Knowledge | The epoch-making cell therapy goes on the market, but also hides explosive industry opportunities

Knowledge | The epoch-making cell therapy goes on the market, but also hides explosive industry opportunities

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A few days ago, Fosun Kate’s Akirensai injection (ie anti-human CD19 CAR-T cell injection, trade name: Yikaida) was officially approved by the NMPA.Become the first CAR-T therapy to be marketed in China.

According to reports, this cell therapy product willFor the treatment of adult patients with relapsed or refractory large B-cell lymphoma after second-line or above systemic treatment, Including diffuse large B-cell lymphoma (DLBCL) unspecified type, primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma and diffuse large B-cell lymphoma transformed from follicular lymphoma.

The so-called second-line or above systemic treatment is a concept aimed at first-line treatment. The latter is effective at the beginning of the patient, but after a period of time, drug resistance is prone to lead to tumor recurrence and progression, so other chemotherapy will be considered Or targeted drugs for treatment, this treatment plan is called second-line treatment. By analogy, if second-line treatment fails, third-line treatment, fourth-line treatment, and so on will be considered.

Prior to this, five CAR-T products have been approved for the market worldwide, namely Kymriah of Novartis of Switzerland and Yescarta of Kate Pharmaceuticals of the United States approved in 2017, and Tecartus and Baidu of Kate Pharmaceuticals approved in 2020. The two CAR-Ts of Squibb in 2021: Breyanzi and Abecma.

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On the similar PD-1 monoclonal antibody track, it has now set off a wave of localization, opening up new imagination for tumor immunotherapy. Does similar success function reproduce in the CAR-T field?

The hidden worries behind the “epoch-making”

For the Chinese cell therapy industry, the launch of the first CAR-T therapy is undoubtedly a milestone.However, this does not mean that the domestic CAR-T has a bright commercialization prospect. At present, it is still full of hidden worries.The secondary market has already expressed its doubts.

The most intuitive manifestation recently is that Lyell, a world-renowned CAR-T manufacturer with a halo of Hillhouse Capital’s shareholding, and domestic solid tumor CAR-T manufacturer Keji Pharmaceuticals, have recently fallen below the issue price of their IPO on almost the same day.

The reason is that there are still many structural problems and contradictions in the CAR-T industry as a whole. It can be divided into two levels:

Target “getting together” and solid tumor “difficulty”

It is not difficult to see from the foregoing that Fosun Kate has no obvious differentiation advantage in indications. The core reason lies in the fact that the targets of the research and development direction “get together”.

Previously, among the five CAR-T therapies approved globally, except for the Abecma co-developed by BMS and Bluebird Bio, which targets BCMA, the remaining four are also targeted at CD19, and three of them all point to large B cells. Lymphoma is an indication.

Today, CD19 is still the “good heart” of many CAR-T therapy companies, and the phenomenon of getting together is serious.

New reports point out that the proportion of CAR-T clinics targeting CD19 has risen to 53% in the world; among the 357 CAR-T clinics in China, there are as many as 175 projects involving CD19 targets.

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It is noteworthy that,Research in the CAR-T field is still trapped in the problem that solid tumors have been unable to break through. A group of followers have chosen “Easy mode” hematomas..

The gap in the number of patients with solid tumors and hematomas is the difference. If only for hematomas, the market space for cell therapy is bound to be limited.

It is reported that hematological tumors (non-solid tumors) are only a small part of many cancers. The latest global cancer data point out:About 90% of cancer incidence is caused by solid tumors.However, there are few clinical trials of cell therapy for solid tumors-According to the data published in Nature Reviews Drug Discovery in 2019, only half of all cell therapy trials since 1993 have been for solid tumors (596 out of 1203).

In other words, the current major CAR-T pipeline is still spinning in less than 10% of the cancer market. In contrast, nearly ten years ago, various pharmaceutical companies have launched hundreds of clinical trials, differentiated competition, and expanded more markets for more than a dozen tumor types on PD-1.

The main reason is that there are many difficulties in the cell therapy of solid tumors, such as the heterogeneity of different types of solid tumors, the lack of unique tumor-associated antigens as CAR-T targets, the inability of T cells to effectively home to the tumor site, Insufficient CAR-T cell persistence and the complex microenvironment within the tumor have a suppressive effect on immunity.

cost!The inevitable problem

Judging from the five CAR-T products that have been approved for listing, the prices are all between one million, which is indeed a heavy burden for the vast majority of ordinary Chinese families.

The source pointed out that the price of Fosun Kate CAR-T products is about 1 million yuan, which is half of the US price.With such a high price, it is still unknown whether doctors in public hospitals tend to recommend this therapy to second-line and above patients. If the patient is not cured after taking the drug, it will also affect their own reputation.

In addition to the limited market space, CAR-T therapy is bound to have a high price due to high R&D and preparation costs, which is mainly due to its own limitations.

To put it simply, the current preparation process of CAR-T drugs includes: performing leukocyte apheresis from patients at the hospital-sending blood samples to GMP production bases to isolate mononuclear cells-using genetic engineering technology to introduce chimeric T cells into them The antigen receptor gene (which allows it to specifically recognize and kill cancer cells)-after in vitro amplification and culture-after qualified and released, sent back to the treatment center at low temperature-returned to the patient to complete the treatment.

CAR-T products that have been approved or are in late clinical stages mainly use patient autologous cells. The biological manufacturing process is the bottleneck of the industry. Because one production batch can only be used for the self-treatment of a single patient, and the process is long, complicated, and large. Dating takes 2-4 weeks (on average about 17 days for Yescarta and 22 days for Kymriah).

This also means thatCAR-T production is more like a laboratory rather than a traditional industrial assembly line production, Its GMP verification is very difficult, which makes the rigid cost of CAR-T production stubbornly high, of which production materials and QAQC costs account for a very high proportion.

In contrast, the production of PD-1 is a standardized process. In principle, as long as the output is larger, the scale effect is more obvious, and the production cost of PD-1 can theoretically be infinitely close to the cost of adding materials to a stainless steel reactor.

At the same time, because CAR-T research and development are too crowded, there will be too many drugs chasing too few patients in the future, making it difficult to produce a company with sufficient scale advantages to reduce costs.

However, there are already domestic CAR-T companies that are trying to reduce costs.

On March 4 this year, Dr. Jiang Xinpo, senior director of Nanjing Legend Biotech, mentioned that raw materials must be made domestically, and lentivirus and magnetic beads must be made domestically. “If the technology for producing lentivirus breaks through the use of suspended cells, the price will come down.” But for now, this idea has not yet landed.

Of course, the development of the industry is still in its early stages, and we must give some time and tolerance to any method that has a chance to cure cancer.

How to dig into the gold mine of industrial development?

The business world has always been cruel. Among the many CAR-T therapy miners, it is obvious that only a few have dig gold and become rich.

It is reported that after Fosun Kate, WuXi Junuo’s CAR-T products will also follow the qualification of “priority review + breakthrough therapy”, and will soon become the second marketed product. In addition, some experts predict that in order to prevent the formation of a “dominant” monopoly in China’s CAR-T market, the drug regulatory authority may cautiously admit two or three companies, no more than five to seven at most.

This means that many small and medium-sized companies that cannot get the “entry ticket” are facing elimination, or have to turn the bow: research and development of allogeneic cellsCAR-T, or point toSolid tumors, or cover more targets.

Allogeneic CAR-T Therapy

In order to get rid of dependence, allogeneic CAR-T has become the direction of the industry’s efforts, that is, universal CAR-T therapy.

The universal CAR-T therapy is also called “off-the-shelf”. It is the collection of T cells from healthy donors or T cells derived from iPSCs, which are engineered to express CAR to identify and Destroy cancer cells. The emergence of this technology makes the production cost of engineered T cells expected to be greatly reduced, which provides the possibility for the large-scale clinical application of CAR-T therapy. At the same time, the patient’s treatment process will be simpler, and the economic advantage will help improve the patient’s accessibility.

At present, the French company Cellectis is at the forefront of the development of general-purpose CAR-T. Two pediatric leukemia patients, aged 11 months and 16 months, had only mild rejection after receiving treatment, and the final sustained remission time reached 18 and 12 months, respectively. In March of this year, Cellectis’ universal CAR-T therapy UCART123 was approved by the US FDA to enter clinical trials, indicating the possibility of clinical application of allogeneic CAR-T technology.

There are also many cell therapy companies in the country that are deploying general-purpose CAR-T therapies, such as Genxi Biology, Bangyao Biology, Beiheng Biology, Longyao Biology, Cree Gene, Maoxing Biology, Senlang Biology, etc. In addition, it is worth mentioning that Dr. Wang Liqun, the founder of Fosun Kate and the former president of the company, left Fosun Kate in a low-key manner this year and established a new company “Xing Yiang” to deploy “off-the-shelf” CAR-NK cell therapy.

However, universal CAR-T cells are not perfect and defect-free, such as: 1) the safety of the donor’s occult infection; 2) the mechanism of GVHD or GVD is complicated, and knockout of one or two genes cannot completely eliminate this. Two-way rejection; 3) The number, resuscitation and generation of uCAR-T cell bank will have a certain impact on the clinical application and treatment effect. 4) A series of potential safety issues that may be caused by “off-target” effects during gene editing.These onesIt is still the current industry needs to solve.

Develop new targets or multiple targets

“(Cell therapy) It is difficult to achieve a good effect by relying on one target alone. People who do antibodies need to have double antibodies, third antibodies, and fourth antibodies. They also want to cover more targets.” Wang Liqun also wrote in the same comment before. Said in the relevant discussions of the organization.In layman’s terms, most of theCAR-T therapy is a target, just like using one hand to catch the ball, it is easy to get out of the hand, while the double target is equivalent to two hands to catch the ball, and the success rate is greatly increased.

Zhang Jishuai, the co-founder of Prikin, believes that “in addition to CD19 and BCMA, there are many alternative targets for immune cell drugs in hematological tumors”, such as PD22, CD5, CD7, and CD30. They can solve the problems in hematological tumors. Unmet clinical needs and other issues.

Up to now, there have been many actual cases in the industry for dual-target CAR-T products.

Recently, C-CAR039 (for the treatment of follicular lymphoma), a new CD19/CD20 dual-target CAR-T cell product developed by Sibman Biotechnology, has been granted orphan drug designation by the FDA.

On May 19, 2021, Reindeer Medical announced that its self-developed fully human anti-CD19-CD22 autologous T cell injection clinical trial application has been accepted by NMPA, and the indication is positive for relapsed/refractory acute B lymphocytic leukemia (B-ALL).

In October last year, the IND for the anti-human CD19-CD22 T cell injection of Hengrun Dasheng dual-target CAR-T cell candidate product was accepted, becoming the first domestic application to submit a dual-target CAR-T candidate drug. For the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia. 

In addition, domestic companies that have a presence in this field include Senlang Biology, Chongqing Precision Biology, Reindeer Medical, and Genxi Biology.

Point to solid tumor

As mentioned above, 90% of cancer patients in the world are solid tumors, which is not in the same order of magnitude as the hematoma market. According to Zhengxingu Capital’s analysis, this is the biggest market opportunity for CAR-T…Liver cancer, lung cancer, breast cancer, colorectal cancer, gastric cancer, and other large cancers have attracted countless trespassers.

Take, for example, a CAR-T product targeting CLDN 18.2 from Keji Pharmaceutical, which targets gastric cancer and pancreatic cancer. CLDN18.2 is a highly selective cell lineage marker, which is commonly expressed in cancer tissues of 70% to 80% of patients with gastric cancer and about 60% of patients with pancreatic cancer. In this field, Legendary Biology, Kaidi Biology, etc. also have products under development.

At present, Yongtai Biotechnology also focuses on the research and development of the treatment of solid tumors. Currently, it has deployed the expanded activated lymphocytes EAL® (non-gene modification technology route). The indications include liver cancer, gastric cancer, lung cancer, etc., among which, it is targeted at liver cancer. The research and development of (prevention of recurrence of liver cancer after surgery) is currently in phase II clinical trials.

Looking for opportunities in the upstream and downstream of the industry chain

Of course, no matter how “involved” the industry is and how difficult the new R&D direction is, the approval of domestic CAR-T therapy is a boon for companies and patients; at the same time, cell therapyThe advent of the commercialization era is also gestating corresponding explosive growth opportunities in the upstream and downstream of the industrial chain.After all, future product price cuts are certain, and so is outsourcing.

The cell therapy CDMO industry is typically favored.A core logic is,The complexity of the production process determines its technical barriers, and pharmaceutical companies have a strong willingness to outsource, so the market for cell therapy CDMO is expected to grow rapidly in the future.

According to Frost & Sullivan’s estimates, the global outsourcing market for gene cell therapy is expected to grow from 1.2 billion in 2017.The U.S. dollar will grow to 3.6 billion U.S. dollars in 2022, an average annual compound growth rate of 25%, which is much faster than the industry average growth rate.

At present, the core cost of CAR-T preparation mainly lies in the parts of materials & equipment and comprehensive operating costs, including the preparation and supply of scientific research reagents and equipment, consumables and viral vectors.

In terms of the special needs of CAR-T products, the process is relatively cumbersome and there are many quality control links.Including: apheresis of white blood cells and clear cells, enrichment and activation of T cells, gene delivery/transfection, cell culture, freezing and transportation, and finally infusion into the patient’s body.ThisNeed to use a variety of equipment, reagents and consumables such as blood cell separation and washing machine.

At present, most of these key equipment and reagent suppliers come from multinational companies, such as GE, Miltenyi, Thermo Fisher and so spite ofThere are also corresponding equipment and reagent manufacturers in China, whose prices are only 1/10 of the imported products. However, to ensure that the prepared CAR-T cells are safe and effective, most domestic R&D companies choose to purchase imported products, which constitutes CAR-T cells. A large part of the cost of the T cell production process.

In addition,The viral vector that delivers the gene is the key component of the final CAR-T product. The large-scale production of CAR-T can be said to be the large-scale production of the viral vector it uses.

In this regard, pharmaceutical companies have only two options, either build their own production system or outsource to CDMO. Obviously,Most companies will choose the latter. after all,CAR-TThe cell’s biological manufacturing process is the bottleneck of its industry, and automation and standardized processing will be the high-barrier technology for this process.

And the large-scale CDMO enterprises undoubtedly have more advantages, the core of which is to reduce costs through automated production, standardized production of lentivirus, plasmids, etc. At present, many companies have seen the opportunity, such as GenScript, Heyuan Biology, and Pizhen Biology.

Not long ago, Heyuan Biotech’s application for science and technology innovation board has also been accepted, and the biological cell therapy CDMO has also ushered in a new stage of development.

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In any case, it is different from traditional medicines that can be commercialized quickly once they are on the market.Cell therapy is too special,If pharmaceutical companies want to win, they must not only compete for the leading edge in drug research and development, but also try to solve the problems that they will face in each link of subsequent commercial production. This also brings explosive growth opportunities to the CDMO track.


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