The Chinese dream of the first innovative drug for diabetes
How difficult is it to launch a first-in-class (FIC) world's first innovative drug in China? Let's start with a set of data comparisons.
According to the data reported by the US FDA's Center for Drug Evaluation and Research (CDER), 37 new drugs will be approved by the US FDA in 2022, of which 20 FIC new drugs, accounting for 54% of the record high.
Similarly, in 2022, the National Medical Products Administration (NMPA) approved 19 Class 1 or Class 1.1 new drugs for listing in the Chinese market (13 domestically produced and 6 imported), of which 3 FIC new drugs, accounting for 15.8% of the Class 1 new drugs approved for marketing that year, which is also a historical high.
Looking at the historical data of the proportion of FIC items in new drugs approved by the US FDA since 1999, the average proportion of FIC projects in new drugs in that year was about 26% in the 10 years from 1999 to 2008. In the 10-year period from 2009 to 2018, this ratio rose to 35.2%.
In the four years since 2019, although affected by the epidemic, the proportion of new FIC drugs approved for marketing in the United States has increased significantly to 44.75%.
It can be seen that the competition on the FIC project, which represents the highest level of innovative drugs and the core R&D capabilities of pharmaceutical companies, is being upgraded among global pharmaceutical giants.
So in China, what is the development trend of FIC new drugs? In addition to the highly sought-after field of oncology drugs, in the field of endocrine and metabolic disease drugs with a large patient population, what is the development process of Chinese innovative pharmaceutical companies in the development of FIC new drugs?
Absolute minority
Looking back at the Chinese market, although the development of innovative drugs has twists and turns, it is in the ascendant, but most of the approved marketing projects are me-too, me-better new drugs, few FIC, and even best-in-class (BIC) similar best projects are relatively few.
What needs to be emphasized here is that China's pharmaceutical industry is developing rapidly, but it is also a fact that it starts late and has a thin foundation, and local pharmaceutical companies have enthusiasm for innovation, but they must also take into account the problem of survival and development.
Even the leading companies with more abundant capital strength and R&D capabilities still choose to focus on the development of me-too new drugs, and the proportion of FIC projects is relatively stable.
According to the public information of the State Food and Drug Administration, among the innovative drugs that have been applied for/carried out for clinical trials for the first time in China since 2018, the proportion of FIC projects has basically stabilized in the range of 20%-25%, and the average proportion of approved marketing is about 10%.
From the perspective of the types of companies developing FIC new drugs, in addition to traditional Class 1 new drugs such as Hengrui Pharmaceutical, Chia Tai Tianqing, Simcere Pharmaceutical, Fosun Pharma, etc., Biotech companies that have developed rapidly in the past ten years, such as BeiGene, Innovent Biologics, Junshi Biologics, and Zai Lab, are more inclined to the development of FIC projects.
So how high is the success rate of FIC projects?
It is true that if European and American countries have a high starting point for new drug research and development, and mature markets with good investment and financing environment, new drug research and development from clinical phase I to final listing are also rare.
According to a study jointly released by BIO, the world's largest biotechnology industry organization, the average success rate of drug development projects from clinical stage to FDA approval in the United States from 2011 to 2020 is only 7.9%, and the average time required is 10.5 years.
The research report surveyed a sample of 12,728 drug clinical development projects from 1,779 companies, which is enough to show the difficulty of obtaining FDA approval for new drugs.
According to the 7.9% success rate of new drugs, the average approval rate of FIC new drugs approved from 2011 to 2020 is 38.6%, which means that the probability of FIC new drugs passing through the clinical stage until they are successfully launched is about 3%.
If we refer to the success rate of new drugs in the United States, considering that the approval rate of FIC projects in NMPA in recent years is 10%-15%, it means that the success rate of FIC new drugs in China is only more than 1%.
For large pharmaceutical companies, a FIC project is only a part, but for some small and medium-sized pharmaceutical companies, the development of a FIC is likely to weigh on the entire life. From preclinical to final marketing, ten years of pharmaceutical research cannot be described as nine deaths.
But there is such an enterprise, born to death. For example, Hua Medicine was established in 2011.
In 2022, there will be 3 new FIC drugs on the market in China, namely Huatannin (Docagliatin) of Hua Medicine, Kaitanib (cardunilimab) of Akeso, and Sanlizo (pesolimab) of Boehringer Ingelheim.
Akeso's parent company, Akeso, has more than 30 innovative drug projects covering oncology, autoimmune and metabolic diseases; Boehringer Ingelheim is not to mention, the world's top 500 pharmaceutical companies.
Compared with these two companies with rich FIC projects, Hua Medicine is a "lone brave" who has created a dawn.
It took 11 years for Hua Medicine to turn dogliatin into "Huatang Ning", using a GK (glucokinase) target that no one had ever succeeded in and created a miracle.
Such a desperate bet and such a miracle creation will undoubtedly have a greater positive impact on more small and medium-sized innovative pharmaceutical companies in China's innovative drug industry today.
Sugar drug research and development accelerated
In terms of the distribution of disease areas and the concentration of popular targets of Class I new drugs approved for marketing in China in 2022, oncology drugs are still the "concentration camp" of ironclad innovative drugs, accounting for 54.5% of the new drugs listed in the same period.
Compared with the enthusiasm of domestic innovative pharmaceutical companies to develop original oncology new drugs, although endocrine system and metabolic diseases with a large patient population are also hot fields, basically Class 1 new drugs and FIC drugs are relatively rare.
In fact, innovative diabetes drugs have been in the limelight in the US and European markets in recent years, and explosive drugs with various targets have appeared one after another.
Innovative drugs in the field of diabetes in China seem to be underpowered. Among the 12 Class 1 domestic new drugs approved last year, only Hua Tangning, which has an indication for type 2 diabetes, is a drug for endocrine system and metabolic diseases. Most domestic diabetes drug companies still prefer to make generic drugs or me-too new drugs.
This is actually not difficult to understand. Although the overall size of the global diabetes drug market is large, the growth potential is clear, and China is the most populous country with diabetes, there are many varieties of drugs in this field and the market competition is quite volatile.
In addition to insulin born in 1920, global diabetes treatment drugs include biguanides, sulfonylureas, glycosidase inhibitors, insulins, thiazolidinediones (TZDs), glinides, DPP-IV, SGLT-2 and GLP-1, a total of 9 categories.
From the 100-year history of diabetes drug research and development, in fact, the past 20 years or so is the stage when new targets frequently appear. Most of the world's top pharmaceutical companies have innovative sugar drug pipeline layouts.
From the perspective of the development of the sugar medicinal drug market, there is far from metformin, which is still selling well today, and a little further away from Bayer Acarbose, which has created sales miracles in the global and Chinese markets, which is also known as Baitangping.
Recently, it is lively, and sitagliptin tablets, which were approved by the US FDA in 2006, are the world's first oral DPP-4 inhibitors on the market, and they are also the star drug of DPP-4 targets.
Although the old variety sitagliptin/sitagliptin metformin has reached the end of its "life cycle", in the 2022 financial report, although the global market sales of sitagliptin fell by 15% year-on-year, it still contributed $4.5 billion in revenue to its original researcher, Merck.
The star drug on the SGLT-2 target is dapagliflozin, originally developed by AstraZeneca, which was approved by the FDA for the treatment of type 2 diabetes in 2014 and approved for marketing in China in 2017.
SGLT-2 inhibitors represented by dapagliflozin are currently in an upward cycle in the diabetes drug market. AstraZeneca's 2022 financial report data shows that the sales of Dagliflozin of $4.38 billion that year increased by 56% year-on-year, making it its second largest variety.
To say that sugar drugs are popular targets at present, it is GLP-1 receptor agonists. Liraglutide, semeglutide, dulaglutide, exenatide, leisnatide, tisiparatide..., GLP-1 field is now Novo Nordisk, Eli Lilly two giants strength match.
According to the 2022 financial report, liraglutide contributed nearly $1.8 billion in sales to Novo Nordisk, but its phenomenal product semeglutide created global sales of $10.9 billion, surpassing Eli Lilly's dulaglutide in one fell swoop. In the same year, Eli Lilly GIP and GLP-1 dual-target tisiparatide was approved by the US FDA, intending to win back the game.
Seeing the amazing sales scale of target innovative drugs such as GLP-1 of multinational companies, domestic pharmaceutical companies such as Innovent Biologics, Gan&Lee Pharmaceutical, CSPC Pharmaceutical Group, Hengrui Pharmaceutical, etc. have also entered phase II clinical trials with sugar drugs with related targets.
Looking at Hua Tangning of Hua Medicine, the only GK target drug listed in the world, it has a somewhat heroic taste. But at least since then, in addition to the 9 types of sugar drugs, there are original drugs that Chinese companies have opened up in another way.
The significance of FIC in China
In addition to Hua Medicine's success in the market, in fact, there is finally a breakthrough in the diabetes drug market by Chinese innovative pharmaceutical companies, which is more important for the entire industry.
In fact, the clinical research of the glucokinase activator GKA has been around for a long time, and many multinational manufacturers have also been developed as important targets.
Before Hua Medicine entered the phase III clinical study, only 6 GKAs entered or completed the phase II study, but they encountered challenges such as limited hypoglycemic effect, high incidence of hypoglycemia, and elevated blood lipid levels.
Even at present, GKA drug research is unpopular, in terms of global registration research, only vTv's TTP399, Parker's PB-201 cooperation with Pfizer, and Yabao Pharmaceutical's Yaglutine 3 projects have entered or are about to enter the phase III clinical research stage.
Although only Hua Medicine's Hua Tangning has been successfully listed, the rarity does not mean that the efficacy is limited, but it further illustrates the difficulty of developing a world's first innovative drug and the "history" it may create.
By repairing the blood glucose sensor GK function, realizing the independent regulation of human blood glucose homeostasis, and solving the problem from the "root", the top experts in the academic field have long affirmed the target direction of this clinical drug research. Franz Matschinsky, the father of GK, was awarded the 2020 "Nobel Prize" Rolf Luft Prize in Endocrinology for his contributions to GK research.
Bayer also signed an exclusive commercialization agreement with Hua Medicine in the Chinese market when Docgliatin is still in the phase III clinical trial stage. After the listing, the sales of Huatang Ning's full channel exceeded expectations, which also shows that diabetic patients have a very high awareness of this new target of hypoglycemic drugs.
Looking at the sales data of some domestic class I new drugs listed in the past three years, they are still dominated by oncology drugs, and most of them are actually decent in sales in the first year, and even "dismal".
In contrast, Huatang Ning's sales reached 49 million yuan in just three months of listing, and there was a "tight" situation of short supply.
According to this estimate, Hua Tangning's sales in the first year are expected to exceed 200 million yuan, which will not only be possible to create a sales record for domestic innovative drugs for type 2 diabetes, but also stand out compared with the market performance of the entire domestic class I new drugs.
In fact, the market has always had high expectations for Hua Tangning. When Huatang Ning was not listed, Guoyuan Securities estimated that Hua Tangning would bring 230 million yuan of revenue to Hua Medicine in 2023, and after entering the medical insurance catalog in 2024, Hua Tangning would create sales of about 1.5 billion yuan, and increase year by year since then. Today, such estimates seem to be slightly "conservative".
Under the escort of the innovation mechanism, Hua Tangning of Hua Medicine is undoubtedly lucky, after all, dare to make a desperate bet on a single FIC innovative drug project, and can successfully produce drugs to become that lucky 1%, and the success of Hua Medicine is difficult to be copied.
The reform of China's drug review system in 2015 changed the industrial development path of the pharmaceutical industry based on generic drugs from the underlying logic and shifted to the direction of original innovative drugs. The effect is immediate, whether it is the influx of capital from the innovative drug industry, or the number of IND applications and NDA approvals for innovative drugs by enterprises, it has increased significantly.
In November 2021, the state issued the "Clinical Value-oriented Guidelines for Clinical R&D of Anti-tumor Drugs", which encourages pharmaceutical companies to carry out real FIC original drug research and development through the consideration of "clinical value", so as to achieve the goal of building a pharmaceutical power by 2030.
The policy side vigorously promotes the improvement of the level of innovative drugs, which is conducive to the innovation and research and development power of pharmaceutical companies, but on the other hand, the industrial ecological environment of the domestic pharmaceutical industry "both wants and wants", specific to the current relationship between new drug pricing and medical insurance payment, domestic innovative pharmaceutical companies will have great concerns about the research and development and market risk of FIC new drugs to some extent.
What's more, according to a research report released by Deloitte in 2018, the R&D return rate of 12 global TOP pharmaceutical companies in FIC projects was only 1.8%. It is necessary to know that these leading pharmaceutical companies can hedge certain market risks in the global market.
The reason why the success of Hua Medicine may be difficult to replicate is that the listing of Hua Tangning is extremely lucky. The main body of the domestic innovative drug industry is still the vast majority of small and medium-sized pharmaceutical companies.
How to continuously help more small and medium-sized innovative pharmaceutical companies like Hua Medicine to improve the success rate of FIC new drug research and development through the optimization of policies and systems is one of the things we need to seriously consider next.
Because the capabilities of FIC are related to our dream of a pharmaceutical power.