Original title: Internet celebrity anti-cancer drug CAR-T is destined to be sky-high?
| Great power creation
At the end of February this year, the Chinese pharmaceutical company Legend Bio (LEGN.NS) independently developed Sidaji Orenza, which was approved by the U.S. FDA for marketing. This is the first Chinese original CAR-T cell therapy drug to go abroad.
So far, a total of 7 CAR-T drugs have been approved for marketing in the world.
As an emerging tumor treatment method, the emergence of CAR-T is regarded as one of the major breakthroughs in the field of cancer treatment, bringing hope for long-term survival to patients with relapsed or refractory hematological tumors.
The problem that cannot be avoided at present is that because it is a personalized treatment drug, the price of each CAR-T is more than one million yuan.
Some pharmaceutical companies take general-purpose CAR-T products as the key research and development direction in the future. Will this make the price more popular?
Domestic break
"Scientists use a gene sequence that can be combined with tumors and release it into T cells through viral infection, making it a T cell that can kill tumors." Xu Pengpeng, deputy chief physician of the Department of Hematology of Shanghai Ruijin Hospital, told Yicai and others before. When the media introduced CAR-T therapy, it said: "The modified T cells are further expanded in the laboratory to make it reach a certain number, and after the in vitro expansion is completed, it is returned to the patient's body."
Conventional cancer treatment includes chemotherapy and targeted therapy. The former has the same lethality to tumor cells and normal cells and is prone to cause a variety of side effects; the latter can precisely attack and kill cancer cells, but it also inevitably has drug resistance.
T cells are the main force against cancer in the body, and T cell therapy has always been regarded as one of the most promising directions for curing cancer.
As a cell therapy technology, CAR-T works by genetically modifying T cells, equipped with chimeric antigen receptors (CARs), which allow T cells to recognize and destroy cells that express the corresponding antigen.
From 2017 to the present, among the 7 CAR-T drugs approved worldwide, the latest one to be launched in the United States is the Chinese pharmaceutical company Legend Bio's Sidaki Orenza.
At the end of February this year, the legendary biological CAR-T drug Sidaki Orenza was officially approved for marketing in the United States, bringing hope to patients with relapsed and refractory multiple myeloma.
Multiple myeloma, considered an incurable blood tumor, is a malignant disease caused by excessive proliferation of plasma cells in the bone marrow.
According to the American Cancer Society, more than 34,000 people in the United States will be diagnosed with multiple myeloma in 2022, and more than 12,000 people will die from it.
Patients who relapse after treatment with standard therapies, including protease inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies, face poor prognosis and limited treatment options.
"For most patients with multiple myeloma, the course of treatment is a cycle of remission and relapse, with fewer patients achieving deep remission after end-line therapy." CARTITUTE-CARTITUTE-M. 1 Principal investigator Sundar Jagannath, MD, said the CARTITUDE-1 study demonstrated that Cidakiolense provides deep and durable responses and long-term treatment-free intervals in a population of patients with multiple myeloma, even after multiple lines of therapy.
This product has not yet been approved in China.
At the recent media meeting, Huang Ying, CEO and Chief Financial Officer of Legend Bio, said that the company is actively communicating with the China Center for Drug Evaluation (CDE) to complete the enrollment and application.
The two CAR-Ts that have been launched in China are Yikaida (Aquilance Injection) from Fosun Kite and Benoda (Ruiji Aurexa Injection) from WuXi Junuo. For the treatment of adult patients with relapsed or refractory large B-cell lymphoma after second-line or more systemic therapy.
Among them, Yikaida is a cell therapy drug that Fosun Kite introduced from Kite (a subsidiary of Gilead Sciences) in the United States, the CAR-T cell therapy product Yescarta, for technology transfer, and was authorized to produce locally in China.
At present, the CAR-T research and development of Fosun Kite and WuXi Junuo has once again ushered in new progress.
On February 27, WuXi Junuo (02126.HK) announced that the China Food and Drug Administration has accepted the marketing application for the second indication of its CAR-T product "Benoda" for relapsed or refractory follicular lymphoma treatment of cancer patients.
At the same time, on March 2, Fosun Kite announced that the clinical trial application of the company's second CAR-T "FKC889" for relapsed or refractory mantle cell lymphoma after receiving second-line or above treatment has been approved by Chinese Medicines Supervision approved.
FKC889 is also a CAR-T product introduced from Kite, industrialized and commercialized in China. It is the second CAR-T drug deployed by Fosun Kite.
Why the sky-high price
CAR-T cell products are still sky-high drugs.
"The price of Cidaki Orenza in the United States is US$465,000, and the price range of several CAR-T products already listed in the US market is US$400,000 to US$470,000, the first CAR-T product with the same target as ours. The price is US$419,500, and based on the difference in clinical efficacy, the premium of about 11% we have formulated is reasonable." Huang Ying believes.
The two CAR-T cell products currently listed in China, if converted into RMB, although the price is less than half of the United States, both are around 1.2 million yuan, but they are still not cheap.
Cell gene therapy is a patient-centered individualized treatment plan. CAR-T is expensive and is also related to a high degree of customization.
Huang Hai, CEO of Fosun Kite, said, "In our production process, a patient is a production line. In the factory, an average of 7 employees serve a patient during the production process. The technical background requirements of business personnel are very high.”
"Every patient is different, and his condition is different, so the difficulty of preparation requires companies to use the highest standards. At present, we have a 10,000-square-meter factory in Zhangjiang, and 2,400 square meters are sterile. This is cell therapy. production requirements." Huang Hai said.
According to a research report released by Industrial Securities, at present, the industry has not developed a mature and fully acceptable CAR-T production process. Many CAR-T products use manual operations, which are very time-consuming and labor-intensive. Difficult to scale up and have a high failure rate.
The entire CAR-T preparation process is very complicated, and the optimization of the corresponding production process is relatively slow.
Industrial Securities said that the current cost of preparing a CAR-T cell is about 200,000-500,000 yuan. In the entire production process of CAR-T, the most expensive is the culture medium, plasmid, and nucleus used for culturing and transducing CAR-T. Consumables such as enzymes and viral vectors account for about 49% to 51% of the total cost.
The high price of CAR-T will affect the accessibility of the drug to a certain extent.
"After we obtain FDA approval, we may receive payment from most commercial insurance and government insurance within a very short period of time. According to common practice in the United States, once the product is approved for marketing, firstly, we can obtain government insurance coverage, and secondly, 90 More than % of commercial insurance will also cover." Huang Ying said.
Fosun Pharma's 2021 annual report released on March 22 disclosed the business expansion of its joint venture, Fosun Kite "Yikaida".
According to reports, as of the end of February 2022, Yikaida has been included in urban Huimin Insurance and more than 40 commercial insurances in 23 provinces and cities. There are 75 registered treatment centers, and about 100 patients have entered the treatment process.
Wu Yifang, Chairman and CEO of Fosun Pharma, told Yicai.com that, regarding the payment method of CAR-T therapy, Huimin Insurance is often a kind of insurance for sick people, and the proportion that can be reimbursed is relatively low. Although it can help patients reduce financial pressure to a certain extent, the overall support is still insufficient. In the long run, we still hope to be included in the national medical insurance.
next breakout direction
The world has been exploring CAR-T therapy for more than 30 years, and a key node that triggered the enthusiasm for R&D in the industry is related to Emily, a 7-year-old girl with leukemia.
In 2012, Emily participated in the Phase I clinical trial as the first minor in the world to use CAR-T therapy.
Eventually, she recovered and was discharged from the hospital in June 2012.
As of 2021, there is still no cancer recurrence in her body, which has become a classic treatment case in cancer medicine.
However, the therapeutic scope of CAR-T is still very limited, all of which focus on the treatment of hematological tumors, and more on the last-line clinical treatment.
Generally speaking, the first-line drug is the first choice for clinical treatment. After the treatment effect is difficult to maintain or is not good (with disease progression), the second-line and third-line drug replacement therapy is selected in turn.
Judging from the application of China's first CAR-T cell therapy product approved for the treatment of relapsed and refractory large B-cell lymphoma, Xu Pengpeng believes that he does not recommend CAR-T therapy for patients who have just discovered lymphoma .
He analyzed that, in principle, 60 to 70 percent of patients can be cured by first-line treatment (chemotherapy or targeted therapy).
At the same time, the vast majority of drugs for first-line treatment are already covered by Medicare.
"First of all, we will look at the patient's medical history to see if it is relapsed and refractory, and secondly, we will also judge whether the patient is suitable for treatment with the CAR-T regimen based on the patient's disease conditions, including laboratory tests." Xu Pengpeng said that some patients The tumor is particularly large, which may reach ten or twenty centimeters. During this (treatment) process, once the tumor dissolves, it is likely to cause complications such as renal failure; some patients have tumors that grow on the intestines and brains. Inside, the risk of using CAR-T therapy is relatively high, and these are all factors that need to be considered.
Xu Pengpeng said that some patients achieved complete remission after CAR-T cell therapy, that is, no lesions were seen on imaging, and no lesions were found. This is a medical "complete remission", but it does not mean "cure". A "complete remission" must last at least 5 years before it may be considered a cure.
It is worth mentioning that most of the seven CAR-T cell products approved globally can achieve a complete remission rate of more than 50%.
Wu Yifang said that the cost of CAR-T is always a problem. If you want to extend a certain lifespan, rather than a curative effect, it is necessary to reduce the cost, so that more people can use CAR-T.
Pharmaceutical companies are trying to develop generic products, and if this path is successful, it is expected to significantly reduce the cost of drugs.
Fan Xiaohu, the chief scientific officer of Legend Bio, said that CAR-T drugs need to consider the issue of patient accessibility, not only costs and drug prices.
Now a large number of patients are progressing very rapidly in the terminal stage of cancer. If the production cycle of CAR-T drugs is too long, many patients will not have the opportunity to use them.
It is crucial to develop general-purpose products, which can greatly improve the efficiency of product preparation.
"Generic products can be distributed like traditional drugs, and patients can use them whenever they need it. This is the focus of our efforts. The company now has at least three different generic CAR-T platforms under development."
In addition, the treatment of solid tumors is also the direction that various CAR-T companies are trying to break through.
"One of the main directions the company is focusing on is the treatment of solid tumors, and this direction is promising. At present, the industry is very active in the development of CAR-T for the treatment of solid tumors, although the efficacy has not reached more than 70% like hematological tumors. However, many companies at home and abroad are still exploring, and even some individuals have been able to achieve a 50% disease control rate, which is not low. Overall, in the field of solid tumors , CAR-T has begun to emerge and has made quite good progress." Fan Xiaohu said.