2021年10月26日

The road is full of obstacles

Today is a time of great change. The world is undergoing profound changes unseen in a century.

Began at the end of 2018’s strong national policy (in) and medicare negotiations to revolutionize China’s pharmaceutical industry rules of the game as sudden, 40 years of reform and opening-up of China’s generic drug market operating mode is a comprehensive rewrite and innovation, this period of history of generic and innovative drug research and development space is being highly compressed.

For generic drugs, the national centralized purchase caused the domestic generic drug profit cliff decline, into the era of low profit, enterprises are faced with the dilemma of “winning the bid miserily, fail to fail miserily”.

As for innovative drugs, driven by capital, hundreds of start-up BIOTECH companies with innovation and research as their main business have emerged, leading to more homogeneity of fast-follow and me-too innovation in China, and unprecedented fierce competition. Under the influence of national health insurance negotiations, Me-too innovative drugs have become “generic” drugs, and the profit margin has been greatly squeezed. The era of obtaining high returns through national policies has completely ended.

Under the background of great changes in the industry, China’s pharmaceutical industry in 2020 will be totally different from the past. In addition to a number of large pharmaceutical companies (excluding patent Chinese medicines and API drugs) that have grown up during the 40 years of reform and opening up, a number of “start-up” Biotech companies (excluding CRO) have also emerged under the driving of capital. These two types of companies have very different backgrounds, so their development goals, paths and strategies are very different.

Since this year, the transformation of eight years of Coren drug research by investors attention, some people support expectations, some criticism. What is the progress of Coren’s R&D transformation? How is the innovation-driven development strategy planned?

Recently, we have the honor to management team leading members of the institute for drugs in koren [crain’s chief scientist, Dr Dean jing-yi wang; institute chief strategy officer, Dr He, vice President of the institute, generics; Dr Zhao Dong, head of the institute, director of the center for innovation, Dr Song Hongmei; clinical center, deputy director of the institute of Dr QingYan 】 visiting, hope from the background of the era of change, to understand koren transformation of research and development, innovation driving the objective reality of development strategy, in order to better solve the social from all walks of life, especially the high hopes for koren r&d investors’ concerns.

Figure 1 Batch production of major domestic generic drug enterprises from January 2017 to November 2020.20

 

(Data: from the CDE website)

Fig. 2 Development of characteristic technology platform in the Keren imitation sector

 

Table 1 Comparison of innovation achievements in the initial development stage of domestic mainstream innovative enterprises

 

(Note: Starting from the first clinical approval of an innovative drug; Data from CDE website)

Table 2 Comparison of innovation investment and pipeline development in the start-up stage (first seven years) between Coren and excellent Biotech

                                                                           

Table 3 Number of members of Coren imitation and innovation team from 2013 to 2020

Year (year-end) & NBSP;     Number of imitation team & NBSP;     Number of Innovation Team

2013                      190                        50 

2014                      284                        90 

2015                      520                        163

2016                      612                        345

2017                      685                        566

2018                      797                        888

2019                      879                        1024

2020                      882                        1038

Author: Kelun Pharmaceutical Co., Ltd. is a leading enterprise in the domestic infusion industry. In 2013, Kelun Pharmaceutical Co., Ltd. started the innovation and transformation of research and development, and continuously increased the investment in research and development, and has gradually ranked in the forefront of domestic research and development enterprises. As a pharmaceutical company starting from infusion manufacturing, how did you think and plan the R&D strategy at the beginning of the R&D transformation? How to evaluate Coren’s 8-year transformation strategy?

Dr. Jingyi Wang (Chief Scientist, Director of the Institute) :

The pharmaceutical research strategy of Coren is based on the background and foundation of the enterprise, and keeps pace with the development stage of the enterprise and the changes of the industry environment, and constantly evolves and optimizes itself.

When Coren launched its R&D transformation in 2013, it was on the eve of big changes in China’s pharmaceutical industry. As the leader in China’s infusion industry and one of the large domestic generic drug enterprise groups, Kelun has tens of thousands of production and sales personnel and hundreds of large-scale production lines in 16 provinces and regions. However, compared with large domestic pharmaceutical enterprises such as Hengrui, Tianqing, Qilu and Yangzijiang, the research and development foundation is extremely weak. Most of these outstanding enterprises have completed large-scale R&D teams and system construction, imitation and innovation pipeline system layout for many years, at least more than 10 years ahead of Kellen.

Different from the start-up Biotech, the research and development transformation of Cron must take into account the corporate responsibility of seeking welfare and long-term development for tens of thousands of employees, as well as the social responsibility of “big pharmaceutical company”, which is to meet the “economy” and “accessibility” of drug use for Chinese people. In the new era of V3, for “big pharmaceutical companies”, it is more necessary to have the research ability of the key elements in the whole process of research and development, so as to better cope with the homogenized competition and ensure the continuous and stable launch of competitive products. Based on this, Coren can only choose the “Big Pharma” research and development concept and mode, starting from imitation quickly, and learning from the global MNC experience, to start innovation; Thus, the “innovation-driven, endogenous growth” development strategy of “based on imitation, promoting innovation by imitation, and driving the future by innovation” is determined.

Coren’s goal is to achieve the fastest possible output in as short a time as possible with as little capital as possible, and to quickly build a pipeline of generic and innovative products and R&D functions that meet or exceed the capabilities and levels of outstanding peers. The figurative metaphor is two well-functioning, well-functioning, complementary and sustainable R&D machines of imitation and innovation.

In order to catch up quickly, Coren almost started from zero. At the same time, it introduced external projects and established pipelines quickly. At the same time, it took multiple measures at the same time.

Since 2015, China’s pharmaceutical industry has entered an era of great changes. From the “weekly policy” of drug evaluation and approval system reform, to the “consistency evaluation” in 2016, and to the national collective purchase with a large reduction of drug price in 2018, all these have profoundly affected and tested the strategic decision-making ability and strategic adjustment ability of pharmaceutical enterprises.

For Coren, these two rapid, nascent R&D machines, born in the V2 era, faced more challenges in times of upheaval. For example, how to quickly adjust the research program to adapt to the endless new review policies? How to effectively improve the difficulty, characteristics, advantages and cost competitiveness of generic drugs? How can innovative drugs focus more on advantages and avoid homogenization? How to accurately evaluate the performance and ability of the new team members from scratch, and how to optimize the management, match the staff and post and enhance the ability in line with the changing times, so as to realize the transformation from good to strong? These are key elements and capabilities that must be made quickly, adjusted in real time, and implemented throughout R&D management.

In order to make the two machines grow into new machines to support the development of enterprise V3 in the new era, a lot of work must be done in parallel. Construction and improvement, adaptive adjustment and further optimization are carried out almost simultaneously, while not delaying pipeline construction and project promotion.

The road is full of obstacles. In the changing and complex environment of the industry, Coren seized the opportunity, made full use of external resources and promoted the project research, and devoted himself to the building and improvement of the two machines. Spent eight years time, less than 4 billion money, formed with good similar scale and efficiency of imitation and innovation research and development team, constructed with excellent similar imitation and innovation product line and development system, realized the not weak in good peer generic products listed achievement (nearly four years 56 product batch production, ranked the second), even in the background, the new products also accumulated nearly three years to reach the new sales income over 4.5 billion yuan, is significantly higher than the domestic head BIOTECH company sales performance of the same period of time [paekche, cinda, jun of accumulative total sales income is 3.3 billion yuan respectively, 1.94 billion yuan and 1.2 billion yuan (data from the annual reports of various companies)], began to gradually enter a virtuous cycle of feedback and support for continuous research and development investment, in the next three years is expected to be listed about 70; On the basis of the healthy development of the R&D pipeline (13 have been approved, 12 are in the PCC to IND stage, and 36 are in the drug discovery to PCC stage), the innovative drugs are about to complete the “last mile” sprint before marketing, thus promoting the transformation of Cologne from pure infusion to high-tech integrated pharmaceutical company.

In the future, Colon will continue to refine and improve the performance of the two R&D machines in accordance with the national policies and industry changes, so as to strengthen strategic confidence and reach the far.

I: We understand that generic drugs are the foundation of Coren’s R&D strategy. The company has laid out a huge pipeline of generic products. Is there any special thinking and design here? How effective is the actual implementation? The intensity of the state’s collective mining is beyond imagination, causing widespread concern among the investment community. How does Coren deal with this?

Dr. Feng Yi (Chief Strategy Officer of the Institute) :

Throughout the world’s outstanding large generic drug companies, all of them have huge and thousands of product pipelines. Their basic strategy is to reduce costs through scale and establish competitive advantages through product clusters.

Combined with the characteristics of the company, Cren followed a similar strategy: starting from infusion and injection dosage forms, the easy first, the difficult second, the advantages first, and then the difficult breakthrough, and continued to build a characteristic and advantageous product cluster.

To achieve rapid listed products, quick returns, fast into the input and output of a virtuous cycle, at the beginning of transition, koren from clinical demand satisfaction, public places, technical difficulty, cost and development cycle and other science and market dimensions, at the top of the generic pipeline design and short, medium and long products pipeline system layout.

Over the past eight years, Colon has formed a positive cycle of continuous research and development investment and continuous output in the fields of general injectable and infusion drugs, general oral preparations, complex generic drugs and improved innovative drugs.

In the field of infusion and injection, which is the basis of the industry, 27 new products have been approved since 2017, including the first major imitation varieties such as parecoxib and zoledronic acid, the iterative varieties such as Ringer sodium bicarbonate and moxifloxacin, and the upgraded varieties such as Duote and Duoja for multicavity infusion of enteral nutrition. At present, the capacity of the 13 infusion production bases is basically saturated, and 62 pipeline projects are under development, which will ensure the continuous value increase of the Colon infusion and injection industrial system.

Oral preparation field, in 2018 the first regular oral preparations of batch production, has approved 24 (generics 10, 14 consistency evaluation), the treatment of which, for the occasional method, mooring paxil, vardenafil, Glenn net products such as approved for logo, koren generics have substantial into the tumor, autoimmune male, major disease, diabetes and other fields. Ten varieties won the bidding in the national collective procurement, and obtained the national market access qualification for non-infusion varieties.

In the field of complex generic drugs and improved innovative drugs, the company has formed a cluster of superior products with the focus on difficult platforms such as liposomes, nanoparticles, fat milk, contrast agents, powder and liquid double-compartment bags, inhalation preparations, and transdermal preparations, and laid out 127 complex generic and improved innovative drug pipelines. In 2020, paclitaxel albumin and propofol medium and long chain fat milk will be launched successively, marking the completion of research and development, clinical and marketing closed-loop of Collen’s complex generic drugs.

Since 2017, 56 products have been approved for production (the first copy/the first 22), ranking second in the approved number in China, second only to Qilu by a difference of two products (as shown in Figure 1).

This batch of new products listed in a row, established a koren in parenteral nutrition, bacterial infection, and products in the field of fluid balance cluster advantages, begin to enter tumor, diseases such as cardiovascular, male narcotic analgesia and areas and gradually strengthened, and has good market returns for columbine, and began to gradually into feedback and support continuous research and development into a virtuous cycle.

In the next three years, more than 70 generic and improved innovative drugs will be launched by Coren. Parenteral nutrition of technical barriers to multicellular bag, fat milk, powder, liquid double chamber bag/emulsions, such as contrast agent platform is expected to enter mass production phase, koren will further strengthen the bacterial infection, parenteral nutrition, tumor, cardiovascular, narcotic analgesic, breathing, male disease fields such as product cluster advantage, and began, diagnostic imaging in diabetes, kidney disease and other major disease or characteristics, form new product cluster.

After 2018, in the face of the challenges in the post-harvest era, Collum has focused on building more advantages and characteristic technology platforms (see Figure 2), further increased the approval and research and development efforts of complex raw materials, complex preparations, NDDs and improved innovation projects, and moderately reduced the approval of projects with low technical threshold. These long development cycle, high technology threshold generic drugs are likely to win no less than the profit returns of innovative drugs. (As shown in Figure 2)

In is a double-edged sword, in the low technical threshold of generic drugs into the red sea, and will accelerate the industry evolution, generics firms highly centralized, industry profits return to normal levels is the foreseeable future, there will be a koren a place here.

I: Over the past year, we have noticed that many investors have paid close attention to the approval of the Claron generic drug project and the high subsidy rate. There have been some criticisms. What is the company’s view on this?

Dr. Dong Zhao (Vice President of the Research Institute, Head of Generic Drug Research and Development) :

Indeed, we media articles asked Coren with a precise list of projects why some generic drug projects have not been approved. In particular, the company commends the authors for their responsible attitude in following Coren’s research over the years. It is somewhat regrettable that the data disclosed in the article are not accurate: Pending projects, there are ten projects already approved but not be counted in the column (hydroxyethyl starch 130/0.4 electrolyte injection, moxifloxacin hydrochloride, propylene ammonia acyl amino acids glutamine (18) injection, long chain fatty milk/amino acids (16)/glucose (16%), the electrolyte injection, amino acid and glucose injection spirit wheat N9G15E (g), amino acid (16)/glucose (48%), the electrolyte injection aa – special (16), fat milk (10%)/amino acids (15)/glucose (20%) injection (N4 interchange, franklin d – 550), Vardenafil tablets, fat milk amino acid (17)/ glucose (11%) injection, propofol medium/long chain fat emulsion injection, etc.); 15 projects have been terminated voluntarily after the team comprehensively assessed the competition situation and future market value under the situation of collective mining; The rest of the projects are on par with their domestic counterparts, with one approval expected in 2020, 12 in 2021, 10 in 2022 and 7 in 2023-2024.

The construction time of the generic drug research and development system of Colon is shorter than that of its excellent peers, but its current research and development level and strength are on a par with each other. There are five passes, beheaded the brilliant, there is also the failure of Mai Cheng frustrated.

For example, paclitaxel albumin is of four generic types. Although the application of Claron was late (the sixth company), it was approved quickly (the fourth company). Docetaxel albumin and irinotecan liposomes are two types of improved innovative drugs. Their research connotation and time requirements are similar to those of innovative drugs, but they are totally different from those of the four types of generic drugs. The progress of Cologn is basically the same as that of domestic counterparts. The clinical sample supply time was delayed due to the need to build a new production line of sterile raw materials for Aripiprazole Microcrystalline, and the clinical progress was slightly delayed. Currently, Aripiprazole Microcrystalline remains the first one in China and is being fully enrolled.

Some investors questioned Claron’s generic strategy by taking the case of Parecoxib in Shandong as a case of 90% price reduction. However, this just proved the correctness of Claron’s generic drug research and development strategy of “speed, characteristics, difficulty and cluster”. Never mind that when Colomperecib was launched in 2013, no one would have predicted that by 2018 there would be a national gathering of drastically reduced prices; It is a very successful case of rapid imitation since its first listing in 2017, and its profit return has been more than 30 times of R&D investment. Moreover, in the field of anesthesia and analgesia, parecoxib is only the first project of Colen, and the follow-up products will be launched continuously, which will ensure the market advantage and continued profitability of Colen in this field of treatment. Propofol and dexmedetomidine, with a market capacity of 2 billion, have been approved.

The construction of product cluster is the consistent generic drug R&D strategy of Colon, and the occurrence of cluster purchase objectively proves the foresight of Colon’s initial strategic choice. The advantages of Colon’s product cluster are enough for the company to calmly deal with the cluster purchase.

At present, Colon imitation R&D has built and gradually improved a matrix R&D and control system that is suitable for the present and future, covering pipeline construction and evaluation, project promotion and control, clinical research, release application and approval, production and commercial transformation. It is particularly worth mentioning that since 2018, Colon has put efforts to build a quality assurance system covering the whole process of imitation research and development. Through scientific and compliant release, research defects have been reduced year by year in the past three years, and no major defects have been issued in 2020. The improvement effect of research quality and efficiency will be reflected and released in subsequent outputs.

Author: The research and development achievements of Claron’s generic drugs are obvious to all. We pay more attention to Claron’s innovative drug research and development. At present, different types of domestic enterprises have different innovation models, some of which are particularly sought after by the capital market. May I ask what kind of strategic thinking and top-level design does Coren carry out for the research and development of innovative drugs? What innovative results have been achieved? How do you evaluate the innovative research and development work of Coren in these years?

Dr Fung Yi:

Coren’s innovation started in July 2013. For seven years, draw lessons from successful experience newsun focus, in the full use of external resources, strengthen the construction of pipelines and promote research projects at the same time, focus on their own ability construction, have to quickly build functional target validation, the molecular design and optimization, preclinical and clinical research, translational medicine is closely involved the complete innovation system, to achieve improved the differentiation innovation research and development success rate, the entire mining clinical advantages, realize the goal of high quality innovative products continue listing.

Compared with the capital-driven, license-in-led Biotech, Coren adopts a different innovation model and path. The construction of functional platform and system is more complex, and it will inevitably take more time to perfect and mature. In the long run, this is the price we must pay and the process we must go through. Coren believes in a simple truth: to sharpen a knife and cut wood, one must sharpen his tools.

Coren’s construction of full-function innovation system emphasizes its own capacity building based on the following considerations:

First of all, only through a sound research system can the design and control of the whole process of the project be achieved, so as to better cope with today’s cruel homogenization competition, and to truly achieve better, best, and even the future first.

Secondly, only with strong ability can we effectively select and use external resources, including CRO, various external cooperation and license-in.

Third, self-research projects will have more project rights and interests and have the opportunity to explore more commercial values based on rights and interests, such as license-out.

Fourth, excellent self-research ability and commercial development ability can make national pharmaceutical enterprises have the opportunity to stand on their own in the global pharmaceutical world.

It is difficult to determine which is better or worse in the short term. I believe that after five to ten years of testing in the commercialization process, a consensus will be formed in the industry when the tide recedes.

At present, 13 clinical research innovation projects (including 3 biosimilar drugs, 5 bioinnovative drugs and 5 innovative small molecules) have been approved by Coren. More than 20 clinical studies have been carried out, including 2 clinical registrations (A167, A140), 1 clinical phase II (A277), 1 clinical phase Ib (A223), 4 clinical phase Ia (A264, A204, A168, A206), 2 clinical preparations (A289, A293), and 2 clinical deferrals (A157, A212). 5 items have been pushed to IND and prepared for IND, and 7 items have been PCC to IND.

Coren has long adhered to the advanced standards in the industry. It can be seen by comparison that the results (number of approved clinical projects) in the first five years after the introduction of Coren’s innovation projects into the clinic are excellent, exceeding the results of some enterprises in the first 10 years (see Table 1). This means that it only takes five years for Colon to complete the workload of these enterprises for 8-10 years, and in this process, it has established a relatively complete innovation research and development team and system, and laid a solid foundation for the output of the next five years. It is expected that Colon will apply for new IND 5-6 in 2021. (See Table 1)

Compared with the emerging excellent Biotech, Colon has built the largest number of clinical pipelines with less investment and the most complete full functional development system for innovative drugs (see Table 2).

Author: Although domestic innovative drug research and development remains extremely hot, the national medical insurance negotiations have made the industry cautious about the prospect of fast-follow and me-too innovations, especially the monoclonal antibody and dual-clonal antibody trends that are extremely hot in the macromolecule field in recent years. How should Karen deal with the serious problem of “homogenization” of domestic innovation?

Dr. Song Hongmei (Director of the Innovation Center of the Institute) :

In recent years, the government policy orientation and capital actively promote the research and development of innovative drugs in China, but the homogeneity is serious, the innovation quality is generally not high.

In 2018, Collum took stock of the situation and began to adjust and optimize its innovation strategy and R&D management system, gradually moving from follow-on innovation to comprehensive pursuit of differentiated advantages and international value innovation, and started to engage in breakthrough innovation with first-in-class opportunities.

In order to ensure the effective implementation of the innovation strategy, Coren has made great efforts to optimize and adjust the management of the innovation research and development system, such as:

The management and control mechanism to guarantee the R&D goals of ME-Better has been established, and the project management elements, processes and decision-making mechanism of ME-Better have been carefully identified “from project approval, new drug discovery, preclinical development, clinical research to production cost control and other processes”, and the matrix management has been implemented through the technology platform driven by the project leader (PL).

Based on target value, the research strategy and market expectations of project classification management and dynamic adjustment mechanism, and based on the technology platform development, build step by step in order to better “similar” (Me – better) is given priority to, a small amount of similar “First” (First – in – Class) biological technology and innovation of small molecule drug development pipeline, retain only a small amount of matching specific disease areas combination needs Me – too Class project.

Focus on strengthening and upgrading superior technology platforms, such as ADC platform and structure-based precision pharmaceutical design (SBDD); In addition, the innovation risk and investment are effectively controlled by means of internal self-research and introduction, cooperative co-development, and phased goal of patent layout for some early projects with high innovation degree.

There are also we-media talk about Karen’s enthusiasm for monoclonal antibody. In fact, it is not only Karen, the leading domestic pharmaceutical companies and Biotech are keen on monoclonal antibody, which is the current global pharmaceutical innovation research and development hotspot. The main reason is that the technology of monoclonal antibody is mature, and the risk of clinical druggability is lower than that of small molecules, and it is easier to fast-follow. Monoclonal antibody projects account for about 40% of the Coren Biotech pipeline, which is relatively reasonable and uses external collaboration to share development risks (e.g., A289, A293). More importantly, the foundation of monoclonal antibody technology is necessary for the deployment of emerging products such as ADC, dual antibody and even CAR-T, and this is how the Collen ADC and dual antibody pipeline was built.

The development of bispecific antibody has been very hot in recent years, and the first project (A337) has submitted an IND application. The core of double antibody is target combination and structure design. Target combination requires in-depth understanding of related biological mechanisms and synergistic effect between targets. In terms of structural design, although there are hundreds of structures in various stages of research around the world, there are still great risks in terms of which ones can actually be transformed and demonstrate the expected efficacy and safety in clinical practice. In this regard, Coren, after a full scientific evaluation, adopted a more cautious attitude, active intervention, but not rushed to avoid becoming a “martyr”.

In health care and the cause of the negotiation general single product profit forecast the future market uncertainty, more than single resistance, all domestic peers rush targets and projects, regardless of the imitation and innovation, will face a big price cuts in crisis and health talks, breakthrough method only differentiation (difficulty and characteristic, the Me – better or more advanced First – in – Class), combination of its own pipeline, drug use and cost leadership.

With the support of mature technology platform and scientific management system, the R&D capability and efficiency of Cologne innovation team have been steadily improved. After A166 and A264, more than 10 new generation ADC projects including different warheads, Linker and antibody strategies have been carefully laid out, covering different indication populations. In addition to strengthening pipelines, it also seeks competitiveness in the cost control of antibody production. By optimizing cell lines to increase the expression level, self-developed culture medium and new process development, and replacing equipment and consumables domestically, the supply chain is optimized on the basis of guaranteeing product quality, so as to achieve the cost equivalent to or lower than that of similar drugs. On the premise of guaranteeing the ME-Better goal, the innovative small molecule focuses on the key projects of the first echelon and makes a breakthrough in resources. Recently, some projects have taken less than 3 years from project approval to pre-IND application, which is faster than the average level of the industry.

I: Clinical research is the last, core and most important work in the research and development of innovative drugs. Just now I mentioned that a large number of innovative projects have entered clinical research or are about to enter clinical research, which is of great concern to investors. Could you please talk about the progress of Coren in this regard?

Dr Fung Yi:

The construction of clinical research system of Coren was started on the weak basis that it could only carry out simple BE research in 2017. It has been less than 4 years since Coren was fully engaged in the construction of clinical research functional system. However, most of the excellent peers such as Hengrui and Tianqing have mature teams, systems and experiences that have been polished for more than 10 years.

The clinical research platform, the last relatively weak link in Colon’s two research and development machines, is in a critical phase of climb. Most of the team members are newly joined, and the learning accumulation of new knowledge, the fluency of cooperation and collaboration, and the operating efficiency of the functional platform are all in the process of progress. It still needs some time to complete the research experience accumulation of the new team in more innovative projects and the run-in of the functional system. Investors are more skeptical about the efficiency of Coren’s clinical research, which is understandable, and the Coren team itself is also worried.

Introducing high-end clinical talents is also not easy. On the one hand, the global newsun focus with innovative Chinese medicine clinical research and scientific management experience all the already scarce high-end talent, on the other hand, the domestic innovation to the war for talent, regardless of cost more in the sham as the genuine, good and bad are intermingled, or part of the talent market goods, need to enterprise cost price more and more time to separate the wheat from the chaff and effective use, koren pay a big price.

Koren clinical research team still in spite of the difficulties in the rapid growth and progress, has formed the project director (PL), medicine, medical science, medical monitoring, medical affairs, medical information, medical writing), translational medicine, project management, operations, data management, statistics, and programming, pharmacovigilance, clinical complete system of laws and regulations, the function such as drug administration affairs platform, team of more than 40 people from early 2017 to about 300 people.

Clinical research management system is the basis of scientific and efficient promotion of clinical research. Since April this year, while continuing to make every effort to introduce high-end clinical research talents, Coren has vigorously promoted the major reform of clinical research management system. The core work is to build matrix management and integration promotion mode based on the whole clinical research process of the project. Based on the scientific connotation and elements of the project in different fields and stages, the internal functional platform, researchers and their teams, the CRO company and the external expert resources in various fields are influenced to fully realize the linkage between internal and external research teams. Formulate project strategy, research path and milestone plan scientifically and organize implementation; Scientific decisions based on data were made at key decision points of the project, and clinical development strategies and research designs were continuously optimized during the research process to create differentiated advantages, which greatly improved the efficiency and quality of clinical research of innovative projects.

After four years of rapid progress, the innovative clinical research system of Coren is doing its best to carry out the “last mile” sprint before the launch of the Pioneer project, striving to complete the clinical research and registration of the first innovative project throughout the whole process. It is believed that the accumulation of these experiences, lessons and Know-How will lay a solid foundation for the rapid promotion of A166, A264, A223, A277, A204 and other innovative drugs with important scientific and market value.

Author: Although Kelun Pharmaceutical has made unremitting efforts in the construction of clinical research system for four years, many investors still think that the research progress of the company’s clinical pipeline projects is not as expected. What is the main reason?

Dr. Yan Qing (Deputy Director of the Clinical Center of the Institute) :

Clinical research is one of the largest link, the enterprise cost at hundreds of giant, need both scientific research level of outstanding strategic design, outstanding research plan and effective implementation, and according to the progress of the projects in the pipeline, data characteristics and advantages of dynamic selection and prioritization of projects forward, this is the overall balance of science and management decisions.

The research progress of some projects in the clinical pipeline of Coren has not been expected by the outside world. This is due to the reasons that the team is still in development and progress, the scientific connotation and technical difficulty of the project itself, and the active strategic adjustment of the company. Such as:

In terms of macromolecules, the initial indications of the A167 project have entered the final sprint before marketing, and multiple drug combinations are being fully developed and promoted. Two ADC projects, A166 and A264, have been adjusted to the highest priority level due to their outstanding characteristics and excellent data. These three projects have received the maximum human and financial support and will soon carry out clinical studies on multiple indications. Other projects, such as A140 and A168, have been affected to a certain extent and are seeking new resources for rapid promotion. Project A157 was put on hold due to poor clinical data from the original study (no positive results were obtained for the indication of chemotherapy-induced thrombocytopenia).

In terms of small molecules, A277, A223 and A204 are progressing smoothly. The healthy subjects’ study data have been obtained, showing good safety and PK data, and the safety risks of proprietary drugs have been basically released. The model-based efficacy verification has been supported by data, and clinical efficacy data will be released one after another as the project progresses.

Non-tumor chronic disease projects (such as A223 and A204) need to be completed in phase I and obtain the dose climbing data of single dosing in healthy people — multiple dosing in healthy people — patients, so as to gradually verify the drug efficacy; Compared with conventional stage I oncology drugs, direct use of patient FIH to explore MTD and indication signals has obvious scientific connotation, research content and difficulty, and the former usually takes one and a half years or longer.

At present, Colon has established a relatively mature mode of promotion and risk control in the clinical development of non-oncology small molecule projects, especially through the integration of medical and clinical pharmacology, which will greatly reduce the subsequent confirmatory clinical risks.

A206 (gemcitabine modification project) has a high degree of innovation in prodrug design and the administration route is changed to oral administration, so it is extremely difficult to verify medicinal properties. The global clinical development of oral dosage form gemcitabine or gemcitabine predrug has not been successful (out of 6, 5 have been terminated, and only 1 soft capsule D07001 is in phase I/II study). Therefore, Coren has adopted a more conservative study strategy for the A206 program and is still in phase I exploratory dosing regimen. The follow-up confirmatory clinical trials will not be carried out rashly before the definite clinical advantage data are obtained and the risk of drug formation is fully released.

A212 (Remazolam Modification Project) had a long period stability defect during clinical initiation, which was caused by the poor physical and chemical properties of the compound itself. After a thorough assessment of the time and expense required to resolve the issue, as well as the competitive landscape and changing business outlook, the team has decided to postpone the clinical push.

As for the project of ceftoam sodium mentioned in the We Media, it is a new drug of IND stage “salt change” which was directly developed and introduced by Kelen from universities before 2012, and was clinically approved in 2016. In the comprehensive evaluation of the team preparing for the clinical study, it was considered that the product did not have significant differentiation characteristics, nor did it comply with the new national CDE review rules, and the risk of future application was extremely high. To make things even more difficult, tens of millions of dollars would have to be spent to build a production line for lyophilized antibiotic preparations for the product, so the project was terminated in 2016.

It is an industry consensus that innovative drug research and development is at high risk, especially for chemical drug small molecules. There are numerous cases of MNC “killing” projects and constantly eliminating substandard projects around the world. Colon’s innovation team and system will inevitably encounter such problems in the process of development and maturity. The team has timely and systematically summarized the experience and lessons, and constantly improved the consideration dimension of early R&D target parameter setting, laying a solid foundation for subsequent research and development of projects with good medicinal properties and differentiated advantages (such as toxin molecules of A277, A223 and A264, etc.).

In order to avoid falling into the dilemma of homogenization, Colon began to upgrade its innovative pipeline layout from the aspects of drug target and mechanism innovation, molecular structure novelty and other aspects in 2018, and will continue to make dynamic adjustments according to the global research and development frontier and the change of competition situation. Therefore, it is inevitable that a few innovative projects will be terminated or suspended during clinical research in the future.

By analyzing the clinical research process of the leading innovation in China, in the first 10 years since the first project was approved, a total of 9 projects entered clinical practice, while the actual number of batch production and listing was only one. This shows the difficulty of innovative clinical research.

Based on the current schedule, Coren expects NDA in 2021 for A167, 2022 for A166 and A277, and 2023 for A140 and A264. The time from clinical approval to NDA is about 4-7 years, with an average of 5 years. According to the analysis of clinical research time of Hengrui’s approved innovative drugs on the market, the period from clinical approval to NDA ranged from 3-8 years, with an average of 5 years. The speed of clinical research of Keren was at the average level of the industry. Compared with the ten years before Hengrui started its innovation, the number of approved clinical trials and the speed of research have been significantly improved in the 7 years since Kelen started its innovation.

Through continuous optimization and adjustment, the clinical research function and operation of Cologne innovation machine has become more complete and smooth. Through the effective use of domestic and foreign innovation resources (such as CRO), it is expected that the follow-up expansion and promotion speed of the project will continue to improve.

Author: Talent is the most basic and core productivity factor of drug research and development. Kelun Pharmaceutical has been expanding its R&D team for 8 years. What is the concept and method of team building of the company? How does the company view the external concerns such as high turnover rate of the company’s R&D team and management problems?

Dr. Jingyi Wang:

If you want to build a temple, find the pillars to help you.

Koren since start transformation, implemented a good soldier of talent strategy, in the industry competitive salary, welfare benefits, from the global pharmaceutical industry continued to introduce with common struggle idea, profound specialized technology, research and development experience and management ability of high-end talents, combined with the research and development function system construction and project development demand, matching appropriate scale of r&d personnel at the grass-roots level. In order to better introduce outstanding talents, motivate the team, and fully bind the interests of team members with the future development of the company, Colon successively launched two exceptional equity incentive schemes for the innovation team and the imitation team, which is unprecedented in China’s big pharmaceutical companies.

At present, the copycat research and development team of Coren is nearly 900 people, which is close to the staff size of well-known domestic pharmaceutical companies. The innovation team, including production quality personnel (more than 300), has a total of more than 1000 people, which is similar to the scale of the top Biotech personnel in China. The development process of team members is shown in Table 3.

After eight years of development, the research and development team of Kelen has grown from small to large, from weak to strong, and has gradually formed a stable and sustainable talent echelon (high-end: middle level: basic level =1:3:6). Koren institute new introduce talents quantity per year is always significantly more than the number of departure (nearly five years, talent net increase the quantity minimum for 209 people a year up to 466 people), high-end talent and always maintain staff turnover rate in a reasonable interval [in recent five years was 11.5%, the average turnover rate of high-end personnel was 9%, below the industry average turnover rate; pharmaceutical r&d industry of foreign enterprises in 2019 the average turnover rate is 27.9%, domestic enterprises for 20.8%; Internally-trained talents start to stand out and step into important positions. Newly introduced or internally promoted newcomers often show higher professional ability and professional quality, and the overall strength of Colon R&D continues to strengthen.

At the same time, the institute attaches great importance to the construction of a research and development system, through which various specialties are organically integrated, so that talents of various specialties can give full play to their strengths. Effectively deposit and inherit the accumulated experience and knot-how through the system; The R&D efficiency is ensured through continuous system optimization, process transformation and institutional improvement, and rapid adaptation to drastic changes in the external environment. With a sound system, the work of the research institute will not be completely dependent on individuals, and the departure of some staff in the system will not have a substantial impact on the research and development work.

There is no rigid management position in the institute. All the management is oriented to improve efficiency, smooth process and clear responsibility, and the development goal is to quickly adapt to the needs of research and development system and innovation ability in the new era of V3. The job responsibilities of managers at all levels are usually adjusted actively according to the system needs and capability assessment results, which is not only necessary for the continuous optimization of the R&D system, but also necessary to actively adapt to the changes in the competitive environment. Enterprise change and resistance often comes from the enterprise internal process optimization, especially the high-level management personnel, out of the comfort zone, active completely-new is never easy, a few team members can not adapt to change, or can’t withstand the temptation, and walked out of phenomenon is very common, enterprise management experience of should have immediate awareness.

A door-hinge never gets worm-eaten, and running water never gets stale. For enterprises, the rational flow of talents is normal, but only a pool of stagnant water is terrible; Only you know how to recognize and use talent, like a shoe that fits your feet. A truly excellent team can only be built by continuing to clean up the sand.

I: Through the interview and interaction with you, I can deeply feel the difficulty of private enterprises’ R&D transformation. As a leader of Coren R&D, I hope President Wang can talk about his personal feelings at last.

Dr. Jingyi Wang:

The year 2020 marks the eighth year of the R&D innovation transformation almost starting from zero. Under the guidance of the development strategy of “innovation-driven, endogenous growth”, the R&D strategy of “imitation-based, imitation-driven, innovation-driven future” of Colon has reached the expectation and achieved remarkable results.

Generic machine not only quickly completed and improved innovation team, research and development and construction of pipeline system, and has set up a schedule to deliver good market back to camp, new products in 2018 has implemented new sales amounting to 4.5 billion yuan, the head BIOTECH companies is significantly higher than the same period of sales performance, and began to gradually formed to endogenous innovation high input feedback and support a virtuous cycle, if did not occur in, perhaps has been achieved considerable efforts to support effect.

The long-cycle and more complex innovation machine has completed the building of two key elements, team and system, and started to work well. There are abundant pre-clinical pipeline reserves. The forward project of the clinical pipeline is sprinting towards the achievement realization of the last kilometer, and the follow-up projects have gradually emerged (such as the ADC project).

Innovation is hard. For koren innovative drug research and development, only seven years of innovative machine itself needs a new grinding and mature process, policy and competition environment change and need koren constantly in the process of maturity to readjustment, optimization and upgrading of the machine, for koren innovative drug research and development management team, this need wisdom, courage, patience and enough time to complete.

Innovative drug research and development of long period (8-10) determines the koren haven’t reached the innovation achievements of stage, high risk and uncertainty determines not every innovation projects can be inevitable success or reach the expected progress, extraordinary money demand determines the koren profits will still be affected by the obvious, koren is trying to explore the feasible path with the aid of capital strength to promote innovation and development.

Coren does not expect all investors to understand and support Coren’s innovation-driven strategy, but only hopes to reach a consensus on understanding with people of insight who adhere to long-term philosophy, have a deep understanding of the connotation of innovative drug research and have a keen insight into the future development trend of pharmaceutical innovation in China. A little more patience and tolerance, a little more awareness of the risk of innovation, and a little more support for the continuous progress of Karen. Coren’s innovative drug research and development has not developed to say that they are excellent or excellent moment, but the team must be the most hardworking, the most selfless group.

Innovative drug development is a marathon, not a race. It is Karen’s consistent style, which can also be called obsession, to keep the original intention and achieve what we want to do. Karen is making steady progress on the long-term road driven by innovation.

As Chairman Liu Gexin said to the institute, “what a gentleman takes is far away, he must be treated accordingly.”

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