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Inventory of Chinese TOP10 biosimilars

Release date: 2020-01-06 Views: 0

Source: Yaodu  

In March 2015, the State Drug Administration (NMPA) issued the "Technical Guiding Principles for the Development and Evaluation of Biosimilars (Trial)", which for the first time clarified the definition of biosimilars and proposed the basic principles for the development and evaluation of biosimilars. , Put forward specific requirements for the content of pharmacy, non-clinical and clinical research and evaluation of biosimilar drugs.

Biosimilars, also known as biosimilars, refer to therapeutic biological products that are similar in quality, safety, and effectiveness to approved reference drugs. With the expiration of original research biopharmaceutical patents and the continuous development of biotechnology, the research and development of biosimilars based on the quality, safety and effectiveness of original research biopharmaceuticals will help increase the availability of biopharmaceuticals and reduce the price. Demand for medication for the masses.

Part 1 A blue ocean of biosimilar drugs in China

1, 4 "domestic" biosimilars approved, ushering in breakthrough progress

2019 is the first year of biosimilars in China. On February 25th, NMPA approved the listing of Fuhong Hanlin's rituximab injection (trade name: Hanlikang®), which is the first monoclonal antibody drug independently developed by Fuhong Hanlin. The first Chinese "domestic" biosimilar. After that, adalimumab injection (brand name: Glorious®) developed by Bio-Bio, adalimumab injection (brand name: Anjianning®) developed by Hisun Pharmaceutical, and Qilu Pharmaceutical Bevacizumab injection (brand name: Ankada®) was approved for marketing on November 7, 2019, December 6, and December 9. This also marks China's breakthrough in the field of biosimilars in 2019.

Figure 1. Appearances of Hanlikon®, Grace®, Angenin®, and Ankada®

2.China's number of biosimilar drug R & D pipelines ranks first in the world

In terms of the number of R & D pipelines in various countries and regions, China has 391 biosimilars, ranking first in the world. India (300) and the United States (262) are ranked second and probe, followed by South Korea (147), Russia (115), Europe (80), Taiwan (72), and Japan (72). 68), Switzerland (67), EU (64). China has the largest number of research projects, which can be described as the "leaders" in the field of biosimilars, which also reflects the fierce competition of domestic pharmaceutical companies in the development of biosimilars.

Figure 2. Number of biosimilars under development in different countries and regions

In addition, there are nearly 180 companies in China with similar biopharmaceuticals, including Suzhou Kangning Jerry, Qilu Pharmaceutical, Zhejiang Hisun, Fuhong Hanlin, Zhengda Tianqing, Sansheng Guojian, Shuanglu Pharmaceutical, Hualan Gene, Biotech, Anhui Anke Bio, Jiahe Bio, Harbin Pharmaceutical Group Bioengineering, Tonghua Dongbao Bio, Xiamen Tebao, Cinda Bio, Shanghai Fudan Zhangjiang Bio, etc.

Figure 3. Ranking of domestic biosimilar drug R & D companies

3. Huge market for biosimilar drugs

Biopharmaceuticals is one of the fastest growing sub-sectors in the pharmaceutical industry in recent years. The global market size is expected to increase from US $ 202 billion in 2016 to US $ 326 billion in 2022, a compound annual growth rate of 8.3%. China's market size increased from 62.7 billion yuan in 2012 to 152.7 billion yuan in 2016, with a compound annual growth rate of 24.9%. Frost & Sullivan predicts that China's biopharmaceuticals will maintain a compound annual growth rate of 16.4% in 2016-2021, and reach a market size of 326.9 billion yuan by 2021. With the vigorous development of biosimilar drugs, their proportion in biomedical drugs is increasing. The next few years will be the golden stage of the development of biosimilars, and the potential market is huge.

Figure 4. Top 10 Best-selling Biopharmaceutical Sales in 2018 (Globally)

Figure 5. Sales of the top ten best-selling biopharmaceuticals in China (China) in 2018

4. Good domestic policy orientation

In recent years, China has formulated and promulgated a number of related policies to encourage the development of biosimilar drugs.

Figure 6. Development of biosimilar-related policies in China

In February 2015, CDE issued the "Technical Guiding Principles for the Development and Evaluation of Biosimilars (Trial)", which for the first time clarified the definition of biosimilars, marking that China's evaluation and management of biosimilars has basics to follow. Principles have laid a good foundation for further standardizing the development of such drugs and improving their safety, effectiveness, and quality control.

In July 2016, the "Registration Regulations (Revised Draft)" further standardized the concept of biosimilars and tightened the approval standards for biosimilars.

In March 2017, the National Pharmacopoeia Commission issued a notice on soliciting opinions on the "Principle of Naming Principles for Generic Names of Biological Products", standardizing the methods for generic names of biological products, and naming biologically similar drugs is no different from the original research. The management of biosimilars in China is gradually on the right track. In the future, similar monoclonal antibody drugs must be declared as biosimilars, and it will be difficult to obtain approval for new drug applications. This will increase the barriers to monoclonal antibody development. Policy-oriented rules.

In July 2017, CDE issued a consultation notice on "Considerations for the Design and Review of Clinical Studies of Bevacizumab Injection Biosimilars". This is the first time that review points have been formulated based on single-species R & D.

In October 2017, the General Office of the Central Committee of the Communist Party of China and the General Office of the State Council issued and issued the “Opinions on Deepening the Reform of the Review and Approval System to Encourage the Innovation of Drugs and Medical Devices”, and once again explicitly proposed to support the development of biosimilar drugs.

In December 2017, the National Development and Reform Commission issued a notice on the "Three-year Action Plan to Enhance the Core Competitiveness of Manufacturing Industries (2018-2020)." The policy once again supported innovative drugs, and at the same time identified the first biosimilar drug as a high-end drug. Encourage the expiration of patents with high market potential and high clinical value, and the development and industrialization of the first chemical generic drugs and biosimilars.

The promulgation of these policies has provided favorable conditions for the development of biosimilars, and has extremely important guiding significance for the development of biosimilars in China.

Part 2 China's TOP10 biosimilar pipeline

The query data found that as of December 2019, there were about 391 biosimilars in China, which is the country with the largest number of biosimilars. In China, it has become a hot topic at present, and with the expiration of a large number of original drug patents, biosimilar drugs have become a must-have, attracting many pharmaceutical companies to deploy.

The targets of biosimilar drugs in China include CD20, EFGR, VEGF, TNF, RANKL and HER2. Includes adalimumab, bevacizumab, trastuzumab, rituximab, etanercept, infliximab, disuclizumab, fegustine, and pegfilgis Ting, ranibizumab, insulin glargine, omazumab and other nearly 50 original drugs.

The author selected 10 representative original research drugs, and organized, analyzed, and summarized their biosimilar drug R & D pipelines in China. Please fill in the inexhaustible points.

Table 1. Chinese TOP10 biosimilars

1.Rituximab

Figure 7. Rituximab structural formula

Rituximab (Melohua®) was jointly developed by Biogen and Roche (including Genentech in the United States and Sino-Japanese Pharmaceuticals in Japan), and was approved by the US Food and Drug Administration (FDA) on November 26, 1997. On May 21, it was approved for listing by the National Drug Administration (NMPA). The drug is a human-mouse chimeric monoclonal antibody targeted to CD20, which binds to the CD20 antigen expressed on the surface of B-lymphocytes, through complement-dependent cytotoxicity (CDC) and antibody-dependent cytotoxicity (ADCC) kills tumor B cells. The approved indications for the drug are non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, pneumocystis vulgaris, granulomatous vasculitis, and polyangiitis under the microscope.

On February 25 this year, the first domestically produced rituximab biosimilar drug, Hanlikang®, was approved for marketing. This drug is the first monoclonal antibody developed by Fuhong Hanlin, which is used for (1) relapsed or resistant follicular central lymphoma; (2) previously untreated CD20-positive stage III-IV filter Vesicular non-Hodgkin's lymphoma; (3) Treatment of CD20-positive diffuse large B-cell lymphoma (DLBCL), which is approved for all indications of original research rituximab in China. As the first biosimilar in China, the approval of Hanlikang® has filled the gap in the biosimilar market in China, enhanced the accessibility of high-quality biopharmaceuticals, and thus benefited more lymphoma patients.

In addition, there are 5 drugs in clinical phase III, 1 in clinical phase II, 2 in clinical phase I, and 1 preclinical phase. The specific information is shown in the following table:

Table 2. Rituximab biosimilar development pipeline

Trastuzumab

Figure 8. Trastuzumab structure

Trastuzumab (Herceptin®) was developed by Genentech (a Roche subsidiary), and was approved by the US Food and Drug Administration (FDA) on September 25, 1998, and obtained National Drug Supervision on September 5, 2002. Authority (NMPA) approved listing. Trastuzumab is a humanized IgG1κ monoclonal antibody that binds to HER2 on tumor cells and mediates antibody-dependent cytotoxicity (ADCC). The drug is used to treat breast cancer patients with HER2 overexpression, metastatic gastric cancer with HER2 overexpression, or adenocarcinoma of esophagogastric junction.

At present, no domestic trastuzumab biosimilar has been approved for marketing. In the first echelon are two drugs for BLA application, namely CMAB-302 of Sansheng Guojian and HLX-02 of Shanghai Fuhong Hanlin. Among them, HLX-02 of Fuhong Hanlin is the first trastuzumab biosimilar that has undergone head-to-head international multicenter clinical research and has received application acceptance, and is expected to become the company's second biosimilar approved in China. medicine.

In addition to 2 drugs for BLA application, there are 5 drugs in clinical phase III, 6 drugs in clinical phase 1, and 9 drugs in preclinical phase. The detailed information is shown in the following table:

Table 3. Trastuzumab biosimilar development pipeline

3.Bevacizumab

Figure 9. Structural formula of bevacizumab

Bevacizumab (Avidin®) is a humanized monoclonal antibody IgG1 prepared by recombinant DNA technology. By binding to human vascular endothelial growth factor (VEGF), it inhibits the binding of VEGF to its receptors and blocks blood vessels. The resulting signaling pathway inhibits tumor cell growth. As one of the important anti-tumor angiogenesis drugs, it is applied to the treatment of a variety of malignant tumors.

Bevacizumab's patent protection in China expired in 2018, and currently only Onda® from Qilu Pharmaceuticals was approved by the National Drug Administration (NMPA) for listing in December this year. The drug is China's first bevacizumab biosimilar approved for marketing and is in the first echelon.

Query data found that there are currently 2 bevacizumab biosimilars in the BLA market application stage in China, namely SB-8 from Shenyang Sansheng Pharmaceutical and IBI-305 from Cinda Bio. In addition, there are 12 drugs in Phase III and 11 drugs in Phase I clinical research. The specific information is shown in the following table:

Table 4. Bevacizumab biosimilar development pipeline

4.Raizumab

Figure 10. Structure of Raizumab

Ranibizumab (Novotel®) was jointly developed by Genentech (a Roche subsidiary) and Novartis, and was approved by the US Food and Drug Administration (FDA) on June 30, 2006 and China on December 31, 2011 China National Drug Administration (NMPA) approved the listing. Ranibizumab is a Fab fragment of a humanized IgG1κ monoclonal antibody that binds to receptor binding sites in the activated form of vascular endothelial growth factor A (VEGF-A), preventing VEGF-A from binding to the surface of endothelial cells. VEGF receptors (VEGFR1 and VEGFR2) bind to reduce tumor neovascularization. The drug is used to treat neovascular (wet) age-related macular degeneration (AMD), macular edema caused by retinal vascular occlusion (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR).

At present, there are two drugs in the third phase of clinical trials in China, one in the first phase of clinical trials, and two drugs in the preclinical research stage. QL-1205 of Qilu Pharmaceutical obtained clinical approval in September 2016, and has now reached the third phase of clinical trials. It is the fastest-growing ranibizumab biosimilar, and the specific information is shown in the following table:

Table 5. Razumab biosimilar development pipelines

5.Cetuximab

Figure 11. Structural formula of cetuximab

Cetuximab (Ebitux®) was jointly developed by ImClone (a subsidiary of Eli Lilly) and BMS, and was approved by the US Food and Drug Administration (FDA) on February 12, 2004, and obtained on December 30, 2005 China National Drug Administration (NMPA) approved the listing. Cetuximab is a human / mouse chimeric monoclonal antibody that specifically binds epidermal growth factor receptor (EGFR) on normal cells and tumor cells and competitively inhibits EGF and other ligands (such as transformation Growth factor alpha) binds to this receptor. At present, the indications approved by the drug worldwide are metastatic head and neck cancer, non-metastatic head and neck cancer, metastatic colorectal cancer, and non-small cell lung cancer.

In 2017, with the expiry of the drug's patent in China, many domestic pharmaceutical companies deployed R & D for the drug, but no cetuximab biosimilar has been approved for marketing in China. Currently the fastest progress is KL-140 of Sichuan Kelun Pharmaceutical, which is currently in the Phase III clinical research phase. In addition to this drug, there are 8 other drugs in clinical phase I. The specific information is shown in the following table:

Table 6. Cetuximab biosimilar development pipeline

6.Infliximab

Figure 12.Infliximab structural formula

Infliximab (GEK®) was developed by Janssen (a subsidiary of Johnson & Johnson), and was approved by the US Food and Drug Administration (FDA) on August 24, 1998 and the State Drug Administration on May 17, 2007 (NMPA) Approved for listing. The drug is a human-mouse chimeric monoclonal antibody. As a tumor necrosis factor (TNF) blocker, it can bind to soluble and transmembrane TNFα with high affinity and inhibit the binding of TNFα to its receptor. The drug's approved indications are Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, and Behcet's disease.

At present, there are five biosimilars in Infliximab in China, including one CMAB-008 (Shanghai Baimaibo Pharmaceutical) in the BLA market application, and two GB-242 (Jiahe Biological) in clinical phase III. ), HS-626 (Haizheng, Zhejiang), and 2 drugs in the preclinical stage, the specific information is shown in the following table:

Table 7. Infliximab biosimilar development pipeline

7, adalimumab

Figure 13. Adalimumab structure

When it comes to the well-known "medicine king" Xiu Mei Le ®, the industry should know everything. It is the world's first fully human monoclonal antibody against tumor necrosis factor ɑ (TNF-ɑ) approved to be marketed. It specifically binds to soluble human TNF-ɑ and blocks its binding to cell surface TNF receptors p55 and p75. Interaction, thereby effectively blocking the inflammatory effect of TNF-ɑ. In addition, adalimumab may also produce antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and induce apoptosis through binding to transmembrane TNF-ɑ. , Remove a part of the target cells that cause disease.

Since 2012, AbbVie's Humira® has been sitting on the top spot in global single drug sales for 7 consecutive years. However, due to high prices, the sales of "Medicine King" in China are not as hot as in foreign countries. It is worth celebrating that on November 28 this year, Xiu Mei Le was officially listed in the National Medical Insurance Drug List by the National Medical Insurance Bureau. After being included in medical insurance, adalimumab medical insurance payment standard is 1,290 yuan / piece, which will benefit the majority of patients.

In view of the broad market space of adalimumab, domestic pharmaceutical companies have been actively conducting clinical trials of adalimumab biosimilars. On November 7, 2019, Biotech Biopharmaceutical Co., Ltd. announced that the company's self-developed Glegli® (adalimumab injection) has been officially approved by the State Drug Administration for the treatment of rheumatoid arthritis, Autoimmune diseases such as ankylosing spondylitis and psoriasis. This is the first adalimumab biosimilar approved in China.

Subsequently, on December 10, 2019, the market application (CXSS1800025) of adalimumab injection (trade name: Anjianning®) independently developed by Hisun Pharmaceutical was approved by the State Drug Administration, and the indication was ankylosing spondylitis , Rheumatoid arthritis and plaque psoriasis. Angenin® is the second domestic adalimumab biosimilar.

In addition to Glorious® and Angenin® which have been approved for marketing, there are 2 drugs in BLA application, 4 in clinical phase 3, 10 in clinical phase 1, and 11 in preclinical research phase. Specific information As shown in the following table:

Table 8. Adalimumab biosimilar development pipeline

8, etanercept

Figure 14.Etanercept structure

Etanercept (Enley®) is the first TNF antagonist approved for rheumatoid arthritis (RA). It was jointly developed by Amgen and Pfizer, and was approved by the US FDA on November 2, 1998. On February 26, 2010, it was approved by the National Drug Administration (NMPA) for marketing. Etanercept specifically binds to TNF molecules and inhibits the binding of TNF-α and TNF-β to TNF receptors on the cell surface. The drug is used to treat rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and severe non-radiographic Axial spinal arthritis and plaque psoriasis (PsO) in patients 4 years and older.

There are 3 domestic etanercept biosimilars approved for marketing in China: Sansheng Guojian's Yisaipu®, Shanghai Sekin Biotech's Junk®, Zhejiang Hisun's Amber®, and their common names are Recombinant human type II tumor necrosis factor receptor-antibody fusion protein. And compared with its original drug etanercept (Enley®), Sansheng Guojian's Yisaipu® was approved for marketing earlier in the country.

Remarks: Sansheng Guojian's Yisaipu®, Saijin Biological's Junke®, and Hisun Pharmaceutical's Amphenol (both are etanercept biosimilars), but because of the structural differences and no After comparative verification of head-to-head clinical trials, these products are not considered internationally as biosimilars in the strict sense.

In addition, there is another QL-0902 Qilu Pharmaceutical in the BLA market application stage, which is expected to become the fourth domestically approved etanercept biosimilar. One drug is in Phase II, one is in Phase I, and two are in preclinical phase. The specific information is shown in the following table:

Table 9. Etanercept biosimilar pipelines

9.Pertuzumab

Figure 15.Pertuzumab structural formula

Pertuzumab was developed by Genentech (a Roche subsidiary) and was approved by the US Food and Drug Administration (FDA) on June 8, 2012, and approved by the National Drug Administration (NMPA) on December 17, 2018. . Pertuzumab is a humanized monoclonal antibody that targets the epidermal growth factor receptor 2 protein (HER2) and inhibits ligand-dependent heterodimerization between HER2 and other HER family members , Blocking the cell cycle and inducing apoptosis. The drug is approved for HER2-positive metastatic breast cancer.

The research and development of this kind of biosimilars in China is focused on the first phase (2) and preclinical (5) research stages, involving Jiahe Biological, Zhengda Tianqing, Biotech, Beijing Tianguangshi, Qilu Pharmaceutical, Shanghai Fu Honghanlin, Suzhou Corning Jerry and other biopharmaceutical companies, the specific information is shown in the following table:

Table 10. Pertuzumab biosimilar development pipeline

10.Disulimumab

Figure 16. Structural formula of disulimumab

Disuzumab (Angavir®) was developed by Amgen. It was approved by the European Medicines Agency (EMA) on May 26, 2010 and was conditionally approved by the NMPA on May 22 this year. Used to treat non-surgical resection or giant cell tumor of bone that may cause severe dysfunction, including adults and adolescents with mature skeletal development (defined as at least 1 mature long bone and weighing ≥45 kg) The drug is a fully human IgG2 monoclonal antibody that binds RANK ligand (RANKL), a soluble or transmembrane protein necessary for osteoclast formation, function, and survival.

At present, there are many domestic pharmaceutical companies deploying disulfumab biosimilars, among which QL-1206 from Qilu Pharmaceutical and LY-01011 from Luye Pharmaceutical are in the leading position and are in the phase III clinical research phase. In addition, there are 5 drugs in the first phase and 4 in the preclinical phase. The detailed information is shown in the following table:

Table 11. Desuzumab biosimilar development pipeline

to sum up

At present, a total of 4 “domestic” biosimilars in China have been approved for marketing, namely Hanhong Kang of Fuhong Hanlin, Glorious of Biotec, Anjianning of Hisun Pharmaceutical, and Anlian of Qilu Pharmaceutical. Up to ®. In addition, there are a number of biosimilar drugs in the BLA marketing application and clinical phase III. The targets include CD20, EFGR, VEGF, TNF, RANKL, and HER2. Clinical trials by major pharmaceutical companies are in full swing. It marked the vigorous development of the domestic biosimilar industry.

The research and development of domestic medicines cannot be separated from the support of relevant policies. From 2015, China issued the “Technical Guiding Principles for the Development and Evaluation of Biosimilars (Trial)”, which guides and regulates the research and development and evaluation of biosimilars, and has subsequently issued a series of related policies. The successive release of these policies and the increasingly clear path of registration approval have undoubtedly provided the necessary conditions for the successful marketing of biosimilars. In the next few years, the scale of China's biosimilar market is expected to show explosive growth, ushering in the "golden age".

References:

Drug crossing database

2.NMPA / CDE / FDA official website

3.Shanghai Fuhong Hanlin, Biotech, Qilu Pharmaceutical and other official websites

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