Starting from the cost of 1.2 million anti-cancer drugs: can we use 200,000 CAR-T?

CAR-T cell immunotherapy is regarded as the most advanced therapy in the field of cancer treatment so far, and is known as the "last hope" for cancer patients with no cure.
Since its inception, it has been receiving wide attention
.

In China in September 2021, this concern reached its peak-one of the CAR-T introduced by Fosun Kate, which was approved in June, treated a patient with chronically cured lymphoma: cells were harvested at the end of June , After the CAR-T cells were prepared by reinfusion at the end of August, the cancer cells in the patient's body disappeared after examination at the end of August
.

However, what has become the focus of controversy this time is still the treatment price of CAR-T in China as high as 1.
2 million
.

"Millions of medicines have no social value in China!" An experienced hematologist said that in his experience, leukemia patients are mostly caused by harsh environments, and most of them are from poor families
.

"Millions of medicines have no social value in China!"

For most Chinese lymphoma patients, the price of 1.
2 million (payable) is clearly out of reach, but for companies, developing a drug that cannot be sold is certainly not the ultimate goal
.

In terms of improving the accessibility of CAR-T, patients and pharmaceutical companies have the same goals, but the high price of 1.
2 million has become a mountain that both pharmaceutical companies and patients need to climb.
It is unlikely that the national medical insurance will pay for 1.
2 million drugs.
Large, commercial insurance also has limited interest, and the payer may only be the patient
.

It is unlikely that the national medical insurance will pay for 1.
2 million medicines, and commercial insurance is also of limited interest, and the payer may only be patients
.

Today, when the CAR-T introduced by the two top domestic pharmaceutical companies, Fosun and WuXi, has been applied clinically, CAR-T was once considered to be a magic drug for a few people
.

However, a drug can only be used by most patients, and its ultimate mission can be completed.

On September 18, 2021, at the annual meeting of the Chinese Pharmaceutical Association , Chen Shifei
, deputy director of the State Food and Drug Administration, stated that “the current cost of CAR-T is too expensive to be used by patients, and the drug reform needs to be further deepened .

” Domestic CAR-T Companies are encouraged, and this is interpreted as an official attitude

Chen Shifei, deputy director of the State Food and Drug Administration, said, “At present, the cost of CAR-T is too expensive for patients to use, and the drug reform needs to be further deepened

Is this really the case?

- 01 - since the end of CAR-T cost: what you where?

- 01 - since the end of CAR-T cost: what you where?

For the reason for the high price of CAR-T, the current general explanation in the industry is due to the particularity of CAR-T itself: it is both a drug and a therapy, which runs counter to the logic of large-scale, batch-based, and standardized production of all drugs on the market.
, It has strong specificity, private order, thousands of people, thousands of medicines, and batch inspection.
The high cost comes from every link of its birth
.

Therefore, the price of CAR-T listed overseas is higher than RMB 2 million, which is more than half higher than the current domestic listed CAR-T
.

One of the two CAR-Ts currently on the market in China belongs to Fosun Kate and the other belongs to WuXi Giant Nuo.
Both of these two companies are joint ventures.
They are approved quickly through technology transfer from foreign companies and the import of raw and auxiliary materials.
Therefore, the industry It is also called "imported CAR-T".
The opposite concept is domestically-made CAR-T.
Domestically-made "CAR-T" refers to Chinese-funded companies, from research and development to production
.

Whether it is "imported CAR-T" or domestically produced CAR-T, the preparation procedures are very different from those of chemical drugs
.

In terms of preparation alone, the CAR-T preparation process is very complicated.
From single collection in the hospital to the final return, including the production of each batch, from the raw materials to the final product, a total of more than 600 steps are required.
More than 100 inspection procedures are required
.

In these preparation links, all key raw materials and auxiliary materials of CAR-T are imported from abroad at present and in the future, even for domestic CAR-T
.

There is a view in the industry that in the current R&D and preparation process, all key raw materials and auxiliary materials of CAR-T are imported from abroad at present and in the future, even if the domestic CAR-T is also the same
.

There is also another view that this is actually because the products of many domestic companies can fully meet the production needs of CAR-T, but in order to facilitate the passage of the CDE and speed up the approval of drugs, they will use the preparations that are already in use abroad instead of Willing to do certification work related to domestic preparations
.

In fact, this is because the products of many domestic companies can fully meet the production needs of CAR-T, but in order to facilitate the passage of CDE and speed up the approval of drugs, they will use preparations that are already in use abroad, and are unwilling to do domestic preparations.
Certification work
.

CAR-T preparation includes two parts: production and quality inspection.
Only after passing the quality inspection can it be released.
In the whole process of production and preparation, about 70%-80% must be imported
.

"The cell preparation system, all the medium added during the production process, as well as the final freezing solution, and even the bottles and cans of cell bags, basically rely on imports

A common sense is that in China, imported products are unlikely to be cheap
.

"Just a small single harvester (blood cell separator) costs 2 million or even tens of millions

"(CAR-T) is expensive because of the industrial technology," said Yu Xuejun, chairman of Huadao Biotech.
At present, GE and Meitianni systems are mostly used for cell preparation in the industry.
"Almost all of them are around 3 million.
" The cell culture cycle is 10 to 14 days, "it means that this set of equipment with a set of 3 million equipment can only be used for two patients a month
.

"

- 02 - If all the "domestic" and at what cost?

- 02 - If all the "domestic" and at what cost?

“Domestic and imported CAR-T are at the same starting line in terms of preparation costs.
Since both need to be imported, the cost of this piece is similar
.

” Song Zhenyuan (pseudonym), a senior practitioner, believes that the domestic CAR-T and imported CAR-T Putting it together, importing CAR-T is expensive in "patent fees", CMO fees, and virus raw material testing fees

And these three parts of the cost will become a short-term gap that domestic CAR-T can break through.
This is not a small gap.
According to the figure given by Song Zhenyuan, remove the technology transfer dividends paid for "imported CAR-T", foreign CMOs, and viruses.
The cost of raw material inspection, the cost of domestic CAR-T can be reduced to less than 300,000
.

Within 300,000
.

This number can be reduced.
Yu Xuejun, chairman of Huadao Biotech, believes that only from the perspective of production costs, the future production cost of CAR-T can be within the order of 100,000.
The current production cost of purely imported CAR-T is 300,000.
Yuan and above
.

The key here is the independent intellectual property rights of the cell preparation industry technology.
“We have our own production equipment, fully-automatic and fully enclosed cell production equipment, disposable consumables, key reagents and personalized cold chain equipment are developed by ourselves.
Research and development started in 2015.

"

Song Zhenyuan’s company did not carry out domestic substitution of the entire industry chain, but in some steps, there are also attempts to localize substitution.

"For every auxiliary material, we will do a comparative study of 5-10 kinds of localization," Song Zhenyuan said.
At present, domestic CAR-T companies are already exploring comparative studies on domestically-made substitutes for excipients
.

In contrast, companies that import CAR-T are subject to technology transfer clauses, and exploration in this area may come a little later
.

However, the cost of imported CAR-T is lower than that of domestic CAR-T, just in clinical trials
.
As it is a technology transfer, Fosun Kate only needs to do a bridging test of 24 cases.
If it is done from the beginning, the cost of a clinical case will be in the millions
.

Domestic CAR-T companies need to do Phase I and Phase II trials one by one.
“It is equivalent to the technology imported by others and knowing that it is salt.
Domestic production must start from scratch to verify that salt is sugar
.
” Song Zhenyuan said
.

- 03 - viral vectors and techniques, CAR-T localization stumbling block

- 03 - viral vectors and techniques, CAR-T localization stumbling block

No matter how low the cost of domestic companies can be, the most important thing is to get the approval to go public first
.
The relationship between approval for listing and cost control is just like the relationship between countless zeros and the first one- if the CDE and the China Procuratorate's regulatory barriers are not passed, all cost control methods are meaningless
.

If the CDE and the China Procuratorate's supervision mark cannot be passed, all the means to control costs will be meaningless
.

According to former Fosun Kate CEO Wang Liqun, domestically produced alternatives to other technologies are okay.
If it is not for the purpose of rushing to the market, the domestically produced preparation system can be slowly developed
.
But for the viral vector system and technology, it is difficult for domestic CAR-T to cross the past, and Song Zhenyuan also agrees with this
.

There is no standard process for the production process of autologous CAR-T.
However, according to the prospectus of CDMO and Metabiology for cell therapy, the production of CAR-T with viral vector as the genetic material delivery system should have three parts: plasmid process and virus process.
, Cell therapy process
.

Plasmid process, virus process, cell therapy process
.

In layman's terms, CAR-T technology uses leukocyte separation to collect patient’s T cells and then activate T cells in vitro; when it is found that the target of T cells attacking malignant tumor cells is not clear enough, a specific navigator targeted killing is added.
Like cruise missiles, T cells are equipped with eyes that can recognize cancer cells, and CAR genes are transferred into T cells to produce CAR-T cells.
CAR-T cells are amplified and purified and then returned to the patient for treatment
.

Viral vectors are the key link in the birth of CAR-T.
Therefore, regardless of whether they are imported CAR-T enterprise personnel or domestic CAR-T enterprise personnel, they believe that viral vectors are the most important part, and it is also the biggest gap between domestic and imported CAR-T technologies.
In part, "If the virus is a little bit worse, the clinical effect may still be a bit different from that of foreign countries
.
" A staff member of an importing CAR-T company said
.

"If the virus is a little worse, the clinical effect may still be a little different from that of foreign countries
.
"

The barrier is that domestic companies have never done a virus before, and the technology is immature
.

The viral vector manufacturing process is cumbersome and complex, and the cost is high.
Building a production line requires an investment of hundreds of millions.
Most start-ups cannot meet all the requirements of GMP in the early stages of clinical trials.
In product analysis, there is also a lack of standardized analysis methods for evaluating the effectiveness and safety of the vector.
, Viral vectors require cold chain logistics, which also increases the difficulty of research and development
.

The way that foreign countries can learn from is that start-ups focus their energy on scientific research and hand over the production of viral vectors to CMOs.
Fosun Kate and WuXi Giant Nuo all produce viral vectors from imported CMOs
.

"The U.
S.
industry chain is very mature and requires virus production CMOs to be quickly found, but domestic research is still underway .
" Song Zhenyuan said that the domestic virus industrialization has a long way to go.
If any CDMO company can produce drug-grade viruses If the carrier is approved by the State Food and Drug Administration, it can occupy the high ground of the industry
.

The domestic virus industrialization has a long way to go.
If any CDMO company can produce pharmaceutical-grade viral vectors and obtain approval from the State Food and Drug Administration, it will be able to occupy the high ground of the industry
.

As a marketed product, the viral vectors of Fosun Kate and WuXi Genuo have naturally passed the regulatory checkpoints of the National Food and Drug Administration and the China National Inspection and Quarantine Institute.
Fosun Kate uses retroviruses, while WuXi Genuo uses lentiviruses.
According to the Soochow Securities Research Report, in addition to Hengrun Dasheng, domestic CAR-T companies mostly use lentivirus
.

"Lentivirus technology is actually easy to master," Song Zhenyuan said.
Lentivirus is a product that can be standardized.
The production process is complex and technical requirements are high.
In the future, it can be mass-produced and the production cost is more controllable
.

In addition, the gap in technology will also make a difference in the efficacy of CAR-T
.

Wang Liqun explained to Shenlanguan that if there is no rigorous or stable process, it may lead to a high failure rate of the product, or the clinical data of the product cannot truly reflect the true level of the product in the test population
.

CAR-T products are "living medicines" with large differences in starting materials.
The production process must have the ability to control and reduce the batch-to-batch differences caused by the variability of starting materials, and use mature processes to produce CAR with a high qualification rate.
-T products
.
This is an important indicator of the maturity of the process.
The scale production process of individualized cell therapy in the pharmaceutical industry will not pass the NDA if the GMP standard for this scale production is not met
.

Industry insiders previously stated that Fosun Kate’s rapid approval was due to the “craftsmanship” leading the way.
Gilead Kate took another two years to complete the CAR-T technology after getting the CAR-T technology from the National Cancer Institute in 2012.
In contrast to Yescarta's preparation process, many domestic companies are stuck in clinical trials and marketing approval documents because the process control cannot pass the CDE barrier
.

- 04 - Limited Patient: commercial enterprise problems and the plight of payment

- 04 - Limited Patient: commercial enterprise problems and the plight of payment

The R&D of CAR-T companies has now entered a stage of fierce competition
.

At present, there are more than 30 domestic CAR-T pharmaceutical companies in the clinical stage, including Science and Technology Biology, Nanjing Legend, Reindeer Medical, and Heyuan Biology.
They basically focus on the research and development of CD19 and BCMA-related drugs, and clinical trials of most drugs are still in preliminary stages.
Phase I and I/II drugs account for the vast majority
.

Many entrants are facing a market that now seems difficult to grow bigger
.

"Pricing is a big issue, and the CAR-T market is difficult to expand
.
" Song Zhenyuan said that from the currently verified targets, CAR-T indications are concentrated in leukemia, lymphoma and multiple myeloma.
Kind of, "There is only a market of 11 billion a year.
If you really want to reach more than 50 billion, you have to expand to first-line and second-line treatment
.
"

"There is only a market of 11 billion a year.
If you really want to reach more than 50 billion, you have to expand to first-line and second-line treatment
.
"

This embarrassment can be seen from CAR-T's sales in overseas markets
.

Kymriah’s and Yescarta’s annual sales in 2020 are not much different, both are around US$400-400 million.
Kymriah’s growth rate is faster than Yescarta.
5%, a year-on-year increase of 14% in the first quarter of 2021, Kymriah's growth rate is faster than Yescarta, but whether it still maintains a growth rate of more than 50% after sales of 500 million yuan has yet to be verified
.

Soochow Securities finally concluded that it may be price factors that limit the heavy volume of these two products-even in the United States, the world's most developed country, not to mention China, which is more sensitive to CAR-T prices
.

CAR-T companies know this well, and they are also looking for solutions
.

Since the approval of CAR-T products for the market, Fosun Kate has actively promoted and included commercial insurance and urban customized insurance.
On July 31, 2021, the National Medical Insurance Administration’s official website released the "2021 National Medical Insurance Drug Catalogue Adjustments Passed the Preliminary Formal Review" In the List of Applied Drugs, 271 drugs have passed the preliminary review, of which Akirensai injection is on the list.
If the preliminary review is passed, CAR-T therapy can enter the follow-up link of the medical insurance negotiation in 2021, and the medical insurance negotiation will not be ruled out in the future.
Achieve price cuts
.

But in the eyes of another industry insider, Liu Hui (pseudonym), none of these can solve the problem of CAR-T accessibility
.

"In the short term, we will not consider entering into medical insurance.
Commercial insurance, welfare insurance, and innovative payment are all being done, but to put it bluntly, they are just a sales strategy.
" Liu Hui said that these attempts by pharmaceutical companies are in a transitional period.
The model is an intermediate stage of exploration.
"It can't actually solve your ability to pay.
It may be higher and higher in performance, in order to expand the scale of the market, but it will not last long
.
"

"It can't actually solve your ability to pay.
It may be higher and higher performance, in order to expand the scale of the market, but it will not last long
.
"

Wang Liqun and Liu Hui agreed that these attempts made by pharmaceutical companies are better than discounting drug prices and directly giving benefits to patients
.

.

The two CAR-T companies currently on the market, Fosun Kate and WuXi Juno, have established commercialization teams
.
Wang Liqun once advocated not setting up a sales team and relying on curative effects to impress doctors.
This idea was not realized in the end
.
At present, Fosun Kate and WuXi Junuo have also established a sales team of hundreds of people
.

In terms of access, judging from the current pharmaceutical companies' active connection with the top three hospitals, the weight of the influence of hospitals and doctors is still very high
.

Fosun Kate announced that it is currently selecting top three hospitals in various provinces and cities across the country to participate in the CAR-T treatment list.
Currently, 50 hospitals have been deployed, and it plans to expand to 70 by the end of this year
.

"But in fact, the most important thing is not how many hospitals to deploy, but to find the most influential hospitals and doctors," Song Zhenyuan said.
CAR-T is not covered by medical insurance.
At first, the main market is to rely on doctors' recommendation.
Importing CAR-T is the first The listing has won the time dividend, but in the later stage, CAR-T compares efficacy and price
.

CAR-T did not enter medical insurance.
At first, the main market was recommended by doctors.
Imported CAR-T was the first to go on the market and won the time dividend.
However, in the later stage, CAR-T compares efficacy and price
.

Regarding this, Liu Hui saw the same thing: “The window period for imported CAR-T is about one and a half to two years.
Once domestically produced CAR-T goes on the market, the pattern will be greatly changed
.
”

Domestic companies, facing a small market where they have lost their head start, can only compete for patients on the differentiation of indications
.

From the perspective of layout indications, domestic R&D values ​​the research of hematoma and solid tumors, but for the reference of foreign drugs and the research of new targets such as CLDN18.
2 and CLL1 to be explored, "Domestic companies have their own strategies.
For example, Hengrun Dasheng wants to do all in blood diseases, and Keji Biology is conquering solid tumors.
" Song Zhenyuan said that the domestic deployment in the solid tumor field is relatively slow, and the acceleration of the deployment of solid tumors is also a period of time for major pharmaceutical companies in the future.
Important strategy
.

Companies with adventurous spirits began to make a fuss about the indications
.

A CAR-T manufacturer whose product has not yet been approved has already built 6 industrial bases in Shaanxi, Chongqing, Changchun, Zhengzhou, Guangzhou, and Shanghai
.
This means that once approved, companies can immediately achieve heavy volume
.

The company gave another point of view: "Leukemia is a small disease, and there are not many patients in a year.
For us, at a price of 200,000, the number of patients that can be treated in one year is 100,000, which is 200.
Billion in the market a year
.
"

His focus is not only on blood diseases.
In his plan, CAR-T is mainly used to solve the problems of cancer patients after surgery and control the metastasis and recurrence of cancer cells.
"Cell medicine can control the metastasis and recurrence of solid tumors after surgery.
It is a market of 70 million people
.
" He hopes that CAR-T can enter the medical insurance system because of the expansion of the indication population in the future
.

Although some of the current production, preparation, and quality inspection technologies are still dependent on foreign countries, the good point is that a lot of funds are now poured into the CAR-T field.
If this therapy uses the virus vector and technology under the capital bubble The problem is solved, and the gap is also opened in other indications, then the entire track (short-term) will also usher in a market ceiling
.
Maybe at that time, we can really see CAR-T therapy with 200,000 times or even lower prices
.