At the 6th China Pharmaceutical Innovation and Investment Conference (CBIIC), Dr. Chen Li, founder and CEO of Hua Ling Pharmaceutical, sat quietly in the last row of the venue. He wore a mask and listened carefully to Dr. Yang Dajun, founder and chairman of Yasheng Pharmaceutical, who presided over the special session on the clinical research data of innovative drugs with novel targets of listed companies. From time to time, people around him recognized Dr. Chen Li and talked with him, and some young people deliberately approached him to exchange business cards.
"When Hua Ling Pharmaceutical was founded 10 years ago, the participants in the venue where innovation and capital were discussed were almost blonde foreigners, and now they have completely changed." Chen Li sighed while listening to Dr. Ma Jianhua, a Chinese diabetic physician, introduce the DREA study results.
In the eyes of some investors and peers, Hua Ling Pharmaceutical seems to have developed less brilliantly. In a decade, the company has developed dorzagliatin, the first innovative drug for diabetes with steady-state regulation of blood glucose, which is too calm compared to its peers who have more than a dozen new drug projects in the pipeline. What did Chen Li think?
Dr. Chen Li
"What medicine people have been thinking about all their lives is whether what you do is beneficial to patients and whether it is beneficial to society." Chen Li said.
In Chen Li's view, the development of Hua Ling Pharmaceutical today does not violate the original intention of that year, nor does it give up halfway. More critical questions lie ahead: Where will the future of Hua Ling Pharmaceutical go?
Open up new treatment options
Back in 2004, Dr. Chen Li had just returned to China to establish the Roche China R&D Center. At that time, he hoped to change the innovative concept, regulatory environment, quality standards and talent environment of domestic medicine through the entry of multinational companies' research and development centers.
In the following years, China ushered in a great wave of innovative development, and the encouragement and support at the national and government levels gave confidence to many pharmaceutical people, and Dr. Chen Li was one of them. He is determined to help China innovate in the field of medicine, just like the name of Hua Ling Pharmaceutical, so that China can lead pharmaceutical innovation.
Just when Dr. Chen Li was thinking about what kind of "works" to show China's pharmaceutical innovation capabilities, a circulation report came into his eyes.
In 2010, Professor Yang Wenying, chairman of the Chinese Diabetes Association, published a survey report on the prevalence of diabetes in China in the New England Journal, showing the real number of diabetics in China for the first time to the world that the real number of diabetes in China was 94 million. Professor Yang Wenying redefined the occurrence and root cause of diabetes, 50% of diabetics in China have normal fasting blood glucose and glycosylated hemoglobin, but the blood sugar is abnormally elevated after meals, which is different from the United States, which also allows Chen Li to discover this huge patient population.
"Solving the unmet clinical needs of patients is the most critical goal of making innovative drugs." Dr. Chen Li said. Therefore, he chose the goal to establish Hua Ling Pharma and approached nearly 200 projects around the world.
He came out of Roche and was well aware of the leading position of tumor drugs in Roche, and Chen Li, who was originally familiar with the development of tumor drugs, chose differential development and introduced the glucose kinase activator project in the Roche R&D Center at that time. Due to strategic adjustment, Roche terminated the research and development of global diabetes drugs in 2010, and Chen Li successfully obtained the global market authorization of glucokinase activators and began preparations for clinical research and development.
In fact, diabetes, as a difficult disease, affects the health of nearly 500 million people worldwide. Since the listing of the SGLT-2is class representative drug, dapagliflozin, in 2014, there have been no new target drugs in this field.
10 years ago, in China, it was rare to be able to gain the favor of international capital such as ARCH Venture, F PRIME, and Venrock and start a business. Recalling this, Chen Li thanked his good brother, Dr. Li Ge, founder and chairman of WuXi AppTec, and Dr. Robert T. Nelsen, founder and executive director of ARCH Venture Partners, for the first round of investment, saying: "At that time, the understanding and enthusiasm of local investors for innovative drugs was far from what it is today. ”
Hua Ling adopts the research and development model of "VC (capital) + IP (technology) + CRO". The VIC model can not only disperse the risk of drug development, but also enable professionals to do professional things at different stages. To this day, it can still be used as a reference for many biotechnology companies. In the future, more small biotech companies in China will transform into biopharmaceutical companies.
In the operation model of Hua Ling Pharmaceutical, the concept of "combining East and West" is vividly reflected in the research and development process of Dorgle Aiting. Dr. Chen Li stressed that from the perspective of human regulation, the problem is a typical Eastern philosophy; at the same time, Hua Ling has brought together experts such as Professor Franz M. Matschinsky, the discoverer of glucokinase, and such a "Western team of experts" directly participated in the target evaluation and clinical research guidance, and finally helped Hua Ling conquer the research and development of this drug.
In the absence of revenue generation, Hua Ling Pharmaceutical has invested about 1.4 billion yuan in R&D since its inception. Dr. Chen Li said that Hua Ling Pharma's ambition is not to do me too, me better, but me first - the world's first in Class.
For the understanding of the first innovative drug, Dr. Chen Li said in an interview with R&D Guest after the Zhangjiang Life Science International Innovation Summit at Shanghai International Biomedical Industry Week that he greatly appreciated the views of Jenny Wood Cook, director of THE US FDA CDER. "Wood Cook once said that every year, the US FDA approves a lot of drugs, but the real innovative drugs are a small number of approved drugs, which are new drugs that can take clinical care to a higher level." And he and Hua Ling Pharmaceutical have been working hard to practice this truth.
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“Products in a small subset of these new approvals, which we refer to as novel new drugs, are among the more truly innovative products that often help advance clinical care to another level. At the end of each calendar year, CDER summarizes these new products.”
——Jennet Woodcock
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The scientific principles associated with glucokinase activators (GKA) and their exploration for more than 20 years have been reported in many literature and media. "Doglia Edin, which is based on the concept of repairing the GK function of the human blood glucose sensor, is fundamentally different from all current hypoglycemic drugs in the therapeutic dimension." Chen Li said that Doglia Edin can treat diabetes from the source, and there are many points in one target, and the steady-state compliance rate is high.
The launch of the first human trial in September 2013 made Chen Li unforgettable. Doglia Edin entered the fast-track review channel as a specially approved variety of the original CFDA. The medicinal application was approved for the first human trial in China within 8 months.
"Nowadays, the new Measures for the Administration of Drug Registration stipulate that the application time for IND is 60 working days, and there are many acceleration channels, but in that year, a new molecular and mechanism of action drug entered the fast track of CDE, which is a new breakthrough for researchers and review institutions." Chen Li said.
According to two phase III registered clinical trials of Hua Ling Pharmaceutical, doglea Edin showed long-term stable efficacy and good safety during clinical treatment, and the drug was treated with a 1.07% reduction in the relative baseline of glycosylated hemoglobin after 24 weeks of treatment, which can effectively improve insulin hypersecretion, improve β cell function and reduce insulin resistance, and has the prospect of combination medication.
In addition, the results of a recent DREAM study led by Chinese diabetic physicians such as Dr. Ma Jianhua of Nanjing Hospital Affiliated to Nanjing Medical University showed that the blood glucose response rate at 52 weeks after dogliastine discontinuation was 65.2% (95% CI 53.4%, 77.0%).
With the success of clinical trials, the drug has the potential to become a basic drug for diabetics. Chen Li summarized three key factors in this regard.
"First of all, the scientific exploration of concepts and mechanisms should be based on unmet clinical needs. The undersatiable needs of the diabetes field are insulin resistance and increased blood sugar caused by impaired islet function, and worsening and severe diseases caused by the continuous decline of islet secretion function. "Diabetes mitigation is the pursuit of doctors and patients around the world. ”
The second is the proof-of-concept test, which should always carry out clinical research around the mechanism of action of the drug and the concept of disease treatment. For Doglia Ettine, the concept of treating disease is the function of repairing sensor damage, reshaping glucose homeostasis regulation, and treating diabetes at the source. This development concept was validated in phase II clinical studies (PoC), laying the foundation for phase III clinical development of the drug.
Third, there are a group of researchers who have very early interventional trial design, including Zhu Dalong, Yang Wenying, Professor Li Xiaoying and a group of Chinese clinical research experts in endocrine diabetes, who have rich experience in the causes, disease progression, treatment and rehabilitation of diabetes. Researchers explored and validated scientific concepts through rigorous and novel trial designs, and more than 100 clinical research centers participated in the trial, and the final results were published in international journals, winning the recognition of peers in the field of diabetes worldwide.
Chen Li said that it is of great significance to do research on original innovative drugs with new global mechanisms and new concepts in China, improve the operation and management capabilities of Clinical Trials in China, and achieve international standards. As Professor Yang Wenying of the China-Japan Friendship Hospital, the lead researcher of the project, said: "This is the best Dr. Chen Li and his team. Through more than 2 years of research process, we learned a very good research work method. ”
The novel mechanism of Doglia Eitin effectively controls glucose on the basis of improving glucose sensitivity in diabetic patients, and achieves a breakthrough in innovative drugs 0~1. It can also be combined with diabetes drugs of other mechanisms to bring hope to patients with diabetes and its complications, thereby expanding the pipeline of Hua Ling pharmaceutical products to achieve the construction of 1 to 10. (See figure below)
Ultimately, personalized treatment of diabetes is equivalent to accurate diagnosis and classification + preventive treatment, and Doglia Ettine will also carry out various studies around the new model of diabetes management - "self-glucose monitoring + diet management + weight management + drug intervention", in order to achieve the long-term goal of improving patient remission rate + islet function improvement + complication management. "In the end, I hope to help clinicians around the world in the diagnosis and treatment of diabetes through China's diabetes prevention and treatment guidelines." Chen Li said.
Future Pipeline: Aim for the three major steady-state
With the success of Dorglea Ettine, Hua Ling Pharmaceutical has completed the largest and most important project. In the future, what are the research and development directions of Hua Ling Pharmaceutical? And what new drugs will be laid out?
Chen Li said that the human body structure is wonderful and complex, through the three major homeostasis to maintain the healthy balance of the human body, including nerve homeostasis, immune homeostasis and blood glucose/ energy homeostasis, the future research and development direction of Hua Ling Pharmaceutical will be based on the research and development work in the three major areas.
"The brain uses almost glucose to supply energy, and a normal adult's brain consumes 120 grams of glucose per day, which is 20% of the total glucose in the human body. In the nervous system, the oxidative metabolism of glucose is the main way to produce ATP, the production of ATP bioenergy is mainly used to maintain the excitatory function of neurons of axonal conduction, the interaction of stellate cells and endothelial cells plays an important role in the change of nerve energy supply and nerve activity, once the brain glucose metabolism is abnormal for a long time, nerve function is easy to degenerate. He explained.
Therefore, Hua Ling Pharma's first future research and development direction is central homeostasis regulation, the force of central nervous system (CNS) diseases, for this purpose developed a series of metabolic glutamate receptor (this target is concerned, is considered to be a highly potential drug action target) allosteric function inhibitors, focusing on Parkinson's disease, depression and fragility X syndrome (FXS), "this is our next effort to develop a global innovation mechanism of innovative drugs." Dr. Chen Li said.
The second research and development direction of Hua Ling Pharmaceutical is immune homeostasis regulation, which mainly achieves immune homeostasis regulation through the participation of glucoskinase in regulating Treg cell migration and immune homeostasis.
Source | Immunity 47, 875–889, November 21, 2017
"Tregs cells are one of the important factors in maintaining immune tolerance in the body. For Treg cells to function properly in immune homeostasis, the cells must migrate to the site of inflammation, a step that requires glucose fermentation with the participation of glucokinase. Dr. Chen Li said that once Treg cells lack the glucokinase-mediated glycolysis pathway, they cannot reach the site of inflammation.
In addition, the human glucoskinase control protein (GCKR) gene loss of function mutation can improve the ability of human Treg cells to migrate, and Hua Ling Pharmaceutical will carry out related drug research and development for glucoskinase-regulated Treg cells.
For the third largest homeostasis glucose homeostasis, since GKA activates liver ChREBP, it helps improve glucose sensitivity reduces insulin resistance, regulates ATP and immune homeostasis, has a protective effect on fructose-induced liver damage, also shows great potential in the treatment of fatty liver disease, or may provide new opportunities for the treatment of non-alcoholic steatohepatitis (NASH).
There is already evidence that fructose intake can lead to metabolic disorders such as NASH, and since the conversion of fructose by ketohexokinase marks the beginning of a metabolic cascade, ketohexankinase may be a new option for the treatment of metabolic diseases. Animal experiments have shown that endogenous fructose may help reduce insulin resistance and liver steatosis, which makes It-Link deploy corresponding research and development drugs in related areas in the future.
How the future of innovative medicines can be closed-loop
The impact of medical insurance control fees and collection policies on drug research and development is an unavoidable topic. Is there a market return on innovative drugs? Is there a future for innovative medicines? In this regard, Dr. Chen Li believes that the purpose of collection is to ensure that within a reasonable price range, generic drugs with expired patents are more accessible and the beneficiary groups are larger and wider. For companies committed to innovation, gathering is not a concern for them.
As an R&D Driven Manufacturer, the market value of innovative drugs is expected to increase the contribution of R&D, production and sales of new drugs to GDP growth in anticipation of the number of patient beneficiaries, corresponding prices and socio-economic contributions.
The state has recently made efforts in intellectual property protection and established a compensation mechanism for drug patent periods, which is to enhance the market return on innovative drugs and start new investment in research and development of innovative products. "This guarantees a return on innovative medicines at the national level."
With the success of Dorglea Ettine, Hua Ling Pharmaceutical has completed the largest and most important project. In 2016, the drug became one of the first pilot varieties of the Marketing Authorization Holder (MAH) system, and in August 2020, a commercial cooperation was reached with Bayer. "The future market development of Doglia Ettine has been entrusted to Bayer, and we have the guarantee of commercial success and the return of innovative drugs." Chen Li said, "We are all people born for innovation. ”
postscript
As early as 2008, due to work reasons, I met Dr. Chen Li, who I had admired for a long time, and then followed him and the Hua Ling team all the way. Dr. Chen Li can be said to be one of the first scientists to start a business from multinational enterprises. In addition to him, there are a large number of new and old scientists and entrepreneurs such as Dr. Du Ying, Academician Wang Xiaodong, Dr. Yu Dechao, Dr. Jiang Ningjun, Dr. Li Ning, etc., in addition to developing innovative drugs, they also shoulder the mission of building China's innovative drug ecosystem, and also witness the development and change of China's innovative drug regulatory policies and clinical research environment. They have also left the most precious mark on the young journey of Chinese biotech companies.
I especially like a quote from Hua Ling: "A group of like-minded people do one thing together, how meaningful it is to win respect by the way, and making a new drug may be something that many developers can't achieve in a lifetime." "Hua Ling Pharmaceutical has carried out one clinical trial after another around Doglia Aytin, which is of high quality, belongs to refined operation, and has a very craftsman spirit. The inspiration from this is that in the current wave of innovation, it seems that R&D people should focus more on one area and accomplish one thing. I wish that Hua Ling Pharmaceutical will have more new drugs in the future, worthy of his slogan - "China Leads Pharmaceutical Innovation".
Editor| Yao Jia layout| Zhang Yue
Issue 1434