ADC Reviews

Hot Targets of Global Innovative Drugs in 2022

drug targets

With the continuous increase in R&D investment of global pharmaceutical companies, the competition in the global pharmaceutical market has become increasingly fierce. Enterprises are increasing their investment in new drug research and development, promoting the continuous discovery and application of new drug targets and treatment methods, and new market opportunities for innovative drug research and development.

On the popular research and development drug targets, there are currently crowded tracks, fierce competition, and serious homogeneity. In recent years, PD-1 has become a hot spot in the innovative drug market. In addition, what other hot targets are there in the field of global innovative drug research and development?

Inventory of the TOP20 hot targets of global innovative drugs

The current top 20 hot targets in the global innovative drug research and development field are: EGFR, HER2, Insulin, CD3, Aβ, Calcium channel, PD-L1, CD19, COVID19 Spike glycoprotein, AR, VEGFR, GLP-1R, DRD2 , NMDAR, bacterial DNA gyrase, PD-1, VGSC, ER, COX-2, TOP2.

Among them, the number of innovative drugs targeting epidermal growth factor receptor (EGFR) totaled 594, including 45 in the drug discovery stage, 135 in the preclinical stage, 3 in clinical applications, 3 in clinical trials, 60 in phase I clinical trials, and 60 in phase II clinical trials. 60, including 11 Phase III clinical trials, 6 applications for marketing, 29 approved for marketing, 45 research terminations, 4 research suspensions, and 193 reports with no follow-up progress.

The total number of innovative drugs targeting human epidermal growth factor receptor 2 (HER2) is 475, including 29 in the drug discovery stage, 133 in preclinical, 3 in clinical application, 58 in phase I, 42 in phase II, and 3 in phase III. There are 13 clinical trials, 2 applications for marketing, 15 marketing approvals, 38 research terminations, 1 research suspension, and 141 reports with no follow-up progress.

The total number of innovative drugs for insulin (Insulin) is 436, of which 23 are in the drug discovery stage, 26 are in the preclinical stage, 19 are in the phase I clinical trial, 16 are in the phase II clinical trial, and 15 are in the phase III clinical trial. 28 were listed, 77 were terminated from research, 2 were suspended from research, 206 were reported without follow-up progress, 1 was withdrawn from the market, and 1 was authorized externally.

The hot target of global innovative drugs TOP1——EGFR

EGFR tops the list of popular targets. Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, also known as ErbB-1 or HER1, and belongs to the ErbB receptor tyrosine kinase family. Structurally, the EGFR protein can be divided into three parts, namely the ligand binding region, the tyrosine kinase active region, and the transmembrane structure anchored on the cell membrane. When the ligand binds to the receptor EGFR, EGFR can exert its kinase activity and activate the phosphorylation modification on the tyrosine residue of the ligand, thereby further activating the downstream signaling pathway to exert the corresponding physiological function.

Other members of this family include ErbB-1 (EGFR), ErbB-2 (HER2/neu), ErbB-3 (HER3) and ErbB-4 (HER4). Overexpression, mutation, or high expression of ligands bound to these family members can lead to the occurrence of some tumor diseases, such as non-small cell lung cancer, breast cancer, head and neck cancer, cervical cancer, bladder cancer, gastric cancer, ovarian cancer, etc. . The EGFR signal transduction pathway plays an important role in tumor cell proliferation, damage repair, invasion and angiogenesis, so drugs targeting EGFR have also become a hot spot in tumor therapy.

According to the TOP10 statistical ranking of the number of drugs for each indication of EGFR target in the world, the number of innovative drugs developed for cancer is 398, ranking first; followed by 190 for breast tumors, 134 for solid tumors, and 119 for non-small cell lung cancer , 95 advanced solid tumors, 85 metastatic breast cancers, 83 metastatic non-small cell lung cancers, 57 gastric tumors, 48 ​​metastatic lung cancers, and 47 glioblastomas.

Ranking of the number of drugs with different indications for EGFR targets

At present, the drugs targeting EGFR to treat tumors are mainly small molecule tyrosine kinase inhibitors (TKIs) and EGFR monoclonal antibodies. At present, the research and development of EGFR-targeted drugs in my country mainly focuses on small molecule tyrosine kinase inhibitors. There are three generations of development.

The first-generation EGFR-TKI representative drugs include AstraZeneca’s Gefltinib, Roche’s Erlotinib, and Betta Pharmaceuticals’ Icotinib. The first-generation EGFR tyrosine kinase reversible inhibitor, belonging to the class of anilinoquinazolines, can competitively inhibit the binding of ATP to the EGFR tyrosine kinase activation domain site, thereby blocking the downstream protein kinase B (PKB /AKT), STAT pathway and mitogen-activated protein kinase (MAKP) activation pathway, blocking the EGFR signal transduction pathway involved in tumor growth and metastasis. Most lung cancer patients treated with first-generation EGFR-TKIs will develop drug resistance about 1 year after treatment. T790M mutation occurs in about 49% to 63% of the tissue samples of patients with acquired drug resistance, which is considered to be the first. The most important cause of resistance to the generation of TKIs.

The difference between the second generation EGFR-TKI and the first generation is that its binding to the tyrosine kinase activation region is irreversible, and it is also a pan-HER inhibitor, which can simultaneously inhibit the three receptors of EGFR, HER-2 and HER-4. Phosphorylation and subsequent kinase activity. Compared with the first-generation TKI, the second-generation TKI has the characteristics of more targets and stronger adverse reactions, which also establishes the general trend that its clinical benefit is more significant than the first-generation TKI, and it also faces poor patient tolerance. the problem. Representative drugs include Boehringer Ingelheim’s Afatinib and Pfizer’s Dacomitinib.

The third-generation EGFR-TKI mainly inhibits the transduction of signaling pathways by forming a covalent bond with the tyrosine kinase binding domain Cys797, avoiding T790M. Third-generation TKIs overcome drug resistance caused by the T790M mutation and are well tolerated. Representative drugs include Osimertinib from AstraZeneca, Almonertinib from Hansoh, Avitinib from Allison, and Furmonertinib from Allison ).

The hot target of global innovative drugs TOP2——HER2

Human epidermal growth factor receptor 2 (HER2) belongs to the ERBB receptor tyrosine kinase family. This family has 4 members, namely ERBB1, ERBB2, ERBB3 and ERBB4. ERBB1 is the EGFR mentioned above. The heterodimer formed by the binding of HER2 and other ERBB family members, after the ligand binds to HER2, the tyrosine kinase of HER2 itself is activated, which in turn phosphorylates its substrate and activates downstream signaling pathways.

HER2 is under-expressed or not expressed in normal adult body tissues, but amplified/overexpressed in breast cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, gastric cancer, prostate cancer and other tumors. In addition, clinically, the expression of HER2 was significantly negatively correlated with the sensitivity of tumors to chemotherapy and biological therapy. These two properties make HER2 an ideal specific tumor therapeutic target and monitoring/prognostic marker.

Ranking of the number of drugs with different indications for HER2 targets

In recent years, technologies targeting HER2 have continued to develop, including “improved” HER2 monoclonal antibodies, bispecific antibodies targeting HER2, and a variety of antibody-drug conjugates targeting HER2. They are expected to effectively target tumor cells that do not express high levels of HER2, thereby expanding the range of patients that can be treated.

At present, HER2-targeted drugs are mainly divided into monoclonal antibodies, small molecule targeted inhibitors and ADC drugs:
(1) Monoclonal antibodies bind to the HER2 receptor to prevent the formation of HER2 dimers or to carry out an immune response to inhibit the breakdown of HER2, ultimately destroying downstream signaling pathways.
(2) Small molecule tyrosine kinase inhibitors bind to HER2 intracellular tyrosine kinase to inhibit the phosphorylation of tyrosine kinase, thereby inhibiting the activity of downstream pathways.
(3) After the ADC mechanism combines with the extracellular structure of HER2 to form a complex, it induces endocytosis and enables the drug to work.

HER2-targeted drug launch timeline

Among them, trastuzumab is the world’s first humanized monoclonal antibody drug targeting the HER2 protein; lapatinib is the world’s first approved HER2 small molecule targeting inhibitor drug; Tocilizumab is the world’s first HER2-targeted ADC drug approved for marketing.

Lapatinib (English name: Tykerb, Generic name: Lapatinib Tosylate Tablets, Abbreviation: Lapatinib), developed by GlaxoSmithKline in the United Kingdom, is an oral drug targeting HER- 1/ A reversible small molecule tyrosine kinase inhibitor of HER-2, which can effectively inhibit the activity of human epidermal growth factor receptor-1 and human epidermal growth factor receptor-2 tyrosine muscle enzymes.

In March 2007, lapatinib was approved by the FDA through the priority review channel. It is mainly used in combination with capecitabine to treat HER2 overexpression, and has previously received an anthracycline, a taxane and trastuzumab. Advanced or metastatic breast cancer patients with monoclonal antibody; or postmenopausal metastatic breast cancer patients with estrogen receptor positive, HER2 overexpression and suitable hormone therapy in combination with letrozole. In January 2013, it was imported and listed in my country by GlaxoSmithKline under the trade name of “Tailisha”.

Trastuzumab and Enmetrastuzumab were developed by Roche. According to the data, among the TOP100 global drug sales in 2020, Roche’s trastuzumab ranked 25th with US$3.978 billion (equivalent to RMB 27.4 billion).

Trastuzumab, which was approved for marketing in the United States in 2013, is an antibody-drug conjugate (ADC) targeting HER2.

The TOP3 hot target of global innovative drugs——Insulin

Insulin is a protein hormone secreted by the pancreatic islet beta cells in the pancreas when stimulated by endogenous or exogenous substances such as glucose, lactose, ribose, arginine, glucagon, etc. The only hormone in the body that lowers blood sugar, while promoting glycogen, fat, and protein synthesis.

Insulin was first applied to a dying 14-year-old boy in January 1922, and it has been a hundred years since then. After Eli Lilly’s epoch-making commercialization of recombinant human insulin in 1982, animal insulin gradually withdrew from the stage of history until it was stopped by the US FDA in 2006. After 1996, the third-generation insulin analogs have been launched one after another, and it has a history of more than 20 years.

Early insulin action time is short, and patients need to inject multiple times a day, which brings inconvenience and pain to patients. In 1936, the long-acting insulin protamine zinc insulin (PZI) was born, and people added excessive protamine and excessive zinc to the insulin to keep the preparation stable. 3-4h after subcutaneous injection, the effect is strongest at 8-10h, and the hypoglycemic effect can be maintained for up to 20h.

In 1982, the first recombinant human insulin was launched. The new generation of insulin overcomes adverse reactions such as high immunogenicity of animal insulin, severe allergic reaction, and lipoatrophy at the injection site. Currently, the commonly used recombinant human insulins include short-acting, intermediate-acting and premixed human insulins. In 1946, a more stable intermediate-acting insulin-neutral protamine zinc insulin (NPH) was successfully developed. NPH is a basal insulin made from the combination of insulin zinc crystals and protamine. It starts 2.5-3.0 hours after injection. The peak time is 5-7 hours, and it can last for 13-16 hours. Injection twice a day can basically cover the basal insulin demand throughout the day. In 1996, the first rapid-acting human insulin analog was launched. Currently, there are three main types of rapid-acting insulin analogs, including insulin lispro, insulin aspart, and insulin glulisine.

In 2000, the first long-acting insulin analog was launched. Currently, common long-acting insulin analogs include insulin glargine, insulin detemir, and insulin degludec. Until 2013, insulin glargine (Lantus®) was the best-selling long-acting insulin. As the world’s first long-acting basal insulin analog, Lantus has dominated the diabetes market for many years, with annual sales reaching US$8 billion.

Novo Nordisk is currently the world’s largest and most comprehensive insulin manufacturer, including fast-acting and long-acting insulin preparations.