Data analysis of diabetes drug research and development in China: 3.1 fierce competition in drug declaration

According to the latest issue of diabetes map released by the International Diabetes Federation, in 2013, there were 382 million adults suffering from diabetes in the world, and by 2035, the number of patients with diabetes is expected to rise to 592 million In 2013, diabetes caused about 5.1 million deaths, with an average of about one dying every six seconds The number of diabetes patients (20-79 years old) in China ranks first in the world, reaching 98.41 million Diabetes has become a serious public health problem worldwide, and the incidence rate of diabetes in almost every country is rising With the continuous improvement of incidence rate, there is a high demand for diabetes drugs which can control the disease in a long time, and it also promotes the rapid growth of the diabetes drug market From 2010 to 2013, the compound growth rate of global diabetes drug market scale will reach 7.9%, and will reach 68.9 billion yuan by 2020, with an annual compound growth rate of 8.7%; in the same period, the compound growth rate of China's diabetes drug market scale will be 13.9%, higher than the global average The diabetes drug market has become an indisputable place Many pharmaceutical companies are committed to the development of new drugs in this field, making great progress in both dosage form and mechanism of action of diabetes drugs With the coming of the patent cliff, the research and development of diabetes drugs in China has also set off a wave of competition and imitation New drug review data: the number of three types of applications has increased sharply From the CDE review data, in the past five years, the number of new diabetes drug applications (only statistical drugs and biological products in this paper) undertaken by CDE has increased year by year, from 45 in 2010 to 140 in 2014, and the number of varieties involved has increased from 17 to 37 Among them, 117 acceptance numbers are clinical applications and 23 acceptance numbers are production applications From the perspective of drug type, the application for new chemical drugs has always accounted for the vast majority, and has been increasing year by year; the number of varieties and acceptance numbers of biological products has increased substantially in 2013, nearly doubling, but slightly declining in 2014 In terms of treatment categories, the number of application varieties for oral glycemic drugs has been kept at 8-10 in the past five years; the number of insulin varieties has increased slightly, but the growth rate is not large; the number of GLP-1 analogues has been maintained at 1-2 in the first three years, slightly increased in the past two years, and increased to 5 in 2014; DPP-4 inhibitors changed a lot, only 1-2 in the first three years, increased to 8 in 2013, increased to 13 in 2014, and the acceptance number increased rapidly from 3 in 2010 to 44 in 2014; sglt-2 inhibitors first applied for new drugs in 2014, with acceptance number of 32, involving 5 varieties From the perspective of registration type, in the past five years, the number of new drug applications for diabetes 1.1 is not large, the number of varieties is less than 5, the number of acceptance numbers is not more than 16, and the number of new drug applications for diabetes 3.1 is growing rapidly, the number of acceptance numbers increased from 10 in 2010 to 94 in 2014, involving varieties increased from 1 to 16 As the risk and cost of the development of new drugs of Category 3 is smaller than that of category 1.1, and category 3.1 has a four-year new drug monitoring period, and category 3.1 with the titles of "new drug" and "first imitation" has a broad market prospect, the competition of enterprise development and application is fierce GLP-1 analogues: more and more long-term sprint dosage forms In recent years, gastrointestinal hormone polypeptide drugs represented by glucagon like peptide-1 (GLP-1) have been widely concerned in the treatment of diabetes GLP-1 is the most potent intestinal peptide hormone that has been found to promote insulin secretion It plays a role by binding with GLP-1 receptor In addition to promoting insulin secretion, GLP-1 can also inhibit the secretion of glucagon after meal, delay intestinal emptying and inhibit appetite Due to the two abnormalities of insulin resistance and insufficiencies of insulin secretion in patients with type 2 diabetes mellitus, β cell apoptosis often occurs in the middle and late stage of the disease At present, the mechanism of oral hypoglycemic drugs in clinical use is mostly to enhance insulin sensitivity or promote insulin secretion to stabilize blood glucose, which can not solve the problem of β cell apoptosis GLP-1 analogues have a unique role in slowing down β cell apoptosis and promoting its regeneration In 2014, 7 enterprises applied for new GLP-1 analogues, involving 5 varieties Except for 3 enterprises participating in the application of exenatide, all other varieties are exclusive Among them, Changchun Baike biotechnology and Qinghai Chenfei pharmaceutical's exenatide are applied for production, and other enterprise varieties are applied for clinical application 1 A new class 1 drug, ibuprofen, is a long-acting GLP-1 analog preparation of me better type, which was developed by Changshan pharmaceutical industry and CO njuchem of the United States LLC developed in 2012 At present, the product has completed phase I and phase II clinical trials in the United States and Canada It is approved to carry out phase I clinical trials in China It is expected to become a large variety of short acting exenatide, which can effectively extend the half-life of exenatide, from twice a day to once a week DPP-4 inhibitors: the guidelines support the popular idea that DPP-4 inhibitors can inhibit DPP-4 activity and prevent insulin inactivation Although DPP-4 inhibitors do not lose weight as GLP-1 analogues, they can improve blood glucose control without weight gain In recent years, DPP-4 inhibitors are the most concerned branch fields, whether it is a new drug approved for market or a project under development According to the existing research results, the efficacy of these new drugs in Asian population may be stronger and more advantageous than in Western population In the 2013 version of China's guidelines for the prevention and treatment of type 2 diabetes (Draft for comments), DPP-4 inhibitors have officially become the second-line treatment drugs, and even can be considered as the first-line treatment drugs to keep pace with metformin in some recommended treatment processes Therefore, the development of DPP-4 inhibitors is also a project for many enterprises The first application for clinical trials of new drugs in China is the class 1.1 new drug of Hengrui in 2009, which is currently in the phase III clinical stage Since then, many enterprises have applied for clinical trials of DPP-4 inhibitors In 2014, a total of 22 enterprises applied for DPP-4 inhibitor new drugs, involving 13 varieties and 44 acceptance numbers In addition to siegliptin of Ouyi pharmaceutical, Qilu pharmaceutical, and rosin pharmaceutical, and Ruiyang pharmaceutical, other enterprises applied for clinical application Among them, Eucalyptus Pharmaceutical Co., Ltd of Sinopharm group has the largest number of declared varieties, including 4, namely, agliptin, ligretin, shagliptin and siggliptin At present, there are seven DPP-4 inhibitors on the market in the world, and Merck's sales volume of cigliptin has reached 4 billion US dollars It is expected to become the best-selling small molecule drug of US $9.7 billion in 2018 The DPP-4 inhibitors that have been listed in China include Merck's sigletin, Novartis's vigletin, Squibb's sagletin, bringer's gliptin and Takeda's gliptin, all of which have performed well in the market, causing domestic enterprises to compete for declaration The number of enterprises applying for agliptin and sagletin is the largest, with 8 enterprises, all of which apply for 3.1 category, while six of which apply for 3.1 category and two for 5 category Sigletin has the best market performance, ranking in the top 20 in the sales of diabetes drugs Its patent will expire in 2022 At present, there are 5 enterprises applying for 3.1 new drugs in China Sichuan Kelun and Shiyao group apply for production, and European pharmaceutical, Jiangsu Haosen, Lianyungang Runzhong and ruyuandong sunshine pharmaceutical apply for clinical application In 2014, there were two DPP-4 inhibitors applying for new drugs of category 1.1, namely, uglietin of Chengdu Yuandong Pharmaceutical Co., Ltd and oglietin of Nanjing Changao Pharmaceutical Co., Ltd Eugliptin is the sixth DPP-4 inhibitor independently developed in China after reggliptin, berggliptin, eggliptin, fuggliptin and eggliptin Reviewing the application of new drugs in the past five years, 34 enterprises have applied for new drugs of DPP-4 inhibitors, involving 19 varieties At the same time, a number of domestic related imported products have been listed and occupied the advantages Because of the homogenization problem, it is more difficult for doctors to accept the products after entering the market Enterprises need to avoid the waste of Limited R & D resources caused by high-level repetition At present, multinational pharmaceutical companies are pursuing the same kind of drugs that can be used once a week How to make the products have the characteristics of differentiated competition and improve the convenience of patients' drug use is the future direction that needs to be considered Sglt-2 inhibitor: first application ready Sglt-2 inhibitor can promote urine excretion by inhibiting glucose reabsorption in renal tubules, so as to reduce blood glucose concentration, and there is no risk of weight gain and hypoglycemia Sglt-2 inhibitor is a new type of drug for the treatment of diabetes This hypoglycemic strategy does not depend on insulin, and has different advantages from other hypoglycemic drugs Since dapagliflozin, the world's first sglt-2 inhibitor, was approved by the European Union in November 2012, several sglt-2 inhibitors have been listed successively In 2013, the US FDA approved the first sglt-2 inhibitor canagliflozin, which was developed by Johnson & Johnson In 2014, FDA approved two sglt-2 inhibitors, dapagliflozin jointly developed by Bristol Myers Squibb / AstraZeneca and empagliflozin jointly developed by Lilly / bringer Ingelheim In addition, in 2014, the European Union approved the listing of dapagliflozin / metformin composite dosage form, an sglt-2 inhibitor drug The same drugs approved for listing in Japan are: tofogliflozin, ipragliflozin and luseogliflozin In 2014, there were 6 domestic enterprises applying for cgreenet, 5 enterprises applying for dagreenet, and all of them were 3.1 products Jiaglijing is another 1.1 new drug applied for the treatment of type 2 diabetes by Shandong xuanzhu, a subsidiary of Sihuan pharmaceutical, after the DPP-4 inhibitor eglitaine As early as before Shandong xuanzhu applied for gagrinone, Jiangsu Hengrui applied for clinical application in April 2012, which was the first sglt-2 inhibitor independently developed in China, and obtained the clinical approval document in April 2013, and now it is in the clinical trial stage.