✔ With its strength in molecular design, CGeneTech has conducted head-to-head clinical trials with selegiline, an optimised DPP4 inhibitor, and has a number of diabetic areas under its belt.

✔ CGeneTech is also leveraging its "integrated drug discovery technology platform" to accelerate its presence in oncology innovation.

✔ CGeneTech has a strong focus on commercial opportunities and possibilities and is therefore involved in a wide range of areas and directions.

　　In 2006, Merck Sharp & Dohme's selegiline was launched for the treatment of diabetes, the first DPP4 inhibitor approved in the world. At that time, Qiang Yu, co-founder and CEO of CGeneTech, was running a company in the US that focused on providing drug precursor compounds using fragmented drug discovery technology.　　After the launch of selegiline, Yu discovered that there was room for improvement in the product's fit with its target, DPP4. Driven by this discovery, Yu Qiang's company synthesised a number of compounds for this target and compared them to the published content of selegiline. These compounds eventually demonstrated comparability with selegiline, which made Yu Qiang realise that this could be the right direction, an opportunity for optimisation.
　　A molecule with potential for optimisation in a promising field became the opportunity for the founding of CGeneTech, and in 2010, Yu Qiang returned to China and founded CGeneTech in Suzhou with Ding Torping. With a strong focus on molecular design, CGeneTech launched a head-to-head clinical trial with selegiline around the optimised DPP4 inhibitor, CGeneTech, and conducted a series of layouts in the diabetes field. And behind the company's vast product pipeline, which encompasses diabetes, cancer, rare drug generics and even class 2 modified products, lies the vision and logic to seize the business opportunity.

　　Centigliptin after the evolution

　　It is clear that CGeneTech was founded with an optimised DPP4 inhibitor as a key direction.
　　After designing, synthesizing, testing and optimizing a total of almost 50 compounds, CGeneTech was selected to enter preclinical development.
　　Yu Qiang said that CGeneTech aims to develop the best-in-class DPP4 inhibitor, so the entire development process of Shengliptin, including preclinical and clinical studies, has been head-to-head with the earliest marketed and highest-selling selegiline in the field.
　　"Chronic diseases require long-term medication, and as a diabetic drug, the main focus remains on the two main components of safety and efficacy. On these two points, Shengliptin is quite comparable to selegiline, and Shengliptin also shows some advantages in some of the indicators." Yu Qiang told R&D Guest.
　　In terms of safety, both preclinical and clinical study data showed a better safety profile for selegiline than selegiline, with selegiline side effects similar to those of the blank control, basically target-related side effects, and no arthralgia, a type of side effect that selegiline has. In terms of the percentage of side effects, there were no serious side effects (SAEs) for either selegiline or saxagliptin, with a lower percentage of AEs for selegiline.
　　In terms of efficacy, the Phase I head-to-head clinical study showed that 50mg of selegiline achieved the same level of glycaemic control as the approved selegiline dose of 100mg and had a longer drug half-life than selegiline. The use of 50mg as the final dose of selegiline means that the product has a greater safety window, lower side effects and lower cost.
　　Centagliptin completed preclinical studies in 2016, formally entered the clinical phase in early 2018 and is currently in Phase III clinical. One of the more noteworthy developments is that in November 2019, Shenggliptin was approved by the Center for Drug Evaluation of the State Drug Administration (CDE) to be exempted from the Phase II clinical phase and enter directly into the Phase III trial. This is one of the key reasons for the product's faster clinical progress.
　　According to Yu Qiang, a more detailed design and data were needed upfront to achieve the Phase II clinical exemption. Firstly, the Phase I clinical trial of selegiline enrolled 194 subjects, which is a large number of cases and allows for more adequate data to be obtained to better examine the safety of the product; secondly, a head-to-head study of selegiline was introduced in the Phase I clinical trial and two cohorts of healthy subjects and patients were set up, which is more convincing; finally, CGeneTech collaborated with Professor Jiang Ji of Peking Union Medical College Hospital, and with the help of Professor Jiang Ji's quantitative Lastly, in collaboration with Professor Jiang Ji of Peking Union Medical College Hospital, we used Professor Jiang Ji's quantitative pharmacology platform to simulate the dosing schedule, dose, and glycemic control and safety of patients after dosing in a Phase II clinical study, in conjunction with the Phase I clinical data of Shengliptin.
　　After this series of preparations, Centene submitted the Phase I data together with the Phase II simulation data to the CDE, and after a comprehensive review by two CDE departments (efficacy and safety, and pharmacokinetics), the product was exempted from the expert meeting and approved to proceed directly to Phase III clinical trials without the need for a Phase II clinical meeting.
　　In accordance with the CDE's requirement of six months for efficacy-related studies and one year for safety studies, Centigliptin has developed a Phase III clinical programme for the product: two clinical Phase III studies have been carried out on Centigliptin, one on its own and one in combination with metformin, which are being promoted in more than 120 hospitals across China and are expected to include a total of around 1,000 patients. The two Phase III studies will draw on each other with some blank samples and high dose groups to examine the final safety profile and seek innovative and cost effective clinical protocols. The Phase III clinical trial has already completed partial patient enrolment.
　　It is understood that the Phase III clinical trial of Centagliptin is scheduled to be completed by mid-2022, with a New Drug Application (NDA) expected to be submitted in July of that year.

　　A DPP4-focused diabetes treatment cohort

　　The treatment approach for type 2 diabetes is related to the course of the disease itself, usually starting with dietary control and increased exercise, after which the first-line oral drug metformin is preferred, followed by a DPP4 inhibitor alone; as the disease continues to progress, a DPP4 inhibitor may be considered in duplex or triple combination with metformin or an SGLT-2 inhibitor; further progression is considered with injectable GLP-1 receptor agonists or insulin.　　As can be seen, DPP4 inhibitors are a rather important part of diabetes treatment. a report published by Evaluate shows that the global diabetes drug treatment market reached a size of US$46.1 billion in 2017, of which global sales of DPP-4 inhibitors and combinations reached US$13.438 billion, accounting for 29.28% of the total size. According to information from the annual report of Merck Sharp & Dohme, the best-selling selegiline and its combination with metformin will have sales of US$5.52 billion in 2019.
　　Precisely because of the importance and market potential of DPP4 inhibitors, the layout of CGeneTech in the field of diabetes treatment is also mainly focused on the DPP4 inhibitor selegiline. According to Yu Qiang, the company has an existing combination product of Shengliptin and metformin in its pipeline, which is in preclinical studies. There is a possibility of developing a combination product with SGLT-2 inhibitor or a triple combination of Shengliptin + SGLT-2 inhibitor + metformin in the future. In addition, the company also plans to introduce an oral GLP-1 receptor agonist, which is expected to be available for pre-clinical studies next year. This layout basically covers the various target directions of oral diabetes drugs.
　　At present, five single-sided DPP4 inhibitors, namely Selegiline from Mercer, Alogliptin from Takeda, Ligliptin from Boehringer Ingelheim, Saxagliptin from AstraZeneca and Vigliptin from Novartis, have entered the Chinese market, while four other combination products, namely Selegliptin Metformin Tablets, Metformin Vigliptin Tablets, Ligliptin Metformin Tablets and Saxagliptin Metformin Extended Release Tablets, have been approved for marketing in China. In 2017, five original single-formula DPP4 inhibitors were included in the national medical insurance catalogue. After entering the medical insurance, sales of several products have increased substantially.
　　When asked how he viewed the fierce competition in the market and what commercialisation strategy Shengliptin would adopt in the competition, Yu Qiang said, on the one hand, the sales of the five original products in China were different, with the main competitors focusing on two or three products, of which selegiline had the highest sales, and Shengliptin had a smaller dose and lower cost compared to selegiline, which held more initiative to reduce the price; on the other hand, Shengliptin On the other hand, the Phase III clinical trial of Shengliptin was carried out in more than 120 clinical centres across China, building a good foundation in terms of doctors' awareness, which is equivalent to establishing a good promotion base.

　　Continuing to take advantage of molecular design in the cancer field

　　In addition to the fast-paced Senggliptin, CGeneTech is also leveraging its "integrated drug development technology platform" to accelerate its presence in oncology innovation.
　　Cancer and diabetes account for approximately 90% of the new drug development market in China, with cancer accounting for up to 70%. The considerable market is one of the reasons why CGeneTech is focusing on cancer and laying out its cancer business.
　　It is worthwhile to examine what kind of strategy and competitiveness CGeneTech upholds in the cancer therapeutic area, where innovative pharmaceutical companies are piling up.
　　In Yu Qiang's view, the advantages of small molecule drugs are mainly reflected in the design of the molecules, and the efficacy and safety of the drugs are closely related to the molecular design. The core team of CGeneTech is composed of four people, all from the chemistry department of Peking University, which is very good at molecular design. Therefore, in the layout of the cancer product pipeline, the company is taking advantage of its own team's deeper understanding of molecules to design better molecules as a starting point.
　　In terms of the selection of specific products for development, CGeneTech follows several principles: the targets that we enter are those that have already been marketed or are already under development, as firstinclass products are riskier and the company has had its share of waterloo in early target development; considering that it is difficult for small molecules in tumour therapy to compete with antibodies such as PD-1/L1, the company focuses on the types of mutations that are difficult for tumour immune antibodies to perform. Considering that it is difficult for small molecules for oncology treatment to compete with antibodies such as PD-1/L1, the company focuses on the types of mutations that are difficult for tumour immune antibodies to be effective, and explores the possibility of combination therapy with antibodies; there is room for improvement of the product molecules and uses Centigliptin as the standard for improvement.
　　Currently, three products in the CGeneTech oncology pipeline have been identified as clinical candidates (PCCs), two of which are patent-written and one of which is patent-pending, and all are scheduled to start formal pre-clinical studies as soon as possible. In April this year, CGeneTech also partnered with Yunxuan Pharmaceuticals to acquire exclusive global development and commercialisation rights for a preclinical chemokine receptor type 4 (CXCR4) antagonist for the treatment of oncology and autoimmune diseases.

　　Commercial horizon under a diversified pipeline

　　In fact, the product pipeline of CGeneTech includes not only innovative drugs in the areas of diabetes and oncology, but also first-in-class generic products for rare drugs and class 2 modified products, which may seem a bit "out of the box".
　　When CGeneTech was founded, the domestic investment in pharmaceuticals was still relatively cold and the company's primary concern was survival. For this reason, before 2015, CGeneTech had to take a multi-pronged development path, including the development of intermediates and class 3 drugs, and in 2015, the company also relied on the sale of the approval for the class 3 drug Asenapine to tide over the financial difficulties.
　　In addition to the historical legacy of survival issues, the consideration of R&D strategy is also the reason for the diversification of the company's product line.
　　According to Yu Qiang, many foreign biotech companies are initiated by doctors or researchers, and such companies tend to focus on more specialized research directions. Unlike this, CGeneTech is very focused on commercial opportunities and possibilities, and therefore is involved in more areas and directions.
　　The development of the first generic version of teriflunomide is a typical example of a commercial opportunity departure.
　　In 2014, just as the Ice Bucket Challenge sparked global awareness of the rare disease Amyotrophic Lateral Sclerosis (ALS), CGeneTech officially launched a project to develop the first generic version of teriflunomide for the treatment of multiple sclerosis. Due to the small number of patients and the small market size, generic versions of rare drugs were not given much attention in China, but Centurion was keenly aware of the opportunities.
　　In 2016, the company was granted clinical approval for the product, but due to the policy requirement at the time to conduct validation clinics, which would cost tens of millions of dollars, CGeneTech put the product development on hold after making technical preparations. It was only in May 2018 that the five ministries jointly released the first batch of rare disease catalogues, with multiple sclerosis in the list and teriflunomide subsequently included in the priority review, and the corresponding favourable policy allowed the product development to bridge to foreign clinics, i.e. only the consistency evaluation had to be conducted. A few days after the release of the corresponding list, CGeneTech immediately restarted the teriflunomide project, quickly completing the process validation and production of the API and formulation, and starting the consistency evaluation. According to Yu Qiang, the NMPA requires the human PK of such products to be 80% to 120% consistent with the original research, while the consistency of the first generic product of CGeneTech reached 98% to 102% of the original research. in February 2020, the NMPA accepted the application for the marketing of the product.
　　There are currently only two domestic drugs for the treatment of multiple sclerosis, of which the original teriflunomide was approved for marketing in 2018 and is the first oral drug. in 2019, teriflunomide entered the NMPA. The market space is visible in the case of rare diseases and their medications that are gaining importance in the country.
　　There is a similar opportunity for the layout in terms of Class 2 modified products. When CGeneTech was established, it introduced a lyophilised flash release formulation platform, a technology that allows the product to be absorbed directly under the tongue. The company used this platform to develop the Class 3 drug Asenapine, which was the only one among the seven companies filing at the time that was identical to the original dosage form. This made Yu Qiang realise that this technology platform had certain competitive advantages, and he decided to use this technology platform as the basis for launching a platform for a new class 2 modified drug.
　　However, because of the production problems it faced, CGeneTech's Class 2 modified new drug platform was also put on hold for a while. It is understood that the company is now planning to set up a formulation plant and will produce its own in the future. Once the production problems are resolved, it is expected to restart the filing of Class 2 modified new drugs at the end of this year at the earliest and early next year at the latest.

　　Source: R&D Guest Author: Cheng Haohong