Editor's note:

Recently, the field of diabetes treatment drugs has ushered in a new member - a new generation of highly selective DPP-4 inhibitor developed by CGSZ Science, sensagliptin. As a leader in the research and development of this innovative drug, Dr. Yu Qiang, the founder of CGeneTech, has spent more than ten years writing a story about perseverance and transcendence.

Yu Qiang's relationship with diabetes drug research and development can be traced back to his years of study in the Department of Chemistry of Peking University. At that time, he studied under Academician Xing Qiyi, the founder of organic chemistry in China, who was an academic leader in the artificial synthesis of bovine insulin, an achievement that has been called one of the closest scientific research achievements in China to the Nobel Prize. Under the influence of Academician Xing, Yu Qiang developed a strong interest in the research and development of diabetes drugs.

After graduating from Peking University, Yu Qiang went to the United States for further study, received a Ph.D. in chemistry from the University of Kansas, and founded a company in the United States in 2006, focusing on providing fragment molecules for drug development. When he decided to return to China in 2010 to start his own business, he chose the field of metabolism, determined to develop an innovative drug that better brings clinical value to domestic diabetic patients.

Dr. Qiang Yu, Founder and CEO of CGeneTech

Sengliptin breaks through the traditional DPP-4

DPP-4 inhibitors are an important type of drugs for the treatment of diabetes, and have become a hot target in the research and development of new diabetes drugs since Merck launched the world's first DPP-4 inhibitor, sitagliptin, in 2006.

Yu Qiang said vividly that for diabetic patients, DPP-4 inhibitors are like the "blood sugar guardians" in the human body. There is an enzyme in the human body called DPP-4, which acts like a magic wand and is mainly responsible for regulating two messengers that are essential for lowering blood sugar - GLP-1 and GIP. These two messengers are originally responsible for sending signals to the body that "blood sugar is rising, release insulin to lower blood sugar", and if the DPP-4 enzyme does not perform magic at the right time, these messengers will be quickly inactivated, and the body will not receive enough blood sugar lowering signals. The DPP-4 inhibitor is the guardian saint who controls this magic wand, which can inhibit the DPP-4 enzyme so that it can no longer destroy those messengers, so as to ensure that GLP-1 and GIP can smoothly transmit the signal of lowering blood sugar, so that the body can release insulin in time to lower blood sugar.

Mechanism of action of DPP-4 inhibitors

Around 2013, several imported liptin drugs were marketed in China, which also opened up a huge market for DPP-4 inhibitors in China. With their medical promotion, more and more doctors and patients have learned about the therapeutic advantages of DPP-4 inhibitors, so domestic pharmaceutical companies have also begun to actively deploy. Yu Qiang recalled that at that time, more than 10 domestic pharmaceutical companies had advanced their domestic new liptin drugs to the clinical trial stage. In the face of such a fierce competitive environment, he firmly believes that only by continuous innovation can we stand out in the fierce competition.

Yu Qiang's entrepreneurial R&D journey began when he founded the company in the United States, analyzing the DPP-4 inhibitor drug market and researching similar drugs. He found that although the marketed drugs have achieved good clinical efficacy, there are still some shortcomings, such as drug efficacy and control of adverse reactions. Therefore, he decided to start from the source of the molecular structure and look for a better DPP-4 inhibitor.

After many attempts, Yu Qiang finally found an improvement direction on the basis of other liptin molecular structures, making the new compound stronger in DPP-4 inhibition. Subsequently, with the help of his own platform at that time, he designed more than 20 kinds of adjusted DPP-4 inhibitor fragment molecules (precursor compounds) and sold them to the outside world. These fragment molecules provide new research and development ideas for DPP-4 inhibitors for foreign front-line researchers, and Yu Qiang also derives innovative inspiration from clinical feedback.

But making money from selling fragment molecules is not Yu's ultimate goal, he is more concerned about which of these fragment molecules is most likely to become a component of the next generation of DPP-4 inhibitors. Yu Qiang found the DPP-4 inhibitor compound with the optimal structure under the conditions at that time, which was the predecessor of sembliptin.

However, there is still a long way to go from precursor compounds to lead compounds to preclinical studies and clinical studies. Yu Qiang knew that his own strength was not enough, and he needed an experienced partner. So, he found his classmate at Peking University, Mr. Ding Juping, who had independently completed dozens of national new drug research and development and application work.

Together, the preclinical research of sengliptin progressed rapidly. Yu Qiang introduced that they conducted a head-to-head comparative study of senpagliptin and the best-in-class products on the market in the phase I clinical trial, covering multiple aspects such as efficacy, safety, pharmacokinetics, toxicology, and pathology. The results showed that Sengliptin outperformed the other in all indicators. This result strengthened Yu Qiang's confidence in Senglitin.

Senpaliptin Clinical Trial "Free Two into Three"

In early 2018, CGeneTech initiated a Phase I clinical trial of sentagliptin. Within 18 months, they completed five Phase I clinical trials that comprehensively evaluated the safety, tolerability, and pharmacokinetic/pharmacodynamic profile of sengagliptin. The results of the trial showed that sengliptin has a good safety and pharmacokinetic profile, and its DPP-4 inhibition ability can well reduce glycosylated hemoglobin when the intake reaches 50 mg. Moreover, sengagliptin can reach the peak blood concentration 1~2 hours after taking the drug, and has a longer drug half-life, which can maintain the steady-state hypoglycemic effect for a long time.

In terms of safety, the performance of sengliptin is even more impressive. Yu Qiang introduced that in the phase I clinical trial, they did not find that senpaliptin had any adverse effects on the patient's body. This is undoubtedly great news for diabetics who need to take medication for a long time.
Due to the excellent performance of senpagliptin in preclinical studies and phase I clinical trials, in September 2019, the drug was officially approved by the National Center for Drug Evaluation (CDE) to exempt phase II clinical trials and directly enter phase III trials. This decision not only created a precedent for DPP-4 inhibitor clinical trials, but also laid a solid foundation for the accelerated marketing of sengliptin.

In the Phase III clinical trial, CGeneTech conducted two pivotal trials in China evaluating the efficacy and safety of senpagliptin monotherapy and in combination with metformin in the treatment of type 2 diabetes. Two trials enrolling approximately 1000 participants with type 2 diabetes showed that sengelliptin was effective in lowering glycosylated hemoglobin (HbA1c). At the same time, the data from both groups of trials showed that the magnitude of the decrease in glycosylated hemoglobin was higher in patients with higher blood glucose levels.

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

In addition to the excellent hypoglycemic effect, what is more commendable is that the incidence of adverse reactions in the 100mg dose group (high-dose group) and placebo group in the second 28 weeks is similar to that of the placebo group, and its safety profile further solves the common adverse reactions in marketed products.

Senlagliptin monotherapy can improve the HbA1c attainment rate in patients with T2DM

The trial was conducted during the difficult times of the pandemic. Yu Qiang still remembers several memorable stories that happened in the process of recruiting patients and advancing research. During the phase III clinical trial, due to the inability of research centers in some areas of the epidemic to carry out normal drug transportation, it was difficult for many subjects to arrive on time for clinical medication.

To this end, the company's clinical researchers moved quickly and contacted research centers in other cities to transport the drugs to these affected areas via cold chain transportation. Subsequently, through the way of human flesh relay, the clinical drugs were delivered to the subjects by hand. This series of efforts not only ensures the continuous treatment of the subjects, but also leads to excellent phase III clinical trial data.

During the trial, some patients were in their villages or communities because of the epidemic, which made it impossible for patients to go to the hospital for follow-up. Faced with this dilemma, investigators, research nurses, and CRCs stepped up. They go to the patient's home to carefully monitor the patient's vital signs, physical condition, blood sugar level, etc., and ask the patient about the patient's condition, medication, and health status in detail. This is all about ensuring that patients are followed up as specified in the trial protocol, so as to ensure the health of the patients and the smooth running of the trial.

He also mentioned that during the trial, it was necessary to enter the obtained data on time and monitor the entered EDC data. However, CRC/CRA is often regulated within different sites. As a result, CRC/CRA often has to work on a small stool in the hallway. Despite the harsh working environment, they still tried their best to enter data on time and complete data monitoring to ensure the timeliness and accuracy of the test data.

Sengliptin was approved for marketing and future blueprint

After a rigorous review process, on December 1, 2024, the marketing application of selegliptin was finally officially approved by the National Medical Products Administration for the treatment of type 2 diabetes. At this moment, the excitement in Yu Qiang's heart was indescribable. "At that moment, I finally saw the results of our own efforts over the years," he recalls. Drug discovery requires patience, perseverance, and persistence. For example, it took nearly 40 years from the discovery of the DPP-4 protein to the successful development of the first targeted drug. But when I saw that senpaglitin was approved and was able to help people with diabetes, it was worth it. ”

Yu Qiang also said that he is grateful to everyone in the domestic clinical experts and team, and it is their joint efforts and dedication that have enabled the successful listing of sengagliptin. He also thanked the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) for its openness and professionalism, which has created an extremely favorable environment for China's biomedical innovation.

It is estimated that by 2030, the market size of DPP-4 inhibitors in China will exceed 30 billion yuan. Yu Qiang introduced that looking forward to the future, 2025 will be a key year for the listing and marketing of sengliptin, and an important part of it is to face medical insurance negotiations. He hopes that the medical insurance negotiation will take into account the quality of innovative drugs and the benefit rate of patients while taking into account the patient's ability to pay. For high-quality new drugs, it is necessary to give them sufficient profit margins to meet the sustainable development of innovative enterprises and continue to benefit patients.

At the same time, Yu Qiang also revealed that the company will continue to promote the IPO process in the capital market in 2025 and complete the last round of financing before listing. With the help of capital, CGeneTech will accelerate the commercialization of Sengripliptin and the advancement of the subsequent innovation pipeline to achieve the company's development from point to surface.

The R&D story of Sengliptin is a journey written by Dr. Yu Qiang and his team for more than ten years, with innovation, breakthrough, persistence, optimism and more moving. Finally, Dr. Yu's poems are dedicated to all those who are struggling on the journey of new drug research and development. (Source: Clinical Research Promotion Public Welfare Fund)

The forests and trees are all natural,

Listed in the hall.

Morning light shines on the clouds,

The prosperous era welcomes the rising sun.

- Yu Qiang