All in one article: Five types of biotech drugs commonly used in registration applications

In recent years, among the top 10 varieties of global sales, biological drugs have completely crushed small molecules.
For example, Xiu Mei Le has been the king of drugs for many years, and the fiery PD-1 monoclonal antibody "K drug" has grown rapidly
.
And whether it is drug development or clinical efficacy, large-molecule biopharmaceuticals are showing advantages, and it is difficult for small molecules to break through large molecules and occupy the market first
.
So, what are the biological drugs we often talk about? What are they in? This article will introduce in detail the five major types of biotech drugs commonly used in registration applications, and provide market information of representative drugs as much as possible, and will continue to introduce the relevant content of the registration and application of biotech drugs in the follow-up
.
Q: What is a biotechnology drug? A: The so-called biotechnology drugs refer to the use of organisms, biological tissues, cells and their components, and the comprehensive application of the principles and technical methods of various disciplines of chemistry, biology, and medicine for prevention, diagnosis, treatment, and rehabilitation.
Products; and here specifically refers to therapeutic drugs produced by recombinant DNA technology or other innovative biotechnology, such as cytokines, plasminogen activators, recombinant plasma factors, growth factors, fusion proteins, receptors, vaccines and monoclonal antibodies, stem cells treatment technology
.
Since the first recombinant drug, human insulin, was launched in 1982, biotechnology drugs have developed rapidly through continuous innovation, bringing revolutionary changes to the pharmaceutical industry
.
Currently biotechnology can be divided into the following categories: genetic engineering drugs, therapeutic monoclonal antibody drugs, gene therapy and nucleic acid drugs, cell and tissue engineering products, genetically engineered vaccines
.
The following will introduce these 5 major categories of biotechnology drugs, and give the market information of representative drugs as much as possible
.
01 Genetically engineered drugs Recombinant cytokines Cytokines are the collective name for small molecular proteins with biological activity secreted by cells
.
Cytokines have a variety of biological effects such as regulating cell physiological functions, mediating inflammation, participating in immune response and tissue repair
.
There are dozens of cytokines discovered so far
.
The research on the use of cytokines in the clinical treatment of diseases began in the 1980s.
In 1986, interferon-α was first used clinically in the United States.
Currently, there are: interleukin-2, interleukin-11, interferon α2a, interference Alpha 2b, interferon alpha 1b, beta interferon, gamma interferon, omega interferon, integrated interferon, tumor necrosis factor alpha, granulocyte colony stimulating factor, granulocyte-macrophage colony stimulating factor, erythropoietin, epidermal growth More than a dozen genetically engineered cytokine drugs such as cytokine, fibroblast growth factor, and nerve growth factor are on the market globally
.
In addition, there are also recombinant cytokines such as ciliary neurotrophic factor, hepatocyte regeneration proliferation factor, tumor necrosis factor-related apoptosis-inducing ligand, thrombopoietin, stem cell factor, macrophage inflammatory protein-1α, etc.
, which are in different clinics.
Research stage, and some results have been achieved
.
Examples of R&D/market conditions
.
1) Interferon: In the global market in 2018, Bayer's interferon β-1b sales were 642 million U.
S.
dollars (it could reach 1 billion U.
S.
dollars in 2014), and Merck's interferon β-1a sales were 16.
97.
Billion U.
S.
dollars (the average annual sales from 2014 to 2018 can be nearly 2 billion U.
S.
dollars, which is excellent in the interferon market), Biogen’s peginterferon β-1a sales are 448 million U.
S.
dollars (2015~2018 The average annual sales are between 300 to 500 million U.
S.
dollars)
.
The interferon domestic manufacturing enterprises, mainly as a triple gene, Sinovac Biotech, Unnamed biological, Anke Biotechnology and so on
.
2) Nerve growth factor: In the field of nerve growth factor, the most domestically developed and clinically applied mouse nerve growth factor for injection, the research and development companies are Shutaishen (sales of nearly RMB 550 million in 2018), Shandong Wei Mingbi (sales of nearly 500 million RMB in 2018)
.
Recombinant hormones and peptides Hormone biotechnology drugs are mainly divided into two categories, namely protein hormone drugs and peptide hormone drugs
.
Protein hormone drugs mainly include: insulin and various human insulin analogues, growth hormone, follicle stimulating hormone, luteinizing hormone, thyroid hormone, etc.

.
Polypeptide hormone drugs mainly include: parathyroid hormone and similar peptides, insulin secretagogue, glucagon and its analogue peptides, calcitonin and its analogue peptides, somatostatin and its analogue peptides, thymosin, gonadotropin Release hormones and their analogs, oxytocin and vasopressin
.
Examples of R&D/market conditions
.
1) Insulin has become an extremely important type of therapeutic drug in the metabolic field.
So far, a variety of long-acting, short-acting insulin drugs with different clinical characteristics have been listed, such as insulin detemir (2018 global sales of 1.
671 billion US dollars) , 2014~2018 annual sales> 2 billion U.
S.
dollars), insulin degludec (2018 global sales nearly 1.
2 billion U.
S.
dollars), insulin glargine (2018 global sales nearly 5.
198 billion U.
S.
dollars, 2014-2018 average sales ＞6.
8 billion U.
S.
dollars)
.
Domestic insulin supply companies are mainly imported from Novo Nordisk, Sanofi, and Eli Lilly; while domestic companies that have invested and output in insulin are mainly Ganli Pharmaceutical
.
Recombinant Enzymes Activasel is the first recombinant enzyme drug approved by the US FDA for the treatment of coronary artery obstructive heart disease
.
Recombinant enzyme drugs include: 1) "Fibrin selective" thrombolytic drugs, mainly tissue plasminogen activator and various mutants, single-chain urokinase-type plasminogen activator and staphylokinase, etc.
; "Non-fibrin selective" thrombolytic drugs mainly include streptokinase, urokinase, prourokinase, and formylated plasminogen-streptokinase activator complex
.
2) blood coagulation factors such as coagulation factor VIIa, VIII, IX and the like
.
3) Other drugs recombinant enzymes, recombinant superoxide dismutase, urate oxidase, glucocerebrosidase enzyme and arginine
.
Examples of R&D/market conditions
.
1) The domestic market of "fiber/non-fibrin selective" thrombolytic drugs is slightly less popular.
For example, domestic manufacturers of recombinant staphylokinase mainly include Tonghua Yujin Pharmaceutical and Chengdu Diao Jiuhong Pharmaceutical Factory; Recombinant Human The main producers of pro-urokinase include Shanghai Tasly Pharmaceutical
.
2) The R&D company of recombinant human coagulation factor VIII is mainly foreign Pfizer (2018 global sales of 513 million U.
S.
dollars), and the R&D company of recombinant human coagulation factor IX is also mainly Pfizer (2018 global sales of 555 million U.
S.
dollars).
Antibody Fusion protein drugs using genetic engineering techniques to build fusion proteins, can produce a variety of new active molecules, including immunoglobulin fusion products, drugs targeted fusion protein
.
The former includes a recombinant human tumor necrosis factor receptor -Fc fusion protein, recombinant human cytotoxic T lymphocyte function-associated antigen antibody fusion protein (CTLA4-IgG1), recombinant human lymphocyte function-associated antigen-3- antibody fusion proteins and the like
.
Targeted fusion protein drugs include cytokine fusion protein and ligand toxin fusion protein, such as recombinant human interferon α2a-tumor vessel specific binding polypeptide NGR fusion protein, recombinant human interleukin 2-diphtheria toxin fusion protein, GM-CSF / IL-3 fusion protein, recombinant human luteinizing hormone releasing hormone - Pseudomonas aeruginosa exotoxin A fusion proteins and the like
.
Examples of R&D/market conditions
.
1) Fusion protein.
The domestic products registered in this field mainly include recombinant tumor enzyme-specific interferon α-2b Fc fusion protein for injection (Zhuhai Livuzumab), recombinant humanized PDL1/CTLA-4 double Specific single domain antibody Fc fusion protein injection (Jiangsu Kangning Jereh Biotechnology), recombinant human glucagon-like peptide-1 analogue-Fc fusion protein injection (Shanghai Hailu Biotechnology), recombinant human VEGFR-Fc fusion protein eye by injection (Beijing Tide pharmaceutical), injection of recombinant human type ⅱ receptor tumor necrosis factor - antibody fusion protein (Qilu pharmaceutical), and the like
.
Exogenous recombinant protein drugs So far, only recombinant hirudin has been approved for marketing, and its indication is thrombotic diseases
.
Examples of R&D/market conditions
.
1) The main domestic development companies for recombinant hirudin varieties include Chongqing Fujin Biology, Military Academy of Radiology, Shanghai Meitong Biology, Chongqing Duotai Pharmaceutical, Shanghai Fosun Biology, Guangzhou Mingkang Biology, Shandong Ahua Biology, etc.

.
Long-acting protein drugs The main focus of the development of long-acting protein drugs is to improve their pharmacokinetic properties
.
Different proteins have different long-term modification strategies and methods, which can be modified by genetic engineering or post-translational modification by other means to achieve the following goals: 1) Increase molecular weight and reduce filtration from the glomerulus; 2) Increase stability To reduce immunogenicity; 3) Convert peptides to non-peptides
.
Long-acting protein drugs such as long-acting insulin, long-acting granulocyte colony stimulating factor, pegylated interferon
.
Examples of R&D/market conditions
.
There are intersections with the above varieties, so I won’t repeat them here
.
02 Therapeutic monoclonal antibody drugs Monoclonal antibody drugs mainly target various microbial antigens or human proteins, including murine monoclonal antibodies (such as Orthoclone, Zevalin), chimeric monoclonal antibodies (such as Erbitux, Remicade, Rituxan, Simulect) Etc.
), human monoclonal antibodies (Avastin, Campath, Herceptin, Humira, Mylotarg, Raptiva, Zenapax, etc.
)
.
Research and development/market situation: Chimeric monoclonal antibodies.
In 2018, Erbitux (cetuximab) had global sales of US$1.
598 billion (average sales of more than US$1.
8 billion from 2014 to 2018), Remicade (infliximab) Anti-) global sales were 6.
437 billion U.
S.
dollars (2014~2018 average sales> 8 billion U.
S.
dollars), Rituxan (rituximab) global sales were 5.
296 billion U.
S.
dollars (2014~2018 average sales> 71 One hundred million U.
S.
dollars)
.
Human-derived monoclonal antibodies, the global sales of Avastin (bevacizumab) in 2018 were nearly 7 billion U.
S.
dollars (2015~2019 average sales ≈ 7 billion U.
S.
dollars), and the global sales of Herceptin (trastuzumab) Sales of nearly 6.
225 billion U.
S.
dollars (2015~2019 average sales of more than 6.
5 billion U.
S.
dollars), Humira (adalimumab) global sales of nearly 20 billion U.
S.
dollars (the "king of medicine" for many years, no need to repeat)
.
03 Gene therapy and nucleic acid drugs Gene therapy is a medical intervention based on modifying the genetic material of living cells
.
With the help of the vector, the therapeutic gene is introduced into the target cell and expressed, and the target protein can play the role of preventing and treating diseases in the body without isolation and purification
.
There are two main types of vectors: viral vector-mediated and non-viral vector-mediated
.
Viral vectors include adenovirus, adeno-associated virus, retrovirus, lentivirus, herpes simplex virus, poxvirus, Sendai virus, etc.
The therapeutic genes carried are mainly cytokines
.
Non-viral vectors include polymer carriers and liposomes
.
Nucleic acid drugs include nucleic acid vaccines, naked DNA therapeutic drugs (plasmids), antisense nucleic acid drugs and small interfering RNA drugs.
Nucleic acid drugs include DNA vaccines and RNA vaccines.
Antisense nucleic acid drugs include antisense DNA, antisense RNA and nuclear enzymes oligonucleotides for triple
.
At present, nucleic acid drugs are mainly introduced into the body by means of gene transfer methods mediated by general physical and chemical methods such as liposome microcapsule mediation, receptor mediation, and electroporation
.
04 Cell and tissue engineering products Cell therapy products are cell-based products for disease treatment, including somatic cell therapy products, pluripotent stem cell therapy products, and some composite products with cells as the main biological effect.

.
At present, somatic cell therapy mainly includes: 1) In vivo infusion of human autologous or allogeneic immune cells, such as lymphokine-activated killer cells, in vivo and in vitro to activate and expand; 2) In vivo inoculation of tumor cells (tumor vaccine) treated in vitro ; 3) Microencapsulated autologous, allogeneic, heterogeneous cells, or cell lines that secrete one or more biologically active factors, such as cell lines that secrete insulin, growth factors, or nerve transfer factors; 4) In vivo implantation Autologous or allogeneic somatic cells genetically modified in vitro, such as hepatocytes, muscle cells, fibroblasts, lymphocytes, pancreatic islet cells, chondrocytes, etc.
; 5) In vivo transplantation of autologous or allogeneic cells expanded or activated in vitro Bone marrow cells
.
Stem cell engineering refers to the manipulation of stem cells in vitro, including in vitro proliferation, directed induction, horizontal differentiation, gene modification, and tissue shaping
.
Embryonic stem cells are derived from the vesicle stage before embryogenesis and can differentiate into various types of cells in the adult and fetal body.
They have been widely used in basic research and treatment of different diseases, such as Parkinson's disease, multiple sclerosis, and spinal cord injury.
, myocardial infarction and tumor stem cell transplantation therapy
.
Adult stem cells exist in almost all tissues of the human body
.
Adult stem cells have been differentiated to a considerable degree.
If they are not affected by external conditions, adult stem cells of a tissue tend to differentiate into various cells of the tissue.
For example, hematopoietic stem cells automatically differentiate into various blood cells in the body
.
The current clinical research on adult stem cells includes bone marrow primitive mesenchymal stem cells, bone marrow mesenchymal stem cells, cord blood megakaryocyte progenitor cells, cord blood erythroid progenitor cells and other products.
The main indications are hematological malignancies and aplastic anemia
.
Most tissue engineering products are derived from stem cells.
In addition to meeting the requirements of cell therapy and stem cell safety evaluation, quality control of the entire vegetation process must be carried out
.
Due to the characteristics of such products implanted in the body, the histocompatibility of long-term implantation should be studied to prevent microbial contamination and cell mutations
.
Examples of R&D/Market Situation
.
1) Stem cells, the domestic research on stem cells, and the introduction of product registration declarations are mainly human umbilical cord mesenchymal stem cell injections (Beijing Beilai Biological Branch, Platinum Life Excellence Biological Technology, Shanghai Aisar Biological Technology, Qingdao Aoke Biological, Shenzhen Beike Biotechnology, etc.
), the original bone marrow mesenchymal stem cells (Chinese Academy of Sciences, Institute of basic Medical Sciences), and so on
.
05 Genetically engineered vaccines Vaccines belong to preventive biological products, which refer to preparations containing antigens that can induce the human body to produce specific active immunity, which can protect the body from the source of infection and the damage of antigenic substances caused by the source of infection
.
In recent years, studies have found that vaccines may also be a powerful weapon for the treatment of malignant tumors, autoimmune diseases and other diseases
.
Genetic engineering vaccines include bacterial vaccines, viral vaccines and synthetic peptide vaccines
.
Examples of R&D/market conditions
.
Globally, the company that accounts for the largest sales in the vaccine field is Merck Pharmaceuticals.
Its varieties are mainly human papillomavirus vaccines (2018 sales of 3.
151 billion U.
S.
dollars) and rotavirus vaccines (2018 sales of 728 million U.
S.
dollars) , Herpes zoster virus (2018 sales of 217 million US dollars); and the domestic vaccine market accounted for a relatively high company Yunnan Watson Bio, its product 23-valent pneumococcal polysaccharide vaccine (2018 sales> 300 million RMB) , Haemophilus influenzae type b conjugate vaccine (including prefilled type) (2018 sales of nearly 280 million RMB)
.
Summary This article mainly introduces the five major types of biotechnology drugs commonly used in registration applications and their research and development market conditions
.
It is not difficult to find that the boundaries of these five categories of biotechnology drugs are not very clear, and there are certain intersections, but they are indeed our most common "biological drugs
.
" On the basis of summarizing the above content, the following will introduce the technical issues of biotechnology drugs (registration related), and I hope to learn and progress together with all my colleagues! Reference: 1.
"Introduction to New Drug Research and Evaluation" 2.
Annual reports of major pharmaceutical companies 3.
National CDE official website