The Road Of Car-T Industrialization: China Faces The Same Dilemma As The United States

The third car cell therapy was launched on July 24. The U.S. Food and Drug Administration (FDA) has approved the launch of Gilead's kit Pharma cell therapy tecartus for adult patients with relapsed / refractory mantle cell lymphoma (MCL). This is the first car-t therapy approved by FDA for the treatment of such patients, which is another breakthrough after the approval of Novartis and kit car-t products in the "first year of car-t" in 2017. Gilead has also become the first company in the world to have multiple commercial car-t products.

Besides PD-1 / PD-L1, car-t is another kind of product that domestic major pharmaceutical enterprises have been laying out one after another and catching up with the global forces. As of July 28, 21st century economic reporter consulted the clinical trials registry clinical trials.gov data showed that there were 556 car-t projects registered and active, with 297 in China.

China's immune cell therapy has become the second largest market after the United States. Although the commercialization of car-t products in the United States continues to accelerate, and no product has been approved for marketing in China on the other side of the ocean. However, since the first car-t clinical application was submitted by legendary biology in 2018, several domestic pharmaceutical companies have entered the clinical research and development of car-t, and the product listing applications of the two companies have been accepted.

With the commercialization of car-t products in China, the regulatory authorities have also shown a more active attitude.

On July 6, the drug evaluation center (CDE) of the State Drug Administration issued the technical guidelines for clinical trials of immune cell therapy products (Draft for comments), which further refined the technical suggestions for clinical trials of immune cell therapy products, and provided more targeted suggestions and guidelines for drug R & D registration applicants and researchers conducting drug clinical trials.

"The follow-up of China's drug regulatory authorities is relatively fast, basically in line with the international approval process, which shows that our regulatory authorities are actively promoting and supporting the cell therapy industry." Fu Xu, director of the science and technology center of Shanghai, said in an interview with the Shanghai Science and technology center.

However, in terms of intellectual property rights, target selection and layout, clinical design, talent and team, clinical application, industrial strength, high manufacturing cost and business model, domestic car-t product companies still have many problems to be solved.

Continuous breakthrough of hematoma

Cell therapy is to directly transplant or import normal or Bioengineering human cells into patients, and the newly imported cells can replace the damaged cells or have stronger immune killing function, so as to achieve the purpose of treating diseases. Car-t is also a highly personalized treatment method. Each patient has received various treatment methods before receiving car-t treatment, such as bone marrow transplantation, chemotherapy, targeted therapy, etc., and the preparation and programming of T cells obtained will be different. From R & D, preparation to production, there are highly specialized requirements.

2017 is the highlight time of car-t therapy. Novartis car-t therapy kymyriah and kit Pharma's car-t product yescarta have been approved by FDA for use in patients with acute lymphoblastic leukemia and lymphoma.

Tecartus is a CD19 targeted gene modified autologous T-cell immunotherapy for mantle cell lymphoma (MCL), a rare non Hodgkin's lymphoma (NHL), which mainly affects men over 60 years old.

Car-t is the most expected drug for lymphoma patients, followed by new Btk inhibitors and CD30 mAbs.

Tecartus's approval is based on a multicenter clinical trial in which 60 adults with refractory or recurrent MCL were followed up for at least six months after the first objective disease response. After treatment with tecartus, the complete response rate was 62%, and the objective response rate was 87%.

It is understood that tecartus will be produced at kite's commercial production plant in El Segundo, California. In the zuma-2 trial, kite showed a manufacturing success rate of 96%, with an average manufacturing turnaround time of 15 days from leukocyte separation to product delivery. Manufacturing speed is particularly important for patients with advanced disease who are seriously ill and at risk of rapid progression. Cytokine release syndrome (CRS) is the most common adverse reaction of car-t therapy, and tecartus is no exception. CRS occurred in 91% (75 / 82) of patients receiving tecartus.

Commercialization and supervision go hand in hand

Cell gene therapy industry is entering a period of rapid development in the world. In 2019, there are 1011 cell therapies in the world, including 568 car-t therapies, accounting for 56.2%, and cellular immunotherapy accounting for about 80%.

By 2030, the FDA alone is expected to approve 40 to 60 cell and gene therapies. "About $7.4 billion will be spent in 2019, and about $2 billion will be spent on cell therapy projects." Brian min, chief executive officer of Genscript ProBio, said at the recent Kinsley cell gene therapy industry development and cooperation forum that there are more than 1000 companies around the world committed to cell and gene therapy projects, of which China ranks second.

Since the first car-t clinical application was submitted by Legend biology in 2018, the industrialization process of domestic car-t products has been started, and the application of car-t products such as Keji biology, Yinhe biology, hengrunda biology has been accepted. In February 2019, Fosun KITT car-t product listing application was accepted. In June 2020, the application for the second car-t product from China was accepted.

In June this year, legendary biology, a subsidiary of Kingsley, landed on NASDAQ as the first share of car-t in China, becoming the largest IPO of biotechnology company since 2020. At the same time, domestic and foreign pharmaceutical companies or car-t R & D companies cooperate more and more closely, such as Fosun Pharmaceutical and kit Pharma, yaomingjunuo and Juno, Chuanqi biology and Johnson & Johnson of the United States, Shanghai sibyman and Novartis Pharmaceutical Co., Ltd. apply for ind at home and abroad at the same time, carry out clinical work separately, and share clinical data.

As for the development of China's commercial technology and technology, the development of car-t has just begun.

From the distribution of financing amount, 42% of the 34 enterprises that have disclosed the financing amount have accumulated more than 100 million yuan, and 5 enterprises have raised more than 500 million yuan, including Shanghai cell therapy, legend biology, Genxi biology, yaomingjunuo and Jikai gene.

Fu Daxu said that compared with the United States, China's car-t technology is particularly lack of innovative research with clinical transformation potential. The core patents of car-t cell therapy are mainly in the hands of Novartis, kit pharma and other industry giants; China lacks core technology patents, and the homogenization competition in this field is even more fierce. Clinically, China started relatively late and the design was relatively simple, lacking excellent immunotherapy clinical scientists and mature medical team, and the operability of clinical research was poor. From the regulatory point of view, China's cell therapy policy has undergone many changes. At present, there is a big gap between China and international giants in terms of dual track management, car-t cell preparation and quality control.

From the perspective of industrialization strength, American pharmaceutical companies cover the whole process from antibody screening, virus production to cell preparation, with a high level of commercialization. Most of China is led by R & D institutions or hospitals, and the role of pharmaceutical enterprises is to provide technical support or provide virus, so it is difficult to effectively encourage domestic enterprises to participate in the industrialization of car-t therapy.

From the manufacturing point of view, car-t technology involves the construction of genetic engineering vector and the preparation of car-t cells, including the collection of patients' immune cells, in vitro cell culture, transfection, amplification and reinfusion preparation and treatment. Due to the high cost of reagents and other consumables, quality control and testing costs of car-t cells, GMP plant operation costs of cell products, third-party certification and quality inspection costs, it is difficult to reduce the terminal cost at present, which will lead to high landing prices in the future, which is also the reason for the high prices of Novartis and kit Pharma products.

Cao Wei, President of Genxi biology, previously told the 21st century economic report that "it is a huge proposition to make enterprises have certain returns and be affordable to the Chinese people. To solve this huge proposition, enterprises need to carry out technological innovation."

For the Industrialization problems faced by Chinese enterprises, Brian For this reason, we have to consider how to make these products more suitable for China's market, and how to make them more suitable for the global market

?