With the advancement of the Healthy China 2030 Plan, chronic disease drugs have become a focus of pharmaceutical research and development. Among them, the development of cardiovascular, lipid-lowering, and hypoglycemic and weight loss drugs has become a hot track in the industry. Recently, R&D clients and Haomai Technology held a "brainstorming session" in Zhuhai, focusing on clinical needs, industry trends, and the latest drug development trends in the field of metabolic diseases. Dr. Yu Qiang, founder and CEO of Shengshi Taike, attended the conference and explored the vast universe of chronic disease drugs with guests starting from metabolism.

Professor Liu Dongyang: The Challenge of Mathematical Models in the Development of New Drugs for Hypoglycemia and Metabolic Diseases

Researcher Liu Dongyang, deputy director of the drug clinical trial institution of the Third Hospital of Peking Medical University, introduced the challenges of quantitative pharmacology model guided clinical research, digital model guided innovative hypoglycemic drug accelerated development strategy and digital model in the development of diabetes drugs. Professor Liu Dongyang elaborated on the definition and role of quantitative pharmacology, which is to improve the efficiency and quality of innovative drug development, and promote the progress of precision drug research.

He proposed that research based on pharmacokinetic virtual humans may be a new model for disrupting new drug development in the future, with quantitative pharmacology as its foundation. He emphasized that the core issue of quantitative pharmacology research is how to enhance the predictive ability of models to achieve accurate predictions.

Professor Liu specifically mentioned that in recent years, both the US FDA and the National Medical Products Administration's Drug Review Center have vigorously promoted MiDD (Model Guided Drug Development), which is a significant shift in the development model of new drugs. The core principle of MiDD is to establish a PK-PD model based on the corresponding data of blood drug concentration (i.e. exposure, PK) and efficacy/safety (i.e. effect, PD), and then set simulation conditions according to the research purpose to analyze the exposure effect relationship of typical and subgroup populations, in order to replace the difficult to obtain dose effect relationship and establish an evidence chain of drug efficacy and safety.

At the same time, in the field of diabetes, Professor Liu's research group has established the first and second generation diabetes pharmacokinetic virtual human; And based on the model methods of predicting human diabetes based on pancreatic islet cell experiments and pre glucose tests abroad, an innovative model method was established to accurately estimate insulin secretion ability and sensitivity based on glucose tolerance test data. He expects the next decade to be the era of personalized drug delivery and recommends using clinical decision-making software to improve personalized drug delivery effectiveness, supporting the "survival" of new drugs after they are launched.

Dr. Yu Qiang: Exploring the Ocean of Stars through Metabolism

Dr. Yu Qiang, CEO of Shengshi Taike, has 30 years of experience in the development of small molecule drugs. After graduating from the Department of Chemistry at Peking University in his early years, he went to the United States for further studies. In 2010, Dr. Yu resolutely returned to China and founded an innovative biopharmaceutical company focused on the research and development of metabolic and tumor drugs. Dr. Yu is full of confidence in the future market prospects of metabolic drugs. He vividly compares it to a vast and boundless sea of stars, full of infinite possibilities and hope.

He introduced that the global diabetes market continues to grow and will exceed one trillion dollars by 2030. According to the International diabetes Federation (IDF), the number of adult diabetes patients in the world will reach 536.6 million in 2021 (the prevalence rate is 10.5%), and it is estimated that the number of adult diabetes patients in the world will increase to 642.7 million (+20%) in 2030. In 2021, the global medical expenditure for diabetes will be about 966 billion US dollars. It is estimated that the total medical expenditure for diabetes will exceed US $1 trillion in 2030. As the lifestyle of Chinese people is changing, diabetes will cause serious public health problems.

China is the world's largest country with diabetes. In 2021, the number of adult diabetes patients in China will be about 140 million, ranking first in the world. Compared with blood glucose management, the prevention, delay and control of complications are the most important in the treatment of diabetes. The chronic complications of diabetes include macroangiopathy, microangiopathy, peripheral neuropathy and autonomic neuropathy.

Taking macrovascular disease as an example, diabetes macrovascular disease mainly involves heart, brain and other important organs and vessels, and common complications include myocardial infarction and stroke. In addition to its hypoglycemic effect, hypoglycemic drugs with important organ protection effects will be more favored by clinical physicians.

In fact, the development of diabetes has a long history. Dr. Yu introduced the action mechanism of DPP-4 inhibitor, clinical research on drug selection in diabetes, and comparison of drug selection in diabetes. At present, DPP-4 inhibitors include lipagliptin, veragliptin, saragliptin, agliptin, and sitagliptin, with oral bioavailability ranging from 30% to 100%.

He introduced the research and development background and positioning of Shengshi Taike's independently developed innovative drug Sengliptin (formerly known as Shenggliptin). The theory of FBDD suggests that the active pocket of many drug targets is composed of multiple sub active cavities, which can fully bind to the target. Sengliptin is also developed based on this principle, which fully binds to the target and has strong specificity and selectivity. According to the preclinical research results, the preclinical data of Sengliptin is superior to the current best products of its kind in the world, which makes him and domestic researchers very pleased.

In July 2019, Sengliptin pioneered the first quantitative pharmacology model in the field of DPP-4 inhibitors, injecting new vitality into the clinical research and development model of new drugs. Through this model, the researchers accurately calculated the change value of HbA1c (glycosylated hemoglobin) after 12 weeks and 24 weeks of administration, thus scientifically predicting the optimal dose of Sengliptin in the phase 3 clinical trial. This makes Sengliptin the first product to directly cross phase 2 and enter phase 3 clinical trials through quantitative pharmacological models. With the increasing prevalence of multiple diseases such as hyperglycemia, hypertension, and hyperlipidemia coexisting, the research and development trend of combination therapy is becoming increasingly apparent, and the application prospects of Sengliptin in this field are broad.

Dr. Xiao Shen: Clinical development and registration pathways for new drugs for cardiovascular, renal, and metabolic diseases

Dr. Xiao Shen, Chief Medical Officer of Shanghai Haisen Biopharmaceutical, introduced a discussion on the clinical development and registration pathways of new drugs for cardiovascular, renal, and metabolic diseases.

In the early development stage, attention should be paid to communication and exchange with regulatory authorities during IND meetings, determination of early doses, evaluation of clinical efficacy, and application of biomarkers. In the late stage of the trial, it is necessary to closely monitor and record all adverse events, select appropriate efficacy evaluation indicators, evaluate the interaction between drugs and other commonly used drugs, collect data on the long-term efficacy of drugs, ensure that the trial complies with all applicable regulations, guidelines, and ethical principles, and ensure the accuracy, completeness, and traceability of data.

In addition, Xiao Shen also elaborated on the considerations for selecting endpoints for metabolic disease drugs in clinical trials, including preliminary efficacy evaluation (POC), determination of effective endpoints, clinical endpoints, alternative endpoints, composite endpoints, patient reported results, and the application of biomarkers.

Dr. Xiao Shen emphasized the FDA's strictness in approving new drugs when introducing cases of cardiovascular and kidney disease drug approvals. He mentioned four examples of FDA rejection, demonstrating that the FDA evaluates new drugs based on their risks and benefits, and has particularly strict safety requirements for chronic disease drugs. FDA approval focuses on drug safety data and clinical endpoint indicators for improving patient clinical quality, and compares them with similar drugs. When developing new drugs, it is necessary to fully consider patient characteristics and drug interactions, and select appropriate clinical endpoint indicators to evaluate efficacy and safety.

Yu Zhong: Research hotspots of GLP-1 from the perspective of big data

Yu Zhong, co-founder of Haomai Technology, said that at present, GLP-1, as a class of drugs for treating diabetes and obesity, has significant pain points in clinical application. Among them, the main problem is the high discontinuation rate caused by side effects (nearly 2/3 of discontinuations within 1 year). After discontinuing the medication, patients are prone to weight rebound, and the decrease in fat free weight (lean meat mass) while losing weight (37%) is also a concern. In addition, the weakened weight loss effect of patients after 2 years, as well as the inconvenience of injection administration, have limited the widespread use of GLP-1 drugs.

Yu Zhong pointed out that the current research and development directions include:

1) Long term strategy: The first generation GLP-1 is mainly modified with amino acid sequences; The second generation introduces fatty acids, fusion proteins, PEG functionalization, and microspheres, achieving a breakthrough of once a week administration; The third-generation antibody coupled peptide, antibody fusion peptide, and atomic layer deposition coating particle controlled release can achieve the goal of once a month administration. By reducing the frequency of administration, patient compliance can be improved. In addition, hydrogel sustained-release and gene therapy are also considered as potential solutions.

2) New dosage forms and administration methods: the development of new dosage forms such as microneedles and inhalation, as well as the development of oral medications, aimed at improving the patient's medication experience and enhancing compliance.

3) Multi target direction: In drug design, in addition to targeting GLP-1 itself, development is also focused on other targets to improve efficacy or expand new indications, such as NASH, AD, kidney disease, heart failure, etc.

4) Combination/compound strategy: By combining or combining with other drugs, achieve the effect of reducing fat and increasing muscle, while reducing adverse reactions.

At the end of 2023, AstraZeneca obtained the development and commercialization rights of ECC5004 from Chengyi Biotechnology outside of China with a down payment of $185 million and a milestone payment of $1.825 billion, sparking widespread attention to GLP-1 oral small molecules. Yu Zhong believes that the disclosure of Orforglipron patent WO2018056453 by Chinese and foreign pharmaceutical companies in 2018, Pfizer's Danuglipron patent WO2018109607, Eli Lilly's acquisition of global development and commercialization rights of Orforglipron by Chinese and foreign pharmaceutical companies with a down payment of $50 million and milestone payment, and the sudden outbreak of global GLP-1 small molecule patent applications in 2018, all indicate that 2018 is the best time for oral GLP-1 small molecule following.

In the second half of 2023, Lilly acquired Versanis ActRIIA/B monoclonal antibody biomagrumab for $1.925 billion. In 2024, Lilly, Anjin, and others invested $170 million in BioAge Labs for a phase 2 trial of Azelaprag combined with telposide for the treatment of obesity, indicating the arrival of a global research and development boom for the clinical pain point of fat loss and muscle enhancement.

Yu Zhong also analyzed the research and development trends of GLP-1 drugs from the perspective of patent big data. China has experienced a rapid outbreak of GLP-1 patents since 2020 and surpassed the United States in 2023. From the perspective of dosage form, both oral and injection GLP-1 patent applications have their own advantages. From the perspective of target combination, GLP-1/GIP, GLP-1/GCG, GLP-1/GCG/GIP continue to maintain a high popularity of patent applications, while GLP-1/PYY and GLP-1/secret have grown rapidly in recent years and are worthy of attention. From the perspective of institutional patent applications, Gasherbrum Bio may be a potential noteworthy institution among new entrants in recent years.

At the end of the meeting, the attending experts had in-depth discussions on the challenges faced by clinical needs, target discovery, and mechanisms of action. It was generally believed that meeting clinical needs is the primary task of new drug development. In response to the challenges faced by target discovery and mechanism of action, experts suggest combining cutting-edge technologies such as genomics and proteomics to deeply explore potential disease treatment targets. At the same time, attention should also be paid to the specificity, affinity, and drug molecule design of the target, in order to improve drug treatment efficacy and reduce side effects.

About Shengshi Taike

Shengshi Taike is a biotech company in the commercialization stage, and its core product, the innovative drug Sengliptin (formerly known as Shenggliptin), is about to be launched. The company was founded in Suzhou Industrial Park in 2010, and its core team has decades of experience in the entire lifecycle of international drugs. It is committed to the research and industrialization of high-quality and differentiated small molecule innovative drugs. With an integrated drug research and development technology platform and a diversified business perspective, the company has built a rich innovative drug pipeline covering hypoglycemic, anti-cancer, and autoimmune diseases.