"Cancer Savior" PD-1 Portrait: The "Pearl" in the center of the stage with a bunch of followers

Per reporter: Liu Chenguang Per editor: Xu Fei

The "all-out war" between humans and cancer has already begun, and an immune drug called pd-(l)1 monoclonal antibody has brought a glimmer of victory. It is understood that pd-(l)1 includes pd-1 and pd-l1, looking at the domestic market, pd-1 monoclonal antibody is as bright as a pearl, and the four products that have been listed have "raced" with the first-mover advantage.

On the afternoon of May 5, a message spread hotly among the anti-cancer community: Hengrui Pharmaceutical (600276, sh) PD-1 monoclonal antibody may have been approved. Wan Jing, who is suffering from breast cancer, also learned of this news at the first time, although it has not been officially confirmed, but this does not affect her and her patients to "spread flowers and celebrate".

Does pd-1 monoclonal antibody really have such a miraculous effect? A number of industry experts told the "Daily Economic News" reporter that in fact, the overall efficiency of pd-1 monoclonal antibody is about 20% on average, but the key is that once the immune drug has a therapeutic effect on the patient, this effect is persistent, and the patient can get a longer survival time.

The reporter's research found that compared with three years ago, the enthusiasm of capital for PD-1 monoclonal antibody has cooled down, and the progress of some research and development projects is lower than expected. But even so, there are still dozens of domestic pharmaceutical companies researching PD-1, a large number of duplicate projects on the horse plus blind capital investment, how should latecomers "survive"?

●Rekindling the hope of treatment

As the biggest hotspot of tumor immunotherapy in recent years, pd-1 and pd-L1 antibodies are both immune checkpoint blocking drugs. Different from traditional chemotherapy and targeted therapy, this type of drug mainly kills tumors by overcoming immunosuppression in the patient's body and reactivating the patient's own immune cells, which is a new tumor treatment concept.

Chen Li, who has been fighting cancer for many years, pays special attention to PD-1 monoclonal antibody. She was diagnosed with melanoma nine years ago, and the treatment process did not go well, after three surgeries before and after, but this year she relapsed again. The attending physician recommended Chen Li to apply for the assistance program of merck PD-1 monoclonal antibody drug Pabli zhu (commonly known as K drug), and now she has received her first injection. Although there is no obvious effect, Chen Li feels that she has found hope for treatment.

In the interview of the "Daily Economic News" reporter for several days, many patients are open to pd-1 monoclonal antibody, and some patients have benefited from the use of pd-1 monoclonal antibody.

Wang Zhong's father, 82, was diagnosed with melanoma last year, with tumors mostly growing in his nostrils. "Saying that the eyeball is to be removed, the wound is too large, and the operation is abandoned." Later, a third-class hospital in Beijing gave me a chemotherapy program, and my father did not want to suffer the crime, so he returned to his hometown. Wang Zhong recalled.

But Wang Zhong did not give up, he found the information of immunotherapy through the Internet. Since K medicine was not yet listed in the mainland at that time, Wang Zhong bought three drugs in Hong Kong. It was these three pills that gave his father hope for life.

"The first stitch felt effective, just not obvious. The third needle can be seen that the tumor that was supposed to grow in the nostrils begins to retract significantly. Later, K medicine was listed in the mainland, and Wang Zhong also insisted on giving his father medicine, and now he has received 12 injections, "(father's) eye swelling gradually disappeared, and there is no bleopia."

"Lucky ones" like Wang Zhong's father are only a minority of the group of PD-1 monotherapy (only through PD-1 monoclonal antibody treatment). Wu Yilong, lifelong director of Guangdong Provincial People's Hospital and honorary director of Guangdong Lung Cancer Research Institute, told reporters that PD-1 monoclonal antibody has a broad spectrum, and theoretically no matter what kind of cancer can play a certain effect, it is less toxic and less toxic than chemotherapy. In patients with advanced cancer, pd-1 monoclonal antibody can prolong the survival time of a small number of people for more than five years, which means that some patients may be cured.

The relevant data show that the average effective response rate of PD-1 monotherapy has been hovering at 20%.

Wu Yilong further explained that there is a basic condition for the production of pd-1 monoclonal antibodies, that is, it must rely on the body's strong immunity, and it can only play a role when immune cells are full of activity. "If a patient has entered the end of life, the body is already very poor, his immune system has basically lost function or is extremely low, and immunotherapy has no way to work."

Deeply cultivated melanoma clinical treatment for decades, Zhang Xiaoshi, chief expert of melanoma in the Affiliated Cancer Hospital of Sun Yat-sen University, believes that the treatment of melanoma is mainly a comprehensive treatment based on surgery. "If you can operate as much as possible, as long as you can cut the tumor clean, you must fight for surgery, and then talk about drug treatment."

In Zhang Xiaoshi's view, the use of pd-1 monoclonal antibody generally includes two situations: one is that a distant metastases have occurred, that is, patients who cannot be treated surgically can only be treated by drugs; the other is that surgery has been performed, but the risk of recurrence after surgical treatment is high, and adjuvant therapy is required with drugs, which is commonly referred to as consolidation therapy.

Any drug can have certain side effects, and immunotherapy is equally inevitable. Bi Cheng, a senior industry researcher at the Investment Research Department of Gao Tejia Investment Group, emphasized the "risk-return ratio" to reporters. "Although immunotherapy has side effects, if you add the efficacy itself, that is, balance between the comprehensive benefit and the risk of treatment, the survival return of the patient is relatively high." Bi Cheng thinks.

In fact, in addition to monotherapy, the combination of PD-1 monoclonal antibody with other drugs is an important breakthrough direction in medicine at present, and has almost become the main way of first-line clinical treatment, especially the combination therapy of PD-1 monoclonal antibody and chemotherapy.

In this regard, Wu Yilong believes that which treatment method to choose depends on how much the patient can pay, "in the current situation, this combination therapy does improve the efficiency, but also pays a large price, is an imperfect combination method." But Wu Yilong also admitted that at this stage, this combination therapy is feasible. He believes that further research should be done on how to combine pd-1 monoclonal antibody with some less toxic drugs under the premise of achieving a certain effect.

In Zhang Xiaoshi's view, combination therapy can not only improve the efficiency of cancer treatment, but also do not need markers, do not need to fear super-progression, "what needs to be paid attention to is how to grasp the toxicity of drugs used in combination, how to grasp the dosage of different drugs, and it is necessary to analyze specific problems according to the actual situation."

● The high-priced "baggage" of new drugs

After the drug is on the market, the patient is faced with a more realistic problem: whether there is enough economic ability to bear the expensive drug costs.

"The price of pd-1 monoclonal antibody is too expensive for ordinary people to bear." More than one patient or family member interviewed lamented to the "Daily Economic News" reporter.

Yang Weishan has been in a very depressed mood recently, all because his nearly old mother was diagnosed with "low-differentiation non-small cell lung adenocarcinoma advanced." But his mother was not suitable for surgery, nor could she find a suitable targeted drug, so she could only undergo chemotherapy with obvious side effects.

In fact, Yang Weishan also considered immunotherapy, "more than 100,000 yuan of wage earners can not stand, in fact, it is already very difficult, continue to treat can only sell real estate." On the one hand, the disease that his mother urgently needed to treat, and on the other hand, the expensive treatment cost, Yang Weishan was caught in a dilemma.

"Daily Economic News" reporter noted that among the four pd-1 monoclonal antibodies that have been listed in China, the mainland price of pembolizumab injection is 17918 yuan (100mg/4ml specification); the suggested retail price of Navuliyuzumab injection (commonly known as o drug) in the mainland is 9260 yuan (100mg/10ml specification) and 4591 yuan (40mg/4ml specification); the final price of Xindili monoclonal antibody injection is 7838 yuan / 100mg (stick) Triprdomab injection is 7200 yuan / 240mg (stick).

In addition, according to current medical evidence, genetic testing and immunohistochemical testing are generally required before the decision to use immunotherapy. Bai Yuezong, strategic marketing director of the domestic tumor diagnosis and treatment integration platform company, believes that genetic testing is currently mainly to detect tmb (tumor mutational burden), immunohistochemistry is mainly to detect the expression of pdl1, of which the former uses second-generation gene sequencing to detect hundreds of genes at about 15,000 to 20,000 yuan.

If combined medication is performed, the price is also expensive. A number of patients or family members told reporters that due to the use of pd-1 monoclonal antibodies on the basis of chemical drugs, targeted drugs, etc., the monthly expenditure of combination therapy is 20,000 to 50,000 yuan.

However, the four PD-1 monoclonal antibodies that have been listed have relevant assistance programs, which can alleviate the economic pressure of some patients to a certain extent. According to the information provided to reporters by a public welfare commissioner of Key of Life, the melanoma assistance program of K-drug has two ways to apply for low insurance and low income: the so-called low income, that is, the proportion of a family's medical expenditure in the family's affordable capacity is equal to or more than 40%; the minimum guarantee refers to the low guarantee that has been approved and issued by the local civil affairs department, and the low guarantee has been received for 12 consecutive months before the project application.

For patients with advanced melanoma, the currently listed pd-1 monoclonal antibodies that cover this indication include perbolizumab injection and treprilizumab injection (trade name: Tuoyi). Zhang Xiaoshi believes that since both drugs have evidence-based medical evidence, in the end, patients must decide which drug to use according to their actual situation.

Zhang Xiaoshi introduced that according to the original price of K drug, patients with high weight need to spend about 600,000 yuan a year; if they meet the conditions for drug donation to buy three courses of treatment and send three courses of treatment, patients with high weight will cost about 300,000 yuan a year, and patients with 50 kg and below need about 150,000 yuan a year. If you meet the conditions for Tuoyi to donate drugs, you will use the plan of buying four courses of treatment and giving four courses of treatment, which will cost about 100,000 yuan a year.

The relevant persons in charge of Cinda Biology and Junshi Biology also made it clear at the performance briefing that medical insurance negotiations are underway and hope that PD-1 monoclonal antibody will enter medical insurance as soon as possible. In Zhang Xiaoshi's view, because PD-1 monoclonal antibody is a long-term drug and has a wide range of indications, how to enter medical insurance is a common problem faced by various countries, "in the future, PD-1 inhibitors will enter medical insurance, but it also depends on which way to use."

● Pharmaceutical companies are competing in groups

Cancer has become the "number one killer" that threatens human health, and the pd-(l)1 drug that shoulders the heavy responsibility of fighting cancer is promising.

The well-known foreign biotechnology website gen released a list of the top 15 global drug sales in 2018, two pd-1 monoclonal antibodies that are hot in the global market - Bristol Squibb's o drug and Merck's K drug jointly "killed" into the top five, with annual sales of more than 7 billion US dollars.

The Chinese market is also not to be underestimated. Junshi Bio achieved revenue of 79.0754 million yuan in the first quarter of this year, an increase of 5299.27% year-on-year, mainly due to the contribution of tripleliumab injection. According to Frost & Sullivan's estimates, the size of China's PD-(l)1 drug market can reach $13.1 billion by 2030.

In addition to the 4 pd-1 monoclonal antibodies that have been listed, there are dozens of pharmaceutical companies in this field. CICC expects that Hengrui Pharmaceutical and BeiGene PD-1 monoclonal antibody are expected to be listed this year, and the indication is Hodgkin lymphoma, which will compete directly with Xinda Biologics.

Recently, some media reported that Hengrui Pharmaceutical's pd-1 monoclonal antibody drug Carelli beads (trade name is Arito) has been approved for listing, but the news has not been officially confirmed. Hengrui Pharmaceutical related people told reporters: "At present, there is no way to confirm the approval, if you get the approval, it will be announced immediately." ”

According to the research report of Everbright Securities, as of February this year, nearly 20 domestic pharmaceutical companies are carrying out clinical trials of PD-(l)1 drugs phase i to III.

Bi Cheng told the "Daily Economic News" reporter that the company is not necessarily for its own PD-1 monoclonal antibody future listing, it is likely to be used with other products in its own pipeline. He also stressed that it is not excluded that some companies have attracted investors to follow up through the research and development of PD-1 monoclonal antibody.

After the reporter's research, it is very difficult for domestic companies to really innovate on the target, many drug research and development are piled up on the same hot target, and the disclosure progress of some companies has been much slower than expected. The person in charge of a domestic innovative drug research and development enterprise told reporters that the pharmaceutical industry "does not open for ten years, opens for ten years", and the probability of the original research drug from the first phase of the clinic to the final success is only 11.5%. The current situation of domestic research and development is that some targets have gathered 10 or even 20 companies, but there are some forms of antibodies with pd-1 and pd-(l)1, and there is a waste of resources.

A pharmaceutical industry insider with decades of experience gave an example to reporters, there is a chemotherapy drug called "pemetrexed", its toxicity is relatively low, the tolerability is relatively good, around 2000 in the domestic market. At that time, there were dozens of domestic pharmaceutical companies investing in research and development, but today, most of the market share is divided by less than five pharmaceutical companies.

In Bi Cheng's view, in the future, pd-(l)1 drugs may have 3 to 5 major varieties occupying more than 80% of the market, and the remaining varieties digest the remaining market, and the polarization is serious, "On the whole, the market performance of listed drugs depends on the difference in efficacy, price, listing order, promotion efforts and academic basis."

Wu Yilong also pointed out that the first 5 pd-(l)1 drugs basically belong to the first echelon, and the 10th can also get some markets, but the opportunities for latecomers will be less and less.

From the current PD-1 monoclonal antibody domestic approved indications, there have been different pharmaceutical companies in the same indication of the head-on "confrontation". Many industry insiders have expressed the same view to reporters: each drug is a new drug, because there is no "head-to-head" comparison in medicine, so it is impossible to judge which drug will have better efficacy.

Pharmaceutical companies are so keen on PD-1 monoclonal antibody, how is venture capital considered? A person who has been engaged in venture capital in the pharmaceutical industry for many years told reporters that today," "the company has stopped investing in PD-1 inhibitors" and mainly focuses on first-in-class drugs.

"Daily Economic News" reporter noted that although pd-(l)1 monoclonal antibody is gradually not favored by venture capital, but pd-(l)1 bispecific antibody is still a very cutting-edge research field, many pharmaceutical companies at home and abroad have devoted themselves to the track, but so far there has been no drug.

(Wan Jing, Yang Weishan, Wang Zhong, Chen Li are pseudonyms)

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