In recent years, with the continuous advancement of science and technology, in the field of diabetes drug research and development, in addition to improving existing insulin preparations, many new targets and new treatment mechanisms have also been developed, among which DPP-4, GLP-1, and SGLT-2 The results of other targets are the most significant.
The current state of domestic research and development is still following the state, especially for new diabetes drugs approved after 2010. The domestic declaration enthusiasm is relatively high, and there are some new drug declarations with similar targets.
A
R & D direction
Main Features of Global R&D Line
The current global diabetes research and development line has the following 4 characteristics:
⒈Combination medication
The compound preparation of combination medicine is one of the hot spots of the market and late stage research and development projects in the past two years, and will become the general direction of diabetes medicine research in the future.
The main directions of the current late-stage clinical project are: compound preparations of SGLT-2 inhibitors and metformin, compound preparations of DPP-4 and SGLT-2 inhibitors, and the development of a combination of insulin and GLP-1 agonists.
The benefits of the compound preparation are obvious: because the two drugs target different pathogenesis, the joint synergy can treat different pathogenesis and pathological links of type 2 diabetes; the combination of the two drugs does not increase the weight of diabetic patients, and some patients still It can reduce weight; compound preparations reduce the number of pills taken by patients and increase patient compliance.
2. Formulation innovation
In order to improve patient compliance, oral and inhaled dosage forms of insulin and GLP-1 agonists are still the focus of research and development.
Insulin and GLP-1 agonists are mainly restricted by the dosage form of their injections. If it needs to be used every day, a corresponding oral dosage form will be developed, and patient compliance will be improved. The only oral insulin project currently in Phase III clinical trials is Diasome’s HDV-1. HDV-1 adopts hepatocyte-targeted liposome technology, which is different from other nanoparticle coating, intestinal penetration enhancer and carrier-utilizing technology. In addition, there are some early projects for oral GLP-1 agonists.
3. Improve SGLT-2 drug tolerance
The new drugs developed for the SGLT-2 target are mainly to solve the tolerability problem of the currently marketed drugs. The canagliflozin, dapagliflozin and empagliflozin that have been marketed all cause genital and urinary tract infections The problem. The early clinical data of the projects bexagliflozin and remoteliflozin under development show better tolerance than the marketed drugs.
4. Insulin development
Insulin development has focused on insulin analogs and ultra-long-acting insulin.
The global insulin market has been dominated by Novo Nordisk, Sanofi and Eli Lilly. Judging from the current late-stage research and development projects, the imitation of insulin analogues has become increasingly fierce.
Eli Lilly and Boehringer Ingelheim’s long-acting insulin Basaglar (insulin glargine analogue) was approved for marketing in 2014, and the insulin glargine analogue Basalog of Indian insulin manufacturer Biocon was launched in Japan in March 2016. There are many imitation manufacturers of insulin glargine and insulin lispro.
Novo Nordisk is still focusing on the development of ultra-long-acting insulin, while Xultophy (Glutulin + Lirarutide) represents the direction of insulin compound preparations.
B
Domestic declaration
Detailed analysis of the four hot categories
DPP4 inhibitor
New drug, category 3.1, category 6 full-line declaration hot
A large number of studies have found that in addition to promoting insulin secretion, glucagon-like peptide-1 (GLP-1) can also inhibit postprandial glucagon secretion, delay intestinal emptying and suppress appetite. However, GLP-1 has a short half-life and is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) in the blood.
In order to overcome this defect, two types of drugs have been researched and developed: one is GLP-1 analogues (including peptides and chemically synthesized GLP-1 drugs), in addition to having the physiological effects of incretin, it also has a positive effect on DPP-4. Degradation is not sensitive, and the half-life is prolonged; the second is DPP-4 inhibitor, which can inhibit the activity of DPP-4 and prolong the duration of GLP-1 stimulation of insulin secretion in order to achieve the hypoglycemic effect.
In addition, DDP-4 inhibitors can also correct the inappropriate secretion of glucagon caused by the abnormal function of α cells, thereby regulating the blood sugar balance and effectively preventing the occurrence of hypoglycemia. It can significantly promote insulin secretion, inhibit the release of glucagon, slow down gastric emptying, reduce blood sugar and glucagon levels, and hypoglycemic and inhibit glucagon secretion are related to glucose.
The main adverse reactions of DPP-4 inhibitors are gastrointestinal reactions, infections, liver and kidney damage and acute pancreatitis, but they are generally mild and safe. The main disadvantage is that the prerequisite for this type of drug to lower blood sugar is that the secretion of GLP-1 in the body must be normal and the degree of blood sugar lowering is small.
From 1998 to 2014, a total of 17 DPP-4 drugs were developed worldwide, of which 10 were already on the market and 7 were still under development. In 2015, Omarigliption and trelagliptin were approved for marketing in Japan.
The DPP4 single drugs currently on the market in China are: AstraZeneca’s Saxagliptin, Novartis’s Vidagliptin, Merck’s Sitagliptin, Boehringer Ingelheim’s Linagliptin and Takeda’s Alogliptin.
According to Xianda V3.2 search, in the field of DPP-4 inhibitors, 7 domestic manufacturers have declared Class 1 new drugs, as shown in Table 1.
In the old category 3.1 applications, the main focus is on 5 anaegliptin tablets, alogliptin besylate tablets, troxagliptin succinate tablets, nategliptin tablets and titagliptin hydrobromide tablets. Variety. Among them, the manufacturers that applied for troxagliptin besylate tablets were the most, reaching 28; followed by alogliptin besylate tablets, with 9 companies reporting.
Due to the problems of preparation technology and future clinical difficulty, compound preparations are rarely declared by manufacturers. However, the author still found that Shandong Luoxin, Hangzhou Baicheng, Zhengda Tianqing and Yichang Changjiang Pharmaceutical have all declared DPP-4 and metformin compound preparations. This is a good signal, which shows that more and more domestic manufacturers dare to challenge the development of difficult projects.
Category 6 imitation is still an important research direction for my country’s pharmaceutical companies. Among them, there are 16 imitation manufacturers that declare alogliptin besylate tablets the most; there are also more than 10 manufacturers that declare linagliptin tablets, sitagliptin tablets, and vildagliptin tablets.
GLP-1 receptor agonist
Various declarations are mostly related to Exenatide
GLP-1 receptor agonists are considered by doctors to be the most effective non-insulin drugs for diabetes. These drugs can effectively reduce glycosylated hemoglobin for a long time and can also reduce weight. However, injection is the biggest obstacle to its popularization, so GLP-1 receptor agonists are still the third-line drugs in diabetes medications.
The current research and development directions are basically in the development of longer-acting or more convenient dosage forms of GLP-1 receptor agonists. There are already a series of oral GLP-1 receptor agonists in the early stages of development, including OG217SC (semaglutide; Novo Nordisk), ORMD-0901 (exenatide; Oramed Pharmaceuticals), TTP054 (vTv Therapeutics) and TTP273 (vTv Therapeutics). If these oral drugs for GLP-1 receptor agonists are successfully developed and can effectively control costs, these drugs may become second-line drugs.
At present, there are 5 GLP-1 receptor agonists on the market worldwide. According to Xianda V3.2 data analysis, there are two products of GLP-1 receptor agonists on the market in my country: AstraZeneca’s Exenatide and Novo Nordisk Laglutide. Lixisenatide, Albiglutide and Dulaglutide, which are already on the market abroad, are only imported from the original research and have not been declared by imitation companies. Table 3 shows the status of new drug declarations for GLP-1 receptor agonists in China.
It can be seen that the domestic research and development of GLP-1 receptor agonists is mainly focused on the improved mode of administration of exenatide. The new structure applications include Benaglutide injection from Shanghai Renhui Biologics, Polyethylene Glycol Losenatide Injection and Noliglycotide Injection from Jiangsu Hausen. It is hoped that these products will be more clinically effective than the existing ones. Listed products have more advantages.
Class 3.1 drug declarations are still focused on exenatide. Although Exenatide is the first approved drug among GLP-1 receptor agonists, it has a short half-life and high dosing frequency, twice a day. In terms of immunogenicity, it is only 53% identical to human GLP-1. Origin, so immunogenicity is strong. The later approved liraglutide has a better hypoglycemic effect than exenatide, so it sells better.
However, so far only two companies, Shenzhen Hanyu Pharmaceutical and Hangzhou Jiuyuan Gene, have applied for the imitation of Exenatide Injection. This result is a bit unexpected.
SGLT-2 inhibitor
4 new drug applications, 3.1 category high fever
SGLT-2 is a new type of diabetes treatment target. Different from the mechanism of traditional diabetes treatment drugs, SGLT-2 inhibitors can excrete excess glucose from the urine, thereby reducing glycosylated proteins, improving the insulin sensitivity of the liver and peripheral tissues, improving β-cell function, and further improving the liver Insulin resistance, which promotes higher glycogen output back to normal. Due to this mechanism of action, SGLT-2 inhibitors can be combined with other treatments and can also reduce the weight of diabetic patients.
AstraZeneca’s dapagliflozin was the first SGLT-2 inhibitor to be marketed, and the product was launched in Europe in the first quarter of 2013. Canagliflozin, jointly developed by Tanabe Mitsubishi and Johnson & Johnson, was launched in the United States in the second quarter of 2013. Later on the market is also: Boehringer Ingelheim and Eli Lilly jointly developed empagliflozin, which can also be used in combination with linagliptin. The current late-stage research and development projects focus on the combination of SGLT-2. (See Table 4)
In China, there is currently no SGLT-2 inhibitor on the market. However, AstraZeneca’s Dapagliflozin and Boehringer Ingelheim’s Enpagliflozin have both declared clinical applications for import. According to Xianda data V3.2, Canagliflozin also filed an import application, but the manufacturer is unknown.
Many domestic pharmaceutical companies are developing new compounds for this target (see Table 5), hoping that these new compounds will have better performance in tolerability.
The popularity of category 3.1 applications is still very high. Among them, there are 23 declarations for kaggliflozin, 16 declarations for enggliflozin, and 13 declarations for dahgliflozin. There are few imitation manufacturers of iggliflozin listed in Japan, but there are still 7 applications for iggliflozin of various salts.
Application for compound preparations of SGLT-2 inhibitors include: Shandong Luoxin’s Enpagliflozin and Linagliptin tablets, and Harbin Zhenbao Pharmaceutical’s compound canagliflozin and Metformin hydrochloride tablets. This is also the mainstream research and development trend of diabetes medication in the future.
Insulin and its analogues
The second and third generation product biosimilar drugs are the main development target
Insulin is the most effective diabetes treatment drug. Whether it is type 1 or type 2 diabetes, the last line of defense in the treatment plan is insulin. Therefore, insulin is called the “ultimate drug” for diabetes treatment and is irreplaceable.
Insulin has gone through four stages of development: animal insulin, human insulin, insulin analogues and ultra-long-acting insulin. At present, foreign research mainly focuses on the development of ultra-long-acting insulin, while domestic research and development mainly focus on the development of second- and third-generation insulin analogs.
The insulin market in my country is still dominated by original research products, especially insulin analogues, dominated by Novo Nordisk, Sanofi and Eli Lilly. Local companies currently have a place in the human insulin product market, representing companies such as United Laboratories, Tonghua Dongbao, and Gan Lee Pharmaceuticals.
The current domestic insulin-related R&D companies are concentrated in: Tonghua Dongbao, Ganli Pharmaceutical, Zhuhai Federation, Hisun Pharmaceutical, Chia Tai Tianqing, Yichang Yangtze River, Jiangsu Wanbang and Hefei Tianmai.
Due to the high technical barriers, complex processes, and difficult production control conditions for biological drugs and biosimilar drugs, the number of companies is much smaller than that of chemical drug development.
At present, domestic manufacturers’ research and development and application projects are concentrated on human insulin and its long-acting preparations. The third-generation insulin is basically applied for 15 categories, which has national standards. Pre-mixed dosage forms of glorine, aspartate, insulin lispro and various human insulins have been declared, which has a certain impact on the domestic market dominated by foreign companies. As for the future market structure, it is necessary for companies to carry out intensive market development on the basis of ensuring product quality.
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