Opportunities and challenges coexist in the development of bio innovative drugs in China (2): opportunities and challenges

Compared with chemical drugs, me too is more feasible The small molecule original drugs are often after several rounds of structural optimization, and the space for structural breakthrough is often not very large If the transformation does not change the mother nucleus, it is difficult to surpass in the efficacy and drug metabolism only on the basis of the mother nucleus However, the structure of the mother nucleus changes so much that it is difficult to predict the effects on drug activity, selectivity, bioavailability, efficacy / safety, etc., so it is not easy to select a compound that can avoid patent protection and has better clinical efficacy But for biological drugs, especially antibody drugs, although the structure is complex, as long as the target or epitope is not protected, some simple improvements are made on the basis of the original sequence, and it is not difficult for most local pharmaceutical companies to re screen and design a me too antibody Take exetane and conbercept, the most representative drugs in China, for example On the basis of erlotini structure, Beida company closed its side chain, and the parent core structure did not change, although it bypassed patent protection But it also led to the decrease of the activity of exetane Erlotinib once a day (150mg / time) became exetane three times a day (125mg / time), and the drug dose was more than doubled to reach the level of the original drug At the same time, the repeatability of this patent loophole is not very good The original research company will pay attention to it later Simple modification or modification is not good in feasibility and clinical efficacy However, conbercept, a class 1 biological drug developed by Chengdu Kanghong, added some sequences of the fourth domain of VEGFR2 on the basis of the molecule of arbacicept, and there was no significant difference in clinical efficacy between the two drugs At the same time, conbercept was optimized on the basis of arbacip to achieve less frequency of administration and maintain similar clinical efficacy Exinib listed in 2011 can only maintain certain competitiveness in China by policy protection and price advantage, and it is difficult to go abroad, while erlotinib has lost patent protection in China, and domestic generic drugs will also bring great impact to exinib; while conbercept listed in 2014 not only gradually occupied the domestic market, but also went abroad, skipping phase I and phase II clinical trials directly The trial submitted a phase III clinical application to the FDA, which can be said to be of boundless beauty At present, more emphasis is placed on the advantages of new drugs and clinical efficacy in China It is difficult for drugs like exetane to succeed in the future For the biological field with weaker R & D level, it is more feasible to make me too or improve some defects of existing products for some target points with clear mechanism and good market sales, and to develop me too or bioletter products with better clinical significance 2 Overseas cooperation is more frequent In June 2017, CFDA joined the ICH (international coordination meeting on technical requirements for registration of human drugs) Overseas cooperation projects are seamlessly connected Overseas new drugs can enter China earlier to carry out clinical trials, shorten the time for clinical application and listing, and provide a longer patent profit period for local pharmaceutical enterprises At the same time, compared with independent R & D, the introduction of imported drugs is faster, which is beneficial to improving the international R & D capacity of local pharmaceutical enterprises Many imported drugs are generally five or six years behind the United States in entering China With small market competition and the support of domestic policies for local pharmaceutical enterprises, domestic pharmaceutical enterprises have more market potential than foreign ones It is difficult for foreign companies with hot target follow-on products entering clinical trials to compare with the previous "first in class", and the market valuation is generally not too high As the second largest emerging pharmaceutical market, China shows great market potential There is no blank period for the introduction of new drugs from abroad, and the market valuation is often several times higher For example, Fosun Pharmaceutical actively participates in cooperation at home and abroad in independent research and development, introduces kit Pharma's car-t treatment product kte-c19 to treat B-cell lymphoma At the same time, local pharmaceutical companies can transfer their own R & D overseas authority to withdraw funds For example, Hengrui transferred the project of PD-1 monoclonal antibody (Code: "shr1210") to Incyte company in the United States, and Incyte company paid a milestone payment of no more than 90 million US dollars to Hengrui On September 27, 2017, Baiji Shenzhou, through the transfer of the development right of the products under research, jointly developed its PD-1 antibody bgb-a317 with new base company, a pharmaceutical giant in the United States, so as to obtain the other party's advance payment of about 263 million US dollars and 150 million US dollars Jin's equity investment and milestone payment of up to US $980 million in the future have found a large amount of working capital for Baiji Shenzhou under the condition of no product profit, and also obtained the rights of Xinji company to inject paclitaxel, lenalidomide and azacytidine for injection in China 3 Improvement of fast "follow on" capability of local pharmaceutical enterprises In the domestic market, on the one hand, the development of a new drug with slightly worse curative effect than the original research but much lower price can solve the unmet clinical needs in China For example, one product of exetane has created a market value of up to 30 billion yuan; on the other hand, the examination and approval cycle of imported drugs in China is long, and the time of listing of the original research drugs in China is far behind that of foreign countries By introducing products from abroad, we can make full use of the domestic market It is even possible to achieve faster listing than the original research and seize the market opportunity The price advantage, policy support and market vacuum period brought by the approval cycle of imported drugs make the hot target "follow on" become the mainstream trend of market research and development In this wave, many companies can accumulate R & D experience in making money and further improve the R & D strength of pharmaceutical enterprises Taking PD-1 inhibitor, the most popular one at present, as an example, domestic pharmaceutical companies have made rapid progress At present, Junshi, Xinda and Hengrui companies have been in the status of BLA application, and Baiji Shenzhou is also in the phase III clinical trial For foreign markets, BMS, MSD and Roche have basically occupied most of the PD-1 inhibitor market Pfizer and AstraZeneca, the new companies, have a flat response in the market, and can only expand the market through differentiation In the domestic market, Baiji Shenzhou, Xinda and Junshi have all won the favor of the capital market by virtue of the local PD-1 McAb In the absence of profit, they have all started to list one after another to win their IPO 2 Challenges of bio innovative drugs 1 Particularity of bio drug research and development Biological drugs are different from chemical drugs and traditional Chinese medicine Due to the differences between species, the effectiveness and safety of many biological drugs can not be reflected in preclinical animal tests, especially for products like car-t and T-cell redirection double specific antibodies At present, it is difficult to have appropriate animal models Only in human tests can we really carry out the effectiveness and safety research, and its technology Technical challenges and potential risks are self-evident 2 The focus of clinical examination and approval talents in Chinese medicine is generics, and the talents for new drug innovation are insufficient Now, drug innovation also puts forward higher requirements for CDE Since 2016, CDE has begun to expand in large quantities, but professionals in this field are in short supply in China Secondly, the current life-long system of new drug approval responsibility makes every official responsible for approval extremely cautious Even if there is a certain potential risk in the listing of new drugs, how to get rid of the habitual attraction of government agencies is also a big problem 3 The competition of clinical resources the most direct problem brought by the trend of new drug research and development is the competition of limited clinical resources On the one hand, the number of clinical bases is insufficient At present, the public hospitals often do not regard clinical research as the key index to evaluate the top three hospitals The number of bases set up in domestic clinical trials is insufficient Secondly, the lack of innovative clinical research ability In the early stage of pharmaceutical industry, generic drugs were the core, new drug research and development were not emphasized, and most hospitals did not have the technology to carry out clinical trials of innovative drugs At present, the new drugs developed abroad can carry out phase I clinical research in China For the local pharmaceutical companies, the capital and clinical trial team are not dominant, and the clinical resources of innovative drugs that are in short supply will become more scarce The potential risks and unknowability of new biological innovation drugs, in today's complex doctor-patient relationship in China, will lead to what kind of crisis, is also an unknown factor 4 The increasing competition at home and abroad for a target, the market capacity is limited, in addition to "first in class" and "best in class", it is difficult to make a breakthrough in the market However, the domestic research and development of hot targets is a little overheated, which will lead to the waste of clinical resources Taking the most popular PD1 / PDL-1 as an example, there are 15 monoclonal antibodies for clinical trials in China, including 3 BLA applications, 1 in phase III, 1 in phase II and 1 in phase I; there are also 10 monoclonal antibodies for PD-L1, including 1 in phase III, 3 in phase II and 6 in phase I How many of these fast follow on products can stand out in the market? In the past, "conbercept" and "ektini" were able to obtain such a large profit without any competition in China Now, the declaration in these hot fields inevitably leads to the waste of resources of some companies In addition, along with the reform of drug examination system, China will directly report the drugs that have been listed abroad, prevent and treat diseases and rare diseases that are seriously life-threatening and have no effective means of treatment At the same time, if it is confirmed that there is no ethnic difference through research, the drugs will be listed with overseas test data, which will also speed up the time of drug listing for 1-2 years It took only 7 months and 6 months for the third generation EGFR inhibitor of AstraZeneca, ositini and keytruda of Merck to complete the domestic listing process For these hot targets, in addition to the competition with the domestic clustering of new clinical drugs, they also face the impact of accelerating the listing of imported new drugs.