What are the current popular drug targets? What are the development trends?

The drug target refers to the binding site of the drug in the human body. The key to the research and development of modern new drugs is to find and determine the target first. The selection and determination of novel and effective drug targets is the primary task of new drug development. The following is a brief review of some of the more popular targets and related drugs listed in my country.

EGFR

EGFR is an epidermal growth factor receptor. After activation, it transmits cell proliferation signals downstream. Therefore, if EGFR is mutated, it continues to transmit cell proliferation signals downstream, cell proliferation is not controlled, and tumors occur.

EGFR Inhibitors or antibody drugs are a hot spot in the field of tumor targeted therapy.

The first-generation EGFR inhibitor Gefitinib: originally researched by AstraZeneca (AZ), it was approved for marketing in my country in 2005. At the end of 2016, Qilu Pharmaceutical's first generic drug was approved, and later generic drugs from Chia Tai Tianqing, Kelun, Hengrui, and Yangtze River were approved for listing. In addition, there are currently many companies applying for listing of generic drugs. Erlotinib: jointly developed by Genentech (acquired by Roche) and Astellas, it was approved for listing in my country in 2007. In addition to the original research, my country currently has Shanghai Chuangnuo's erlotinib generic drug on the market. Icotinib: It was developed by Betta Pharmaceuticals and was launched in my country in 2011. It is my country's first self-developed small molecule targeted anticancer drug.

Afatinib, the second-generation EGFR inhibitor, was developed by Boehringer Ingelheim and was approved for marketing in my country in 2017. At present, only Hausen's generic drugs are listed in my country, and many other companies have submitted listing applications, including Kelun, Qilu Pharmaceutical, Yangzijiang, Zhengda Tianqing, Jiangxi Xiangshan, CSPC, etc.

The third-generation EGFR inhibitor Ositinib: developed by AstraZeneca and was approved for marketing in my country in 2017. Ametinib: It was developed by Jiangsu Hausen and was approved for listing in my country in March this year.

EGFR monoclonal antibody At present, the anti-EGFR nimotuzumab marketed in my country was developed by Biotech and was approved for marketing in 2008. It is my country's first anti-EGFR monoclonal antibody drug with independent intellectual property rights. At present, Biotech is carrying out 3 phase III clinical trials to broaden its indications. In addition, Maibo Pharmaceutical-related projects are in phase III clinical trials.

At present, domestic R&D attention is mainly focused on the best-selling third-generation EGFR inhibitors and biosimilars of EGFR monoclonal antibodies.

PD-1/L1

The PD-1/PD-L1 antibody can bind to the PD-1 protein of immune cells or the PD-L1 protein of tumor cells, so that PD-1 cannot bind to PD-L1, so that the immune cells can maintain their activity, thereby preventing tumors. Cells produce lethality.

The PD-1/L1 antibody drug has brought a brand-new tumor treatment model, with dozens of tumor indications, and the market is advancing all the way.

Data show that there are currently 267 drugs related to PD-1/L1 targets, and 115 are in clinical trials. Up to now, my country has launched 4 imported anti-PD-1/L1 drugs, namely nivolizumab, pembrolizumab, duvalizumab, and atelizumab; 4 domestic anti-PD drugs -1 Drugs, namely terelimumab, sintilizumab, carrelizumab, tislelizumab. Among them, nivolumab and pembrolizumab have the most approved indications.

The eight domestic manufacturers of listed drugs have formed the first echelon, starting the battle for indications, prices, and channels. Each has more than 10 indications that are undergoing clinical trials.

The second echelon represented by the local innovative drug company Fuhong Hanliu, etc. is also looking for "strange tricks" to break out of the siege, such as differentiated indications. Yuheng Pharmaceutical's GLS-010 has entered the stage of application for listing. A number of clinical trials of Fuhong Henlius have entered Phase III.

At present, the first and second echelon have gradually formed, and the domestic track is gradually crowded. However, the single-drug efficiency and drug resistance of the PD-1/L1 antibody are still problems that need to be solved urgently, so each target drug used in combination with it is a new choice for various R&D pharmaceutical companies.

GFR

Angiogenesis is the necessary pathway for almost all tumors. VEGF (vascular endothelial growth factor) inhibitors can often target multiple tumor indications.

Small molecule VEGF inhibitors The research and development cycle of small molecule VEGF inhibitors is relatively short. At present, my country's currently marketed drugs include apatinib approved by Hengrui in 2014, Anlotinib approved by Zhengda Tianqing in 2018, and Hutchison Fruquintinib approved by Huangpu in 2018. In addition, several drugs are in the stage of applying for marketing.

VEGF monoclonal antibody VEGF monoclonal antibody is also a drug that major pharmaceutical companies are competing to deploy. Except for ophthalmic drugs, bevacizumab is currently on the market in China. Bevacizumab was developed by Roche and was approved for marketing in my country in 2015; Qilu Pharmaceutical and Cinda Bio's biosimilar drugs were approved at the end of last year and June this year, respectively. In addition, there are currently more than 20 domestic companies deploying the drug. Hengrui's product has already been declared for listing, and the varieties of companies such as Biotec and Jiahe have advanced to the phase III clinical stage.

In addition, the combined use of VEGF inhibitors and PD-1 inhibitors is also a research direction.

The domestic biosimilars of bevacizumab have fierce competition. Not long ago, the price of this variety of Cinda Biologicals has reached a new low. For the subsequent enterprises of the same variety, the price is the basic and the channel is more important.

GLP-1

There are many different types of hypoglycemic drugs. The development trend of GLP-1 receptor agonists is divided into three types: short-acting injections (daily injections), long-acting injections (weekly injections), and oral drugs.

At present, the short-acting GLP-1 receptor agonists approved for marketing in China include Exenatide from AstraZeneca/Sansheng Pharmaceutical, Liraglutide from Novo Nordisk, Risenatide from Sanofi, Renhui Biological benaglutide; long-acting GLP-1 receptor agonists include AstraZeneca’s exenatide microspheres, Eli Lilly’s dulaglutide, and Hausen’s loxenatide; only oral Novo Nordisk's Semaglutide. Long-acting GLP-1 receptor agonists are currently the main battlefield of domestic pharmaceutical companies, with more than 30 companies in the layout, and the competition is fierce.

Metformin's first-line position in hypoglycemic drugs has not allowed the domestic market share of GLP-1 receptor agonists to increase significantly; GLP-1 oral drugs may become the mainstream direction of future research and development.

CD20

CD20 is a hydrophobic four-pass transmembrane protein, and its function may be involved in regulating B cell activation and proliferation. The current typical drug is Rituximab (Rituxan). The drug is also one of Roche's "troika". It was launched in the United States in 1997 and is currently the best-selling CD20 targeted drug on the global market.

In 2000, Rituxan entered the Chinese market and approved indications for relapsed or drug-resistant B-cell non-Hodgkin’s lymphoma, CD20-positive stage III-IV follicular non-Hodgkin’s lymphoma, CD20-positive diffuse large B-cell lymphoma Non-Hodgkin's lymphoma.

In February last year, Shanghai Fuhong Henlius' rituximab biosimilar (Han Likang) was approved for marketing in my country, and recently it was approved for two new indications.

There are also many domestic CD20 antibody drugs. At present, the rituximab injection developed by Innovent has passed the priority review and approval procedures and is in the review state. In addition, companies such as Hisun Pharmaceutical, Chia Tai Tianqing, and Hualan Biology are also actively developing and registering rituximab biosimilar drugs.

There are many domestic companies deploying CD20 target drugs, and the competition is fierce. The dual-antibody circuit layout may be a good choice.

TNF, BTK, JAK

TNF is a popular target for autoimmune diseases, and the typical drug is adalimumab. Adalimumab was originally developed by AbbVie and was approved for marketing in the United States in 2002 and approved for marketing in my country in 2010. In November and December 2019, Biotech and Hisun’s adalimumab biosimilars were approved in my country.

There are also many domestic companies that have deployed adalimumab biosimilar drugs. Among them, Chia Tai Tianqing, Junshi Biological, Fuhong Henlius, and Xinda Biological have already applied for listing.

Among BTK inhibitors, Johnson & Johnson's Ibrutinib and BeiGene's Zebutinib are currently on the market in my country. Ibrutinib is the world's first marketed BTK inhibitor. It was approved by the US FDA in 2013 and approved for marketing in my country in 2017. Zebutinib was approved in my country in June this year. In addition, Nuocheng Jianhua's BTK inhibitor has also been applied for listing.

Among JAK inhibitors, Pfizer's tofacitib was approved in the United States in 2012 and launched in my country in 2017. Generic drugs from Chia Tai Tianqing, Qilu Pharmaceutical, Kelun, Yangzijiang Pharmaceutical, and Simcere have also been approved in my country. Listed. In addition, Novartis's Rocotinib and Eli Lilly's Baritinib have also been approved to enter the Chinese market.

Because JAK inhibitors have potential effects on multiple autoimmune diseases, many pharmaceutical companies are vying to deploy JAK target drugs. Among them, the layout of selective JAK1 inhibitors is relatively crowded, and there are fewer companies deploying pan-JAK inhibitors.

The more popular the target track is, the more crowded, the later the entrants will have less market space in the future. At present, domestic pharmaceutical companies are actively transforming. With the rapid listing of biosimilar drugs and various target innovative drugs, my country's pharmaceutical market will have a further leap.