· The phase I trial of senlagliptin boldly undertook a head-to-head study with sitagliptin;

· Senrigliptin obtained the qualification of the first clinical trial in the field of hypoglycemic drugs in China.

· Yu Qiang has high hopes for the company's first Sino-US dual-reporting project, the CXCR4 antagonist CGT-1881;

· CGeneTech continues to advance the IPO process this year.
Qiang Yu, the founder and CEO of CGeneTech, a doctor of chemistry from Peking University, founded a biotechnology company in the United States at the beginning of this century, and later returned to China to found CGeneTech and developed a new type 2 diabetes drug, a new generation of DPP-4 inhibitor senpaglitin, which has now been approved for marketing.
Yu Qiang believes that there is an element of luck in his success, "People like me who are not smart can successfully make a new drug, and 'smart' entrepreneurs and scientists should be able to." He laughs.
However, entrepreneurship is a serious matter for him, "requiring solid scientific research and perseverance". As a medicinal chemist, Yu Qiang is very proud of the sembleggliptin that he has optimized himself. In clinical practice, he was highly praised for obtaining the qualification for the first clinical trial in the field of hypoglycemic drugs.
Fragment molecules: the cornerstone of drug development
Yu Qiang's fate with diabetes drugs can be traced back to his tutelage in the 90s of the last century under the tutelage of Academician Xing Qiyi, a professor of chemistry at Peking University and a well-known organic chemist in China. Academician Xing was once an academic leader in the synthesis of bovine insulin, an achievement that has been called one of the closest scientific research achievements in China to the Nobel Prize.

Dr. Yu Qiang

After receiving his Ph.D. in chemistry from the University of Kansas, Yu founded a company in the United States in 2006 focused on providing fragmented molecules for drug discovery.
"Fragment molecules, in short, are the building blocks of small molecule drugs." Yu Qiang explained.
In the development of small molecule drugs, targeted drugs are undoubtedly a revolution. With the deepening of research, scientists have gradually discovered that certain enzymes can be used as targets for drug action, and these active targets provide space for small molecule drugs. Taking diabetes as an example, the DPP-4 target is one of the typical ones. By designing a molecular structure to compete with the original ligand of the enzyme, it can affect the enzyme's signaling pathway and achieve the therapeutic effect.
But the complexity of living organisms is far beyond what one might think. Enzymes are not as regular as originally thought, and can be simply put into a molecule. In fact, the structure of the enzyme is more like a hand, with complex shapes and bumps. Therefore, if a regular molecule is designed to bind to the enzyme, it may only encapsulate a part of the enzyme and not penetrate deep into it to adequately inhibit or stimulate the activity of the enzyme.
"That's why fragment molecules are so important in drug discovery. They can serve as building blocks for building more complex and active small molecule drugs. Yu Qiang said metaphorically, "Fragment molecules are like words in our poems, which can be flexibly embedded in different verses. Similarly, these fragment molecules can also be embedded into different drug structures. On weekdays, Yu Qiang is also good at writing poetry.
The fragment molecule was the earliest source of inspiration for sengliptin.
At the end of
2006, Sitagliptin, the first DPP-4 inhibitor launched by Merck, was approved in the United States for the treatment of type 2 diabetes, causing a global sensation. DPP-4 inhibitors help control blood glucose levels by inhibiting the activity of the DPP-4 enzyme, increasing and prolonging the effects of GLP-1, thereby promoting insulin secretion and inhibiting glucagon secretion.

Mechanism of action of DPP-4 inhibitors

Yu Qiang sighed: "Historically, most targeted drugs have mainly focused on tumors, and diabetes, the field with the most patients in the world, whether it is insulin or metformin, has no clear targeted concept. Although the hypoglycemic mechanism is effective, the signaling pathway is not clear. Many companies have tried to develop new targets for diabetes, but most have been unsuccessful. "
The DPP-4 enzyme was discovered in 1966 and its target is very clear and potent. After 40 years of long research, it finally came out in 2006 in the form of sitagliptin. "The process of developing a new drug is full of failures and requires at least two generations of effort." "Therefore, the successful development of the world's first DPP-4 inhibitor in 2006 has had a huge impact on the industry as the first new drug with a clear mechanism and clear target in the field of diabetes.
At that time, the single crystal structure of the DPP-4 enzyme had been successfully resolved, which provided an important basis for understanding the environment in which the molecule binds to the enzyme. At that time, there was no AI technology that is prevalent today, but there was a technology called Computer-Aided Drug Discovery (CADD) to help drug discovery.
During his postdoctoral career, Qiang Yu participated in a lot of CADD work. So, when Sitagliptin came out, he saw an opportunity. He carefully studied Merck's marketed products and found that there was still room for improvement in some specific aspects, which left Yu Qiang with an opportunity to surpass.
He and his team found that the chemical structure of sitagliptin is made up of two main parts, one of which is a benzene ring with three fluorines. Merck has conducted in-depth research on this issue and published relevant research results. Therefore, Yu Qiang and his team focused their research and development on the adjustment of the amino-containing parallel ring structure on the other side, because there was obvious room for improvement in this part. His intuition told him that these improvements might lead to new prospects, so he made extensive attempts to optimize the molecular structure.
Yu Qiang decided to conduct in-depth research from the source of the molecular structure. In the process of developing fragment molecules, Yu Qiang followed certain standards. These criteria are closely related to the design of the fragment molecule. First of all, the design should consider how to leave the interfaces, just like Lego bricks, there need to be a variety of interfaces to connect different parts. Secondly, it is necessary to consider the physicochemical properties, which are an important part of the design of fragment molecules. At the same time, we strive to do better, including how to improve the affinity with the DDP-4 enzyme.
When Yu Qiang successfully sold a large number of fragment molecules, he realized that many pharmaceutical scientists were working on DPP-4, which proved the value of DPP-4 inhibitors. After seeing this trend, Yu Qiang had the idea of developing this drug on his own and had the idea of starting a business. "I've always had a dream to be able to launch a drug that goes into the clinic, and it's a lifetime honor for me."
From
2008 to 2009, the state began to vigorously implement the support policies for biomedicine and launched a major national new drug creation project. Although the domestic biopharmaceutical industry was still in its infancy at that time, Yu Qiang seized this historic opportunity and decided to devote himself to this promising field.
In 2010, Yu Qiang and his classmate at Peking University, Ding Juping, founded CGeneTech in Suzhou BioBAY. They synthesized a range of compounds and tested them for enzyme activity. Due to limited funds, they had to opt for relatively inexpensive testing methods. But excitingly, they found that some compounds were surprisingly well active.
After several rounds of refinement and optimization of the molecular structure, finally, they launched sengliliptin. This is a new generation of highly selective DPP-4 inhibitors, which is unique in that it can form a stable eutectic structure when combined with DPP-4, which confers greater activity and a better safety profile on sengliliptin, making it excellent in improving glycemic control in adults with type 2 diabetes.
Yu Qiang said that this is largely due to the fact that there is an additional methyl group in the molecular structure design of sengliliptin, the presence of which makes sengagliptin more suitable to match the binding pocket of DPP-4, thereby improving the binding efficiency between the drug and the target.
As a result, CGeneTech has continuously received support from the national "12th Five-Year Plan" and "13th Five-Year Plan" major new drug development projects. This was undoubtedly a huge affirmation for a startup with only a dozen employees at the time.
Pioneering DPP-4 "No II to III"
In the phase I trial of senlagliptin, Yu Qiang and his team conducted a head-to-head study with sitagliptin, recruiting subjects who included not only healthy people but also patients with type 2 diabetes, which was a very bold decision.
They decided to conduct a large-scale phase I trial involving about 200 subjects, which is equivalent to the size of a phase II clinical trial. Under the guidance of Professor Jiang Ji, a well-known clinical pharmacologist and former Clinical Pharmacology Center of Peking Union Medical College Hospital, 6 phase I clinical trials were completed within 18 months. Finally, according to the results of the clinical trial, a quantitative pharmacology model was introduced, and under the guidance of Professor Jiang Ji, Dr. Wang Lu from the Phase I Clinical Research Center of Jiangsu Provincial People's Hospital completed the modeling.
The results showed that sengagliptin had a good clinical effect, and the 50 mg dose could well reduce glycosylated hemoglobin, and the DPP-4 inhibition ability was comparable to that of 100 mg sitagliptin, and the plasma concentration and DPP-4 inhibition rate peaked quickly, the half-life was long, and the steady-state hypoglycemic lowering was more durable. In terms of safety, senrangliptin did not have unintended adverse effects on patients.
Yu Qiang still remembers that night, because the research data is exceptionally good, Professor Jiang Ji dialed the phone of the company's co-founder Ding Juping late at night, and said excitedly: "I have never seen a domestic drug in this field show such excellent data performance!" In October
2019, based on good phase I trial data and PK/PD model, senpagliptin was approved by the CDE to exempt phase II clinical trial and directly enter phase III, creating a precedent for DPP-4 inhibitors to "enter III without II". Yu Qiang said that CDE's decision was based on two points: first, the phase I clinical data of senpaliptin was better; The second is to use patient data to validate the quantitative pharmacology model, and the model predictions are highly matched with the actual data.
The phase III clinical trial was led by Professor Ji Linong of Beijing People's Hospital, a well-known diabetes expert, and conducted two pivotal trials in China, enrolling a total of about 1,000 subjects with type 2 diabetes, to evaluate the efficacy and safety of sengliptin monotherapy and combination metformin in the treatment of type 2 diabetes, respectively.

Professor Ji Linong delivered a speech at the 2023 Peking University Diabetes Forum

The results showed that sengliptin 50 mg reduced glycosylated hemoglobin levels by 1.08% in patients treated with monotherapy, and after 24 weeks of treatment, the proportion of patients with glycosylated hemoglobin levels below 7% reached 45%, which was 3.5 times that of the placebo group, and the proportion of patients with glycosylated hemoglobin less than 6.5% was 10 times that of the placebo group. For patients who are not adept with metformin monotherapy, the combination of senrigliptin can further significantly reduce the glycosylated hemoglobin level by 1.23%, and after 24 weeks of treatment, the proportion of patients with glycosylated hemoglobin level less than 7% increases to 51%, which is 3.5 times that of metformin alone, and the proportion of patients with glycosylated hemoglobin less than 6.5% is 5.5 times that of metformin alone.
In the phase III trial, they also encountered a number of challenges. For example, the number of recruits and the cost of recruiting are a headache for them. However, in order to demonstrate the superiority of senpelliptin, they decided to conduct trials in both the low-dose group (50 mg) and the high-dose group (100 mg), and in the following safety trials, all patients in the low-dose group were transferred to the high-dose group to verify the safety. This is another bold attempt, however, Yu Qiang and his team always trust their own research and judgment.
Eventually, their efforts paid off. The results showed that the sengliptin 50 mg low-dose group was effective in reducing glycosylated hemoglobin, and the reduction in glycosylated hemoglobin was higher in patients with higher blood glucose levels. In addition to the excellent hypoglycemic effect, the incidence of adverse reactions in the 100mg high-dose group and the placebo group in the second 28 weeks was similar to that of the placebo group, and its safety profile further addressed the common adverse reactions in marketed products.
In the waiting stage for approval, the Food and Drug Inspection Center of the National Medical Products Administration conducted an on-site inspection of the research centers of the two clinical trials of sengliptin, and finally passed with high quality, which made them very gratified. "This shows that our research is solid and the data is reliable." Yu Qiang said proudly.

Willing to be a paving stone for China's innovative drugs Yu Qiang said that although the success of sengliptin has an element of luck, solid scientific research is essential. He said that every step of scientific research must be rigorous and meticulous, otherwise it is likely to fall into trouble in the future. At the same time, persistence is the key to success.
In 2015, CGeneTech faced a financial dilemma. To get by, they had to sell one of the pipeline product in progress. In addition to selling their "children", they also raise funds through the sale of API intermediates, etc., and even the management team pays out of their own pockets to support the company's operations.
"I hope the government and investors can understand the hardships of innovation in the pharmaceutical industry." Yu Qiang said.
2025 is the 15th year of CGeneTech's founding, and it will also be a key year for the launch of Senajettin, an important part of which is to face medical insurance negotiations. Yu Qiang hopes that the medical insurance negotiation will not only take into account the patient's ability to pay, but also fully consider the quality of innovative drugs and the benefit rate of patients.
At present, metformin combined with liptinoids has become the main treatment option for the clinical application of type 2 diabetes, according to the Sullivan research report: by 2030, the market size of liptins in China will exceed 30 billion, with broad market prospects.
In 2025, the company will also continue to promote the IPO process in the capital market. With the help of capital, CGeneTech will accelerate the comprehensive layout of the commercialization of Sengliptin and the rapid advancement of the subsequent innovation pipeline, so as to achieve the leapfrog development of the company "from point to surface".
Now, CGeneTech has developed to a certain scale, but Yu Qiang still has unfinished dreams.
"I want to make another new drug and prove that our success is not accidental." Yu Qiang said with a smile. He is now optimistic about the CXCR4 antagonist CGT-1881, which has almost completed phase I clinical trials, and clinical data shows that its application in stem cell mobilization and WHIM syndrome is very certain. It is also the company's first new drug project in both China and the United States, and has a wide application prospect and market value in the treatment of malignant tumors, stem cell mobilization, immune diseases, genetic diseases, etc. in the future.
Finally, he expressed his hope that more founders can devote themselves to the cause of new drug research and development and stick to it. "I am a paving stone for China's innovative drugs, and I am willing to pave the way of hope for a healthy China to the future." Finally, we used Dr. Yu's poems to encourage all new drug R&D personnel: "
Sen Mu is all natural, and
Lie Cai is in the palace".
The morning sun shines on the clouds, and the prosperous era welcomes the
rising sun.