On September 15, 2023, the official website of the State Food and Drug Administration drug approval certificate delivery information showed that the original import of ezetimibuatin calcium tablets (I) and (II) was approved for marketing for the treatment of hypercholesterolemia and homozygous familial hypercholesterolemia.
Just a week later, on September 22, the first domestic ezetimibuatin calcium tablets (I) and (II) declared for production registration by Jiangxi Shimei Pharmaceutical were accepted and entered the review stage. Shimei Pharmaceutical's action can be described as super-fast and worthy of praise.
Source: CDE official website
A blockbuster new variety of blood lipid lowering
Ezetimibuatin Calcium Tablets were originally developed by Schering-Plough Corp and currently held the rights to Merck. In 2013, ezetimibe atorvastatin calcium tablets were approved by the US FDA for the treatment of elevated LDL-C in patients with primary or mixed hyperlipidemia and to reduce cholesterol levels in patients with homozygous familial hypercholesterolemia (FH); In 2016, it was approved in the EU for reducing the risk of cardiovascular events in patients with coronary heart disease (CHD) and acute coronary syndrome (ACS) who had previously received or not received statin therapy.
The approval of this variety in China is a full 10 years later than in the United States. However, this also buys time for the generic development of domestic enterprises, and Shimei Pharmaceutical, as the first declared manufacturer, is expected to win the first imitation of this variety.
Pharmacologically, ezetimibe atorvastatin calcium tablets are fixed compound preparations of ezetimibe and atorvastatin, both of which have been widely used clinically to reduce low-density lipoprotein cholesterol (LDL-C) levels.
Among them, atorvastatin reduces the synthesis of liver cholesterol by inhibiting the rate-limiting enzyme of the cholesterol synthesis pathway-hydroxymethylglutaryl-CoA reductase; ezetimibe reduces intestinal cholesterol absorption and reduces hepatic cholesterol stores by selectively inhibiting small intestinal cholesterol transporters.
According to the available clinical data, ezetimibe combined with statins can reduce blood lipid levels from different routes of action, not only can play a stronger lipid-lowering effect, but also complement synergy, so as to achieve the effect of 1+1>2. The cholesterol synthesis of the liver and the absorption of cholesterol in the intestine are in a process of homeostasis, when atorvastatin calcium plays a role and cholesterol synthesis is inhibited, the absorption of cholesterol in the intestine will be further increased.
When statins are used alone, although cholesterol synthesis is inhibited, cholesterol absorption in the intestine increases relatively. At this time, if the patient's blood lipids do not meet the standard, only by increasing the statin dose, only about 6% of the hypolipidemic effect can be improved, and the effect is not ideal. If the dose is increased, the risk of adverse effects such as elevated aminotransferases, myalgia, and elevated blood glucose caused by statins is further increased, and the patient's tolerance to the drug will be affected. However, when ezetimibe is used in combination, ezetimibe will further reduce cholesterol from the perspective of inhibiting intestinal cholesterol absorption, so the combination of the two can play a complementary role and control blood lipid levels more effectively.
In practical clinical applications, the combination of different types of unilateral preparations not only has the problem of difficult to grasp the dose ratio and difficult to ensure drug safety, but also from the perspective of economy, the cost of medication is often higher. In contrast, compound preparations can not only improve drug safety and reduce the occurrence of side effects through precise proportioning, but also become more convenient and economical, and are becoming the mainstream choice for clinical medication.
So, as a new variety of ezetimibe atorvastatin calcium, what is the market prospect?
Trend of compounding
According to the World Health Organization, about 17 million people die of hyperlipidemia every year, accounting for about 30% of the total deaths of similar diseases worldwide. Dyslipidemia is more common in the elderly over 60 years old, and the overall prevalence of dyslipidemia in the elderly in mainland China is as high as 47%.
At the same time, dyslipidemia in mainland China tends to be younger, and according to the survey data of the National Center for Cardiovascular Disease, the overall prevalence of dyslipidemia in people aged 18 and above in mainland China has increased from 18.6% to 40.4%. Driven by the dual drive of stock and increment, the hypolipidemic drug market has broad development prospects.
In 2022, the market size of lipid-lowering drugs in mainland China will be about 47 billion yuan, with a compound annual growth rate of 10%, and the market size is expected to exceed 50 billion yuan in 2023.
Market size forecast and growth rate of China's lipid-lowering drug industry from 2017 to 2023
Source: Reference 2
Among the single preparations of hypolipidemic drugs, atorvastatin calcium and ezetimibe are large varieties. According to Yaodu data, in 2022, among the top 10 varieties of lipid-lowering drugs in China, atorvastatin calcium and ezetimibe ranked first and third respectively.
Atorvastatin
Atorvastatin is the fifth marketed product in the history of statin development, designed and synthesized by Parke-Davis (a division of Warner, later acquired by Pfizer) based on Merck's previous research results, and was launched in December 1996 under the trade name "Lipitor". As the world's top lipid-regulating drug, atorvastatin has achieved excellent results since 1998. Lipitor occupied 20% of the market share of lipid-lowering prescription drugs in the year of its launch; Since 2004, sales have exceeded $10 billion for many consecutive years.
In China, atorvastatin reached a peak sales of 12.277 billion yuan in 2019, and after entering centralized procurement, the market size shrank by 64.5% to 4.358 billion yuan. However, it is slowly recovering, according to Yaodu data, in 2022, the total sales of atorvastatin will be 4.491 billion yuan, a year-on-year increase of 3.36%.
Ezetimibe
As the world's first cholesterol absorption inhibitor new lipid-lowering drug, ezetimibe was developed by Merck, approved by the US FDA in 2002, and entered the Chinese market in 2006. After the drug was launched, sales were stable at more than $2 billion from 2010 to 2016. In China, ezetimibe sales increased year after year until 2022, when it was included in the seventh batch of centralized procurement, with winning bidders including Fangsheng Pharmaceutical, Fuyuan Pharmaceutical, Shenghuaxi Pharmaceutical and Laike Pharmaceutical.
According to Yaodu data, in 2022, the total sales of ezetimibe will be 1.255 billion yuan, a year-on-year increase of 19.6%. The original pharmaceutical company Merck Sharp & Dohme occupies the main market share, reaching 79.8%, with sales of 1.002 billion yuan; the first domestic imitation was won by Fangsheng Pharmaceutical in September 2020, with sales of 244 million yuan in 2022, accounting for 19.48%, up 3.21 times year-on-year.
Atorvastatin (left) and ezetimibe (right) market landscape in 2022
Source: Yaodu Data
We have seen that atorvastatin and ezetimibe have entered centralized procurement, and the market scale has suffered a large contraction. Ezetimibe atorvastatin calcium tablets as a compound preparation, but also as a newly approved new variety on the market, there is no worry of centralized procurement, is expected to replace atorvastatin and ezetimibe monopoly preparation part of the market share.
Scarce "four-wheel drive" development model
Under the business philosophy of "imitation of creation, promotion of creation, imitation of creation, and combination of imitation", Shimei Pharmaceutical has been continuously attacking the city in the field of high-end generic drugs in recent years through the differentiated R&D strategy of "first imitation, imitation, and high difficulty imitation".
The chiral hypotensive drug L-amlodipine besylate tablets independently developed and commercialized by Shimei Pharmaceutical have successively won the Jiangxi Provincial Technology Invention Award and won the "Twelfth Five-Year Plan" major special project of science and technology for the creation of national major new drugs. In December 2021, this variety was approved for marketing, becoming the first batch of domestic companies that passed the consistency evaluation of levamlodipine besylate tablets (2.5mg specification), and it is also the only variety that has passed the consistency evaluation of non-reference preparations so far, creating a precedent for non-reference preparations to be evaluated, and playing a demonstration role in how to conduct consistency evaluation of domestic unique varieties.
Starting with levamlodipine besylate tablets, Shimei Pharmaceutical independently established and developed a series of compound preparations with amlodipine as components, such as irbesartan amlodipine tablets, valsartan amlodipine tablets, etc. At the same time, according to the idea of improved innovative drugs, it has established and developed a series of compound preparations with levamlodipine as the component, continuously upgraded and iterated the products, and always maintained a leading position in the subdivision industry in the field of chiral reduction.
Ezetimibu atorvastatin calcium tablets were also developed under this line of thought.
Up to now, Shimei Pharmaceutical has a total of more than 195 independent research and development projects, including more than 173 self-developed generic drug projects, 19 Class 2 improved innovative drugs and 3 Class 1 innovative drugs; It has obtained 28 drug registration certificates and transferred 31 independent R&D technical achievements to customers; There are 29 self-developed projects in the CDE review and approval stage; The self-research project has not yet achieved transformation, and has completed three batches of process verification, BE tests and BEs have completed a total of 15 varieties.
Not only that, Shimei Pharmaceutical acquired 100% of the shares of CRO company Shandong Innovation in 2016, entering a stage of leapfrog development. Shandong Innovation's main business is generic drug research and development, consistency evaluation, innovative drug research and development, etc., and has a certain market reputation in the domestic CRO industry. Since the acquisition, Shimei Pharmaceutical has opened up the whole industry chain of pharmaceutical R&D, and gradually possessed the "four-wheel drive" comprehensive service capability of CDMO from pharmacy to clinical CRO and from raw materials to preparation, which can not only support internal R&D needs, but also meet the individual needs of external customers.
This "four-wheel drive" development model with CRO Shandong Innovation as the drainage entrance and Shimei Pharmaceutical carrying the commercialization transformation is very scarce and extremely advantageous when looking at China.
epilogue
Among the many drugs for chronic disease management, compound preparations have become a trend in research and development, and the domestic market for such compound preparations has just emerged. Especially after centralized procurement, the market scale of some previous star varieties has suffered a cliff-like decline, and compound preparations have become a major way out to extend the product cycle. From the current development focus of Shimei Pharmaceutical, it can keenly grasp this part of the market gap, and is rapidly seizing the market under effective strategies, and its development is quite interesting. How the future development is, Yaodu will continue to pay attention.
Resources
1. Shimei Pharmaceutical's prospectus
2. "The Lipid-lowering Drug Market is Undergoing Pattern Reshaping (TOP10 Combing)", Yaodu Generic, 2023-8-7-31
Article source: [Yaodu Daily] public number/Huang Zhongping original