Recently, FiercePharma released the 2019 global drug sales list Top 10. As can be seen from the chart below, Humira is followed by a series of super antineoplastic drugs, and six of the top 10 drugs are anti-cancer drugs:

As we can see from the picture above, the functions of these anticancer drugs seem to be different. For example, Merck & Co Inc's Keytruda prevents cancer cells from escaping the body's immunity, Roche's bevacizumab inhibits angiogenesis, and Johnson & Johnson's ibutini is a targeted drug, but their common characteristics are cancer drugs.

Why is that? This article will explain the growth of cancer cells and escape from human immune surveillance in an easy-to-understand way, and finally explore investment opportunities for cancer drugs.

The formation mechanism of cancer

Cancer is not a disease, but many diseases. We call it "cancer" because they all share a common feature-abnormal cell growth. Which key links went wrong that led to these cancers?

The first step: an error occurred during DNA replication

Any cell is born from DNA, and cancer cells are no exception.The primary reason for the birth of cancer cells is that the DNA of normal cells is wrong.In a study published in 2017 in the journal Science, they analyzed risk factors for genetic mutations in 32 common cancers.Surprisingly, the biggest risk factor for cancer gene mutation is not the environment or heredity, but random errors.

The main cause of cancer gene mutation is random errors in the process of chromosome replication, which accounts for 66%.On the other hand, environmental and genetic factors together account for only 34%. Such as bone cancer gene mutations: random errors accounted for 99.5%, heredity accounted for 0.5%; thyroid cancer, random errors accounted for 98%, heredity accounted for 1.5%.

The reason is simple: first, cell division requires replication of chromosomes, and then genetic information is evenly distributed between the two new cells. But the workload is so heavy that the human genome has 3.16 billion base pairs, and each split of these 3.16 billion base pairs has to be replicated. Too much work is bound to make mistakes, and as these mistakes accumulate, more and more mistakes will be made, and the more likely they will become oncogenes.

Although the epithelial cells of the middle-aged esophagus look exactly the same as normal cells under a microscope, genetic analysis has found that more than half of the cells have cancer-related genetic mutations, according to a study in the journal Science. Therefore, age is the biggest risk factor for cancer. As we can see from the picture below, the longer the average life expectancy, the higher the incidence of cancer."living long" is the single biggest risk of cancer.

The second link: tumor suppressor gene mutation

The human body produces a large number of unqualified cells every day, but these unqualified cells can not survive in the human body.It is mainly because the human body has a mechanism of apoptosis, which allows these unqualified cells to destroy themselves.The gene that directs cell apoptosis is called tumor suppressor gene, and the famous p53 is one of the tumor suppressor genes, which can direct unqualified cells to destroy themselves.

However, if the tumor suppressor gene is mutated, it will not be able to direct the unqualified cells to be destroyed automatically, then the cancer cells will be lucky to survive.

The third link: promoting angiogenesis and providing adequate nutrients

We all know that the survival of any cell is inseparable from the supply of nutrients (blood vessels), and cancer cells are no exception. But it is worth noting that cancer cells are characterized by rapid growth and infinite division, so it is doomed that cancer cells need more blood vessels to provide nutrients.

Cancer cells are particularly flexible and can promote more signals for angiogenesis, andReduceSignal that suppresses angiogenesisIn this way, nutrients can be supplied continuously to the tumor tissue.Therefore, clinically, most malignant tumors usually have abundant blood flow. Doctors even use this feature to distinguish between benign and malignant tumors.

When the cancer cell successfully escaped the first three links, but then faced with the following links.

The fourth link: escape from the monitoring of the human immune system

Under normal circumstances, the body's immune cells actively look for and attack cancer cells. But some cancer cells have also broken through. these cancer cells will forge a "fake ID card" to evade the monitoring of the human immune system and break through smoothly. This mechanism is called immune escape of cancer cells.

T cells, known as "human guardians", can recognize human tumor cells and carry out killing attacks. But the tumor cell is more cunning, it sees a protein on the T cell called PD-1, and then the tumor cell extends a PD-L1 protein (the ligand of PD-1). When the two small hands (PD-1 and PD-L1) combine, they provide inhibitory signals that induce T cell apoptosis and inhibit T cell activation and proliferation.

The fifth step: constantly replenish the telomere length

There is a limit to normal cell division in our body, and in 2009, the discovery of this mechanism won the Nobel Prize in medicine, that is, there are telomeres at the ends of chromosomes. Each time the cell divides, the telomere shortens in part. Normal cells divide about 50 times, and the telomeres run out. Without telomeres, cells can only die.

But cancer cells are different. there is an enzyme in the cells that can constantly replenish the length of telomeres, ensuring that the cancer cells can divide indefinitely.

(note: "telomerase" drugs based on the telomere effect are currently on the market to extend telomere longevity, but in some cases cancer is caused by taking drugs that enhance telomerase activity. )

The sixth link: cancer cell metastasis

Normal cells will follow the navigation, follow the rules, will not grow randomly, and the cells in the stomach will never grow to the nose. But cancer cells are different. they can move flexibly within and between tissues, which is why cancer is prone to invasion and metastasis. Cancer cells will grow crazily, and the end point is to die with the human body.

Investment opportunities for anticancer drugs

In the past, when the mechanism of cancer was not clear, the treatment was more surgical resection and chemotherapy. When the tumor is a benign tumor, the effect of surgery is very obvious. However, when the tumor is a malignant tumor, it shows that the cancer cell has metastasized, the doctor's surgical resection can not solve the problem, and then need chemotherapy, radiotherapy and so on.

Chemotherapy is a systemic treatment and one of the main means of tumor treatment.Chemical drugs usually work by blocking cell division and then inhibiting the growth of cancer cells. cancer cells proliferate faster than normal cells, so they not only kill tumor cells, but also kill both normal cells and immune (resistant) cells.(to put it simply, chemotherapy drugs kill a thousand enemies and self-destruct 800.)

With the human understanding of cancer cells, we have developed drugs for the relevant aspects of the cancer mechanism. As long as one of the links in the mechanism of cancer formation is destroyed, it will inhibit the survival of cancer cells in the human body, and these treatments are more effective and have less side effects than chemotherapy and radiotherapy.

Now our main programs for treating cancer are focused on the first, third and fourth links.

1) targeted drugs

Targeted drugs, also known as "biological missiles", aim at the treatment of cancer-causing sites that have been identified. When the drug enters the body, the tumor cells will die specifically without affecting the normal tissue cells around the tumor. Therefore, compared with chemical drugs, targeted drugs have more obvious effect and less side effects, but are easy to produce drug resistance. (targeted drugs produce drug resistance on the same principle as antibiotics.)

For example, about 30% of lung cancer patients in China carry EGFR mutations, and 22-290000 lung cancer patients with new EGFR mutations are added each year, which is a very large market. According to the figure below, there are first-to third-generation cancer drugs with EGFR mutations, mainly because patients develop drug resistance after using Iressa / Trocke / Comena for one year and may need to take the third generation of AstraZeneca PLC's oxetinib.

Focus on the target companies: AstraZeneca PLC, Novartis, Bristol-Myers Bristol-Myers Squibb Co, Merck & Co Inc, etc.

2) Vascular endothelial growth factor inhibitor

Vascular endothelial growth factor inhibitor is aimed at the characteristics of rich blood vessels in cancer tissue, inhibit the growth of blood vessels, and also inhibit the growth of tumor. From the global sales of Top10 drugs in 2019, we know that vascular endothelial growth factor inhibitors have Roche's bevacizumab, ranking sixth.

Roche's Avetine, approved by FDA in February 2004, is the first anti-tumor angiogenesis drug approved to be marketed in the United States. With the widespread use of "Avetine", it has become the basic drug for anti-tumor therapy in European and American markets, but the side effect is that it can cause serious complications in cancer patients, such as intestinal perforation in patients with colon cancer.

Domestic situation:Roche's original drug, Avetine, entered the Chinese market in 2010 and entered the national category B health insurance catalogue with a price drop of nearly 60% in 2017. Qilu Pharmaceutical "Ankeda", the first biological analogue of bevacizumab in China, was listed in China in December 2019 and included in the health insurance catalogue. INNOVENT BIO's Dayoutong ®is the second domestic bevacizumab bioanalogue approved. In addition, Hengrui Pharmaceutical, Shengdiya Biology, Green Leaf Pharmaceutical Co., Ltd., Beida Pharmaceutical Co., Ltd., and Baiotai have also submitted applications for the listing of new drugs this year.

Focus on the targets: Roche, INNOVENT BIO, Hengrui Pharmaceutical, Green Leaf Pharmaceutical, Beida Pharmaceutical, etc.

3) PD-1 inhibitor

PD-1 inhibitors belong to immunotherapy, which is very different from surgery, chemotherapy, radiotherapy, targeted drugs and vascular endothelial growth factor inhibitors. To put it simply, the former is essentially external intervention, with the help of foreign aid to help the human body kill the enemy.The latter's PD-1 immunotherapy is to stimulate the body's immune system to destroy cancer cells, immunotherapy is also known as the most promising cancer treatment of this era.

PD-1 inhibitors bind directly to human T cells, so cancer cells cannot bind to human T cells and activate the body's immune system to destroy cancer cells.Therefore, theoretically speaking, PD-1 inhibitors are suitable for many cancers, such as lung cancer, liver cancer, gastric cancer and so on.In addition, PD-1 inhibitors do not produce drug resistance and can be used for a long time.

According to the global Top10 global drug sales list, the performance of PD-1 antibody in 2019 is brilliant: Merck & Co Inc's Keytruda (K medicine) and BMS's Opdivo (O drug) ranked second and fifth with sales of US $11.13 billion and US $8.06 billion respectively. Merck & Co Inc's K medicine rose one place to the second place last year, an increase of 54%.It is expected to reach the top and become the "king of medicine" in 2022.

Domestic situation:According to relevant statistics, the sales of PD-1 drugs of Hengrui Pharmaceutical, INNOVENT BIO, BeiGene, Ltd. and Junshi Biology have exceeded 3.5 billion yuan in the first half of 2020.

Hengrui Pharmaceutical is the leader in the domestic pharmaceutical industry, with strong sales capacity such as pharmaceutical representatives, so 2020H1's sales of PD-1 inhibitors exceed 2 billion.

INNOVENT BIO's Dabeshu ®(Xindilizumab injection) is the only PD-1 inhibitor listed in the national health insurance drug catalogue. After entering the health insurance, the price of Dabeshu ®is more friendly to the people, with a drop of more than 60%, and there is more protection in the sales channels. At the same time, INNOVENT BIO and Eli Lilly and Co Pharmaceutical have expanded their cooperation, and Eli Lilly and Co will push Dabeshu ®to foreign markets.

BeiGene, Ltd. is most willing to "spend money" on R & D investment, but the loss is also the most serious. In the first half of 2020 alone, BeiGene, Ltd. invested 4.068 billion yuan in R & D, an increase of about 70 percent over the same period last year, far exceeding that of similar enterprises.

Overall, INNOVENT BIO has a slight advantage, the four pharmaceutical companies are basically at the same starting line, it is still difficult to win or lose.

Focus on targets: Merck & Co Inc, Bristol-Myers Bristol-Myers Squibb Co、 INNOVENT BIO, Hengrui Medicine、 BeiGene, Ltd.

Summary

From a scientific point of view, this paper simply analyzes several major links in the mechanism of cancer cell formation: errors in DNA replication, mutations in tumor suppressor genes, nutrients provided by dense blood vessels, escape from the human immune surveillance system, continuous replenishment of telomere length, and cancer cell metastasis.

With the human understanding of cancer, we have developed related anticancer drugs for the above links, such as targeted drugs, vascular endothelial growth factor inhibitors and PD-1 inhibitors. Different from surgery, chemotherapy, targeted drugs and other treatments in the past, PD-1 inhibitors belong to immunotherapy, which is also known as the most promising cancer treatment in this era.