significant The top 10 leading hospitals were responsible for a total of 250 projects, accounting for 74% of the total number of new trials The level of clinical trials in drug development in the United States is more homogenized In contrast, people inevitably have the feeling that China's clinical trial water is far from the international Professor Lu Wei, who gave a presentation at the International Conference
The charm of Leading PI in the development of new drugs
the leading researcher (Leading PI) plays a very important role in clinical trials of new drugs, and the trend of China's PI and the tendency of competent people to work harder Leading PI in 2019, 15 more than in 2018 More than 20 PiIs were responsible for more than 5 trials, with a total of 221 clinical trials, accounting for 65% of the new trials in 2019 Most of them work in authoritative hospitals or oncology centers, and are authoritative experts in the field of cancer treatment The real appeal of Leading PI lies in the understanding of innovative drugs, the ability to make professional judgments on clinical design sings, and provide constructive advice on the entire experimental design Some experienced Leading PI will also organize international multi-center clinical trials to pave the way for the internationalization of future drugs Now some innovative drug designs have even seen a shift from Global for China to China for Global "China's innovation to go to today, not behind closed doors to play in China itself, need to have a certain vision and a certain method to prove that the drug can go international, a major sign of innovation is ultimately can go international!" Professor Lu said so in the field of lung cancer treatment, can represent China's "out to sea" innovative drug is undoubtedly Hutchison Whampoa's Volitinib This is a targeted drug for the treatment of NSCLC for the treatment of MET exon 14 jump mutation As the lead author of the Volitini China Phase II clinical trial, Professor Lu shared the research and development story behind Volitini met exon 14 jump mutation shady mutation shaded in a small group of patients with non-small cell lung cancer In order to meet the treatment needs of this part of the patient, Germany Merck, Novartis and other multinational companies have carried out related drug research and development China's pharmaceutical companies are not willing to show weakness, joined the MET inhibitor research track this year, Germany's Merck's Tepotinib and Novartis's Tabrecta were approved Originally thought that China's MET inhibitor research and development will end without disease, on May 29, Professor Lu Qi officially released the data at the annual meeting of the American Society of Clinical Oncology (ASCO) The data show that Volitinib shows promising anti-tumor activity and good tolerance It is worth mentioning that on the same day, And Huang Pharmaceutical announced that China's State Drug Administration has accepted the application for the listing of new drugs in Volitinib excellent clinical trial data for Volitinib means that in met targets, Chinese and international synchronization have first-in-class drugs, rather than the first-in-class drugs that have followed the emergence of the international market in the past for local research and development in China At present, The Company and AstraZeneca are working together to conduct clinical trials of volitinib monopills and combination therapies around the world for a wide range of solid tumors the birth of innovative drugs such as Walitinib today has allowed the world to see the power of Innovative Medicineinos in China However, Professor Lu was not blinded by the immediate success, he saw that China's new drug innovation process has fatal defects: the relative isolation of production and research Looking at the international new drug research and development enterprises, we can easily find: in the outstanding multinational pharmaceutical companies in the CMO positions are big-name professors, have a deep academic knowledge is the lack of such talent for China's domestic pharmaceutical companies Therefore, in Professor Lu's view, there is a deviation in the understanding of the new compound, and the error in clinical trial design is inevitable If china's research and development of new drugs is a considerable challenge to gain a foothold in the world, if it cannot break through the relative isolation of production, education and research How to get through the "two veins" of industry, science and research? Professor Lu believes that it is necessary to start from the national level, reform the constraints on development in the existing system, learn from foreign experience, such as allowing big-name professors to stay without pay and enter pharmaceutical companies to hold positions;