Is high level repetition the next worry of China's biopharmaceutical industry? Alert: PD-1 or the earliest explosion!

Since 2000, there are more than 20 monoclonal antibody drugs on the market in China In 2017, recombinant human tumor necrosis factor receptor antibody fusion protein for injection and baliximab entered the medical insurance catalog, and in 2017 and 2018, all the negotiated drugs had McAb products entered the medical insurance catalog At present, Amgen's "enli" (enacep for injection) is the most popular product of biosimilar drugs on the market in China The biosimilar drugs on the market of domestic manufacturers are recombinant human tumor necrosis factor receptor antibody fusion protein for injection In 2005, Sansheng Guojian took the lead in listing, and now three enterprises have been approved In 2017, there were 8 biological drugs in the top 10 drugs in the world, all of which were monoclonal antibodies Xiumeile, the king of monoclonal antibodies, continued to rank first with us $18.4 billion Although the sales of the three monoclonal antibodies of Roche's family decreased, the total sales were also close to us $20 billion The market potential of the original research drugs is so attractive The research and development of biological similar drugs is not only in China, but also in the world Biological similar drugs have large space, heavy weight, high barriers and low price reduction (10% - 35%), which can obtain larger market and higher profits, which is the reason for many enterprises' layout At present, the research and development of biological drugs in China are mainly focused on six categories of products: rituximab (non Hodgkin's lymphoma), trastuzumab (breast cancer), bevacizumab (colorectal cancer), adalimumab (rheumatoid arthritis, mandatory spondylitis), etanercept (rheumatoid arthritis) and infliximab (rheumatoid arthritis) Taking the current hot CD20 target as an example, the target antibody drugs can be divided into three generations: the first generation of representative products are rituximab, tiemomumab, mainly mouse derived or chimeric monoclonal antibody; the second generation of humanized monoclonal antibody OLAM and the third generation of atozumab (Fc fragment is glycosylated), and the treatment field is not limited to non Hodgkin's lymphoma, It also includes multiple sclerosis, immune thrombocytopenia and so on From the application and registration of the first generation of rituximab, we can know how hot the domestic high-level repetition is: a total of 14 manufacturers have entered the registration and application progress, 10 of which have started clinical application, and only Shanghai Fuhong Hanlin and Shanghai CITIC Guojian have applied for production In 2015, the clinical self-examination was started, and after Shanghai CITIC Guojian withdrew the self-examination, Sansheng Guojian, who received the order, restarted the clinical trial of the product in 2018 The second generation of humanized mAb Shanghai Pharmaceutical also applied for recombinant anti-CD20 humanized mAb injection and was approved for clinical use The third generation of atozhu monoclonal antibody (Fc fragment was glycosylated) at present, baiaotai has applied for recombinant FC glycosylated anti-CD20 humanized monoclonal antibody injection and has been approved for clinical use Table 1: domestic manufacturers of the newly approved products of the first generation of rituximab that have not yet reported for production and clinical application have also been arranged for a long time Patozumab injection was approved in December 2018 in China Patozumab injection mainly produces anti HER2 effect by inhibiting heterodimerization and homology of HER2 Patozumab can combine with HER2 extracellular region II, which is the key region for the formation of dimerization According to Xianda data v3.5, Qilu Pharmaceutical Co., Ltd and Lizhu Pharmaceutical Co., Ltd declared recombinant anti HER2 domain II humanized monoclonal antibody injection as early as 2014 and 2016 This case reflects that the project establishment and research of Chinese pharmaceutical enterprises have been closely following the progress of FDA for a long time 2 as of December 25, 2018, three PD-1 have been approved by the State Drug Administration, namely, imported nevulizumab, pabolizumab and domestic trepril mAb At present, we have also reported the production of shr-1210, Cinda silizumab and tislilizumab / bgb-a317 In addition, more than 30 PD - (L) 1 antibodies in China are in different stages of ind or clinical development Table 2: indications of PD - (L) 1 with high response rate are mainly Hodgkin's lymphoma, fibroproliferative melanoma, Merkel cell carcinoma, etc., with response rate of 50-90% The indications of moderate response rate were non-small cell lung cancer, head and neck cancer, gastroesophageal cancer, renal cell cancer, liver cancer, cervical cancer, etc Baiji Shenzhou, Hengrui and Xinda applied for conditional approval of listing of Hodgkin's lymphoma with high clinical response rate of PD-1, while Junshi was melanoma Bristol Myers Guibao navulieu monoclonal antibody was officially sold on August 28, with a conscience of pricing of 100mg / 10ml of 9260 yuan; 40mg / 10ml of 4591 yuan, with an annual cost of 332-442000 yuan, about 58% of the cost of Hong Kong (58-767000 yuan) On September 19, the retail price of pabolizumab of mosadong company was RMB 17918 (100mg / 4ml) The annual treatment cost was about 300000-600000 for different weights Traprizumab injection, Chinese trade name is tuoyi, industry news said its price is 5000-6000 yuan / 240mg If the price is calculated as 5000-6000 yuan / 240mg, the price of domestic PD1 is only about 20% - 50% of K / O medicine Patients can save at least 100000 yuan a year, and the annual cost is about 120000-150000 yuan 3 the main target of cart in China is CD19, which has 20 clinical products Compared with the European and American cart, it is an attempt of various next-generation technologies, such as allogeneic, controllable, adding McAb switch, new target and so on The research and development direction of China is more homogeneous Nanjing legend's share price fell on September 27, 2018 due to a short report by Yan fire research The query points in the report include that Kingsley biotechnology lacks education and industrial experience in innovative research and development of car-t therapy; legendary biology's patent application has been repeatedly blocked, making it difficult to form a patent protection system; clinical data published on ASCO is suspected of fraud; management chooses high-level cash arbitrage, and steals the interests of public shareholders through hidden share based payment of subsidiaries The questions questioned by Yan Huo Research Institute are actually some common problems of domestic innovative drug enterprises: the achievements of biological innovative drugs in the laboratory stage are gratifying, but the industrial production is basically difficult to achieve amplification; the establishment of intellectual property system is not systematic; the domestic clinical research results are always successful Table 3: reasons for the cluster of cart products 4 targeting CD19: media pursuit? Enterprise transformation needs? Reason 1: media hype? In the Internet age, the publicity of new technology and new products by professional media can be regarded as a side reflection of investment enthusiasm When the academic, industrial and investment circles in the United States talk about high and low technology, the Internet, big data and artificial intelligence often cite the type cycle recommended by Gartner It is worth noting that "type" is not meant to be maturity In English, hype refers to publicity, and tends to refer to an over hyped and exaggerated way of publicity The maturity curve shows the five key stages of emerging technology, which are technology trigger period, expectation inflation period, disillusionment trough period, enlightenment climb period and production peak period Technology trigger is just a concept when technology is just born It has no usability and cannot evaluate the business potential There are reports in the media, which have aroused the interest of the outside world At this stage, with the excessive media coverage and irrational rendering, the popularity of products is everywhere However, with the emergence of the shortcomings, problems and limitations of this technology, the actual failure cases are greater than the success cases During the peak of inflated expectations, technology gradually took shape, and some radical companies began to follow up The media began to report that the popularity of the products reached a peak The excessive attention of the early public has led to a series of success stories - of course, there are many examples of failure, but in the face of the failure trend, only some companies take remedial measures, while most of them are indifferent When the technology is at the peak of the expansion period, the media will be very optimistic about its prospects, most of which will be over touted, and investors will rush in to invest in these technologies with enthusiasm The market potential of biological products, media reports, high-tech threshold, science and Technology Forum, etc all give domestic enterprises very high expectations for the market of McAb, PD-1 / PD-L1, cart During the Trough of Disillusionment, the limitations and shortcomings of technology gradually revealed that the technology still has many bottlenecks, far from what it claims to be, and its expectations will be reduced to freezing point Most of them are eliminated or failed by the market, only those companies that find early users survive hard Media reports are cooling down Investors also withdraw from the market because of the loss of hope; during the slope of enlightenment, the advantages and disadvantages of technology become more and more obvious, the details become clear, more and more people can analyze more rationally what it can really do, and the social evaluation of it will gradually pick up With the emergence of the second generation and the third generation products, the replicable successful use mode appears, which has been highly noticed by the main media and the industry on the market During the peak period of production, after continuous development, the technical standards have been clearly defined, which are more convenient to use, and the market share is higher and higher, entering the stable application stage There is a consensus in the industry From the current media reports, PD-1 / PD-L1 and cart have entered the expected inflation period What China's China's innovation is rarely reported before listing is that the first generation of biological drugs often face price wars after the first few listed companies The price will go into the bubble disillusionment after the war, and finally the manufacturers will beat a retreat Finally, the manufacturers will first divide the market, which is why a company has not Before being approved, it is the most competitive time in China, because everyone always has the expectation that their achievements will be in the forefront of approval The same situation is not only in the field of innovative drugs, but also in the conformity evaluation of generic drugs The second reason: the transformation of enterprises? In addition to media reports and market potential, the urgent need for differentiated transformation of Chinese pharmaceutical companies is also the cause of over investment In the past, there was no foundation in the field of biopharmaceutical cdmo in China With foreign brands entering and traditional enterprises setting up new business segments, scientists in the field of biopharmaceutical R & D and production in foreign countries took the opportunity to choose to start their own businesses, which brought out so many enterprises to participate in the competition Due to the number of manufacturers leading to poor competition, the price of the first generation of growth hormone, EPO and GCSF listed in China around 2004 was less than 1 billion in total domestic sales after the war, which was far lower than the international level of similar drugs For the price war with serious homogenization, domestic enterprises think that the low-level construction of ordinary solid constant release dosage forms has been over invested and started to fight the price war If they want to obtain higher profits, they should invest in higher level industries Few enterprises will choose to invest in large-scale production capacity, improve efficiency and reduce the overall level of the industrial chain in order to earn profits For example, after "4 + 7" volume procurement, enterprises with integrated production of raw materials and preparations can win more opportunities for medical institutions to purchase Many comments in the industry believe that industrial maturity is the integration of production of raw materials and preparations, but with reference to automobile, electronics and other industries, the real industry is mature