At the end of February this year, the Sidakiola Ronsai independently developed by Chinese pharmaceutical company Legendary Bio (LEGN.NS) was approved for listing by the US FDA, which is the first Original Chinese CAR-T cell therapy drug to go abroad.
So far, a total of 7 CAR-T drugs have been approved for marketing worldwide. 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, giving patients with recurrent or refractory hematological tumors hope for long-term survival.
At present, the unavoidable problem is that because it is a personalized therapeutic drug, the price of each CAR-T is more than one million yuan. Some pharmaceutical companies will take general-purpose CAR-T products as the focus of future research and development direction, will this make the price go to civilian?
Domestic breakout
"Scientists use a genetic sequence that can bind to the tumor and release it into T cells through viral infection, making it a T cell that can kill the tumor." Xu Pengpeng, deputy chief physician of the Department of Hematology of Shanghai Ruijin Hospital, previously said when introducing CAR-T therapy to first finance and economics and other media: "After that, this modified T cell is further expanded in the laboratory, so that it reaches a certain number, and after in vitro expansion, it is reinfused back into the patient's body." ”
Conventional treatment of cancer includes chemotherapy and targeted therapy, the former of which has the same lethality for tumor cells and normal cells, which is prone to a variety of side effects, and the latter, which can accurately attack and kill cancer cells, but also inevitably has drug resistance.
T cells are the main force of anti-cancer in the body, and T cell therapy has always been considered one of the most promising directions for curing cancer. As a cell therapy technique, CAR-T works by genetically modifying T cells, equipped with chimeric antigen receptors (CARS), which allow T cells to recognize and destroy cells expressing the corresponding antigen.
From 2017 to the present, among the 7 CAR-T drugs currently approved around the world, the latest to be listed in the United States is Sidakiola Olansai, a legendary biological of Chinese pharmaceutical companies.
At the end of February this year, the legendary biological CAR-T drug Cidaki olonsay was officially approved for marketing in the United States, bringing hope to patients with relapsed and refractory multiple myeloma. Multiple myeloma is considered an incurable blood tumor and is a malignant disease caused by excessive proliferation of plasma cells in the bone marrow.
The American Cancer Society estimates that more than 34,000 people in the United States will be diagnosed with multiple myeloma in 2022, and more than 12,000 will die as a result. Patients who relapse after treatment with standard therapies, including protease inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies, face poor prognosis and limited treatment.
"For most patients with multiple myeloma, the treatment process is a cycle of constant remission and recurrence, with only a small number of patients achieving deep remission after end-of-line treatment." Dr. Sundar Jagannath, Professor of Hematology-Oncology at Mount Sinai Medical College and principal investigator of CARTITUTE-1, said that the CARTITUDE-1 study shows that Sidakiolasil provides deep and long-term no-treatment intervals in patients with multiple myeloma even after multiple lines of treatment.
This product has not been approved in China. At a recent media meeting, Huang Ying, CEO and chief financial officer of Legendary Bio, said that the company is actively communicating with the China Drug Review Center (CDE) to complete the enrollment and declaration.
The two CAR-Ts currently available in China are Ivy Kaida (Agironse Injection) from Fosun Kate and Benoda (Regquiola Injection) from WuXi Juno, both of which are used to treat relapsed or refractory large B-cell lymphoma in adult patients after second-line or above systemic treatment. Among them, Yikaida is a cell therapy drug that Fosun Kate introduced CAR-T cell therapy product Yescarta from Kite (a company of Gilead Sciences) in the United States for technology transfer and was authorized to be locally produced in China.
At present, fosun Kate and WuXi Juno's CAR-T research and development have once again ushered in new progress.
On February 27, WuXi Juno (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 the treatment of patients with relapsed or refractory follicular lymphoma.
At the same time, on March 2, Fosun Kate announced that the company's second CAR-T "FKC889" clinical trial application for relapsed or refractory bushel lymphoma after previous treatment of second-line and above has been approved by the China Food and Drug Administration. FKC889 is also a CAR-T product imported from Kite, industrialized and commercialized in China, and is the second CAR-T drug laid out by Fosun Kate.
What a sky-high price
CAR-T cell products are still high-priced drugs.
"Cidakiolensay is priced at $465,000 in the U.S., the pricing range for several CAR-T models already on the U.S. market is $400,000 to $470,000, and the first CAR-T product with the same target is priced at $419,500, and based on differences in clinical efficacy, the premium of about 11% we have formulated is reasonable." Huang Ying thinks.
The two CAR-T cell products currently listed in China, if converted into RMB, although the price is less than half of that of the United States, both are about 1.2 million yuan, but they are still not cheap.
Cell gene therapy is an individualized patient-centered treatment plan, and CAR-T is highly priced and highly personalized.
Huang Hai, CEO of Fosun Kate, said, "In our production process, a patient is a production line. In the factory, an average of 7 employees serve a patient during the preparation process, and the technical background requirements for production personnel, scientific researchers, including 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 10,000 square meters of factory building in Zhangjiang, and 2400 square meters are sterile, which is the production requirement of cell therapy. Huang Hai said.
According to a research report released by Industrial Securities, at present, the industry has still not developed a mature, fully acceptable CAR-T production process, many CAR-T products use manual operation, very time-consuming and labor-intensive, and difficult to expand, and the failure rate is very high. The entire CAR-T preparation process is very complex, and the optimization of the corresponding production process is relatively slow.
Industrial Securities said that at present, the preparation of a CART cell, the cost of about 200,000-500,000 yuan, in the entire production process of CAR-T, the most expensive is the culture medium, plasmid, ribozyme, virus vector and other consumables used in culture and transduction of CAR-T, occupying a total cost of about 49% to 51%.
The high price of CAR-T will affect the availability of drugs to a certain extent.
"After we obtain FDA approval, we may receive the vast majority of commercial insurance and government insurance payments in a short period of time, according to the common practice in the United States, once the product is approved for marketing, first of all, we can get government insurance coverage, and secondly, more than 90% of commercial insurance will also cover." Huang Ying said.
Fosun Pharma's 2021 annual report released on March 22 revealed the business expansion of its joint venture company Fosun Kate "Yi Kaida". According to reports, as of the end of February 2022, Yikaida has been included in the urban Huimin Insurance and more than 40 commercial insurance policies in 23 provinces and cities, and the number of treatment centers on the record has reached 75, and about 100 patients have entered the treatment process.
Wu Yifang, chairman and CEO of Fosun Pharma, told the first financial reporter that regarding the payment method of CAR-T therapy, Huimin Insurance is often a kind of insurance with illness, in fact, the proportion of reimbursement can be relatively low, although to a certain extent, it can help patients reduce financial pressure, but the overall support is still insufficient, in the long run, it is still hoped to be included in the scope of national medical insurance.
The next breakout direction
The world has been exploring CAR-T therapy for more than 30 years, and a key node that has triggered the enthusiasm for research and development in the industry is related to Emily, a 7-year-old leukemia girl. In 2012, Emily participated in a 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 range of CAR-T is still very limited, focusing on the treatment of hematological tumors and more on the end of the clinical line.
In general, the first-line drug is preferred for clinical treatment, and after the treatment effect is difficult to maintain or poor (there is disease progression), the second-line and third-line drugs are selected in turn to replace the treatment.
Judging from the application of China's first approved CAR-T cell therapy product for the treatment of relapsed refractory large B-cell lymphoma, Xu Pengpeng believes that for patients who have just discovered lymphoma, he does not recommend CAR-T treatment. He analyzed that in principle, 60 to 70% of patients can be cured by first-line therapy (chemotherapy or targeted therapy). At the same time, the vast majority of first-line treatments are already covered by Medicare.
"First of all, we will look at the patient's medical history, whether it is relapsed and refractory, and secondly, we will also judge whether the patient is suitable for treatment with the CAR-T regimen according to the patient's disease situation, including tests." Xu Pengpeng said that some patients' lumps are particularly large, may reach more than ten, twenty centimeters, in this (treatment) process, once the tumor dissolution, it is likely to cause complications such as kidney failure; some patients' tumors are grown on the intestines, inside the brain, the risk of using CAR-T treatment is relatively large, these are factors that need to be considered.
Xu Pengpeng said that some patients have achieved complete remission after CAR-T cell therapy, that is, they cannot see the lesion from imaging, and no lesion has been found, which is a medical "complete remission", but it is not equal to "cure", at least "complete remission" lasts for 5 years, and perhaps it can be said to be cured.
It is worth mentioning that most of the 7 CAR-T cell products approved worldwide can achieve a complete response 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 life, rather than a curative effect, but also to reduce costs, so that more people can use CAR-T.
Pharmaceutical companies are tackling the development of general-purpose products, and if this path is successful, it may be expected to significantly reduce drug costs.
Fan Xiaohu, chief scientific officer of legendary Biology, said that CAR-T drugs should consider the issue of patient accessibility, not only the cost and price of drugs. A large number of patients now progress very quickly in the terminal stage of cancer, and if the car-T drug production cycle is too long, many patients will not have the opportunity to use it.
It is crucial to develop general-purpose products, which can greatly improve the efficiency of product preparation. "The ability of a generic product to be distributed like a traditional drug, ready for use by patients when they need it, is the focus of our efforts, and the company now has at least three different general-purpose CAR-T platforms under development."
In addition, the treatment of solid tumors is also the direction that 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 the remission rate of more than 70% and more than 50% of the complete remission rate like blood tumors, but there are still many enterprises at home and abroad in exploration, and even a few have been able to achieve 50% disease control rate, which is not low in substance. Overall, in the field of solid tumors, CAR-T is beginning to emerge and making fairly good progress. Fan Xiaohu said.