2022 is the 10th year that Emily Whitehead, the world's first child with leukemia cured by CAR-T cell immunotherapy, has achieved cancer-free survival.
In 2012, Emily, who suffered from B-Cell Acute Lymphoblastic Leukemia, participated in a CAR-T clinical trial for pediatric B-cell acute lymphoblastic leukemia initiated by Philadelphia Hospital in the case of a second recurrence of the disease and no drug to treat. With CAR-T therapy targeting CD19, after three weeks, Emily's cancer cells completely disappeared. After 10 years, there is still no recurrence.
Emily photo
(Source: public information, invasion and deletion)
The tumor cure "miracle" that appeared on Emily has inspired countless scientific research and industry elites to explore CAR-T cell immunotherapy in depth, and in recent years, related products have been approved - there are 6 CAR-T products approved by the US FDA, 3 CAR-T products approved by the European Union, and 2 CAR-T products in China.
Global CAR-T products are currently approved
(Arterial network mapping after public information collation)
Emily's "miracle" is a very typical case in cell therapy products, but in fact, there are other immune cell therapy products including DC products and stem cell products including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), etc., which stage a "miracle" similar to Emily in different patients.
Recently, the top academic journal "Nature" published a study on the long-term potential and stability of CAR-T cells in the treatment of leukemia. A team led by Professor Carl June, the father of the world-renowned CAR-T, found through long-term research that in two patients with chronic lymphocytic leukemia, after ten years, active CAR-T cells can still be detected, although the number is low, but measurable, and retains lethality, so that the patient's condition has been continuously alleviated.
图源：Melenhorst, J.J., Chen, G.M., Wang, M. et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 602, 503–509 (2022).
The intertwined hopes and emotions behind these miracles have contributed to the fiery development of the global cell therapy track - Europe and the United States have now approved dozens of cell therapy-related products. Looking at China, with the approval of 2 cell therapy products last year - Fosun Kate's Yi Kaida (Agilunsey Injection) and WuXi Juno's Benoda (Regquiola Injection) have been approved, this year's legendary biological/Johnson & Johnson BCMA CAR-T therapy product Cilta-cel (trade name Carvykti) successfully "went to sea", which greatly boosted the confidence of the domestic industry and the market in the development of the cell therapy industry. It also takes their enthusiasm for the cell therapy track to the next level.
Countless companies are riveting and actively promoting the research and development of their own cell products; countless capital has been scattered and bet on their own optimistic cell therapy start-ups.
The situation is that the number of clinical trials of cell therapy in China is currently in the leading position in the world, second only to the United States; in 2020 alone, the total amount of financing in the field of domestic cell therapy reached 12.6 billion yuan, and the compound growth rate of the financing amount in the field of cell therapy in 2016-2020 reached 118.8%.
Investment and financing of the domestic cell therapy industry from 2016 to 2021
(Source: Frost & Sullivan report)
The entire cell gene therapy industry began to enter the industrialization stage on a large scale. The success rate and speed of product development have become the key to the success of enterprises.
The industrialization verification of cell drugs and the development of pharmaceutical processes are the "speed limiting steps" that plague the current innovative drug companies to promote the industrialization of cell drugs. Therefore, how CDMO can help the industrialization process of cell therapy has become the focus of attention in the industry - the fiery development of the cell therapy track has directly spawned the arrival of the "spring" of the cell therapy CDMO industry.
For the cell therapy industry
The demand for CDMO is even stronger
The function of cell therapy CDMO is mainly to provide cell therapy enterprises with process development and preparation of clinical new drugs, as well as process optimization and large-scale production services for listed drugs, including the production of preclinical and clinical trial research drugs and commercial drug production.
CDMO service content overview
Its role in the industry, including reducing the production risk and cost of early research and development of cell therapy drugs, shortening the research and development cycle of enterprises, and meeting the compliance requirements of regulatory agencies for product quality and safety, is similar to the application requirements of cdMO in the field of traditional drugs.
But the difference is that the demand and willingness of the cell therapy industry for CDMO is stronger.
The reasons behind this are mainly reflected in three aspects:
1. As an emerging track, related enterprises are mainly start-ups, and many companies tend to spend funds on pipeline development and team building;
2. Compared with traditional drug research and development, cell therapy drugs require higher investment in research and development;
3. The production process of cell therapy drugs is complex and the threshold is higher.
As an emerging track, the relevant enterprises in the cell therapy industry are mainly biotechnology startups, and the traditional pharmaceutical companies with larger volumes are in the minority. However, start-ups are often not strong enough in terms of funds, talents and other resources, but they face problems such as high cost of funds for the construction of their own production capacity, slow construction speed, long verification time, need for mass production, QC and other personnel. Therefore, compared with the demand for CDMO in other traditional pharmaceutical fields, the demand for CDMO in the cell therapy track is more exuberant and urgent.
According to Frost & Sullivan' report, R&D spending on cell/gene therapies in the discovery and preclinical phases ranges from US$900 million to US$1.1 billion, and clinical phases range from US$800 million to US$1.2 billion; the high investment in cell therapy drug development makes cell therapy companies need to reduce drug development costs with specialized outsourced R&D and production teams.
Regarding the cost of cell therapy drugs, Wang Liqun, founder of Xingyi Ang Bio and former CEO of Fosun Kate, has publicly stated that once the CMC of cell therapy drugs is changed, it is a "completely different product", and once the product is declared, there is not much room for cost reduction. Therefore, the cost reduction of cell drug products should be considered from the beginning of the project. "You can use the experience of the first product to the second and third products through innovation." Wang Liqun said.
However, due to the lack of experience in the development of cell drugs by most companies, and the success of the first product is extremely critical, at this time, professional cell therapy CDMO with mature cell therapy basic research capabilities and development and transformation experience provides another more secure choice for pharmaceutical companies. By providing a full range of solutions, CDMO can help companies improve R&D efficiency and control risk, ultimately commercializing cell products.
In addition, due to the difficulty of large-scale production of cell therapy drugs and the high research and development challenges of process optimization technical barriers, the demand for CDMO services in enterprises in this field is more intense. Compared with traditional macromolecular and small molecule drugs, cell drugs have higher R & D and production requirements: not only need to build a cell bank, virus vector selection and optimization, large-scale cell amplification and culture, but also have more stringent requirements for quality detection, inter-batch stability, preparation and transportation, and medication.
Cell therapy CDMO companies usually have large cell or vector libraries, which can help pharmaceutical companies select suitable cells or vectors and optimize the process, thereby reducing trial and error costs, improving R&D efficiency and success rate; its rich production platform and strict quality inspection measures can help pharmaceutical companies cut commercial production costs and time - professional QA/QC personnel and strict supervision of the whole process will ensure that the production of cell therapy products meets the national GMP quality standards. In addition, some cell therapy CDMO companies can provide one-stop new drug clinical trial application (IND) and new drug market application (NDA) and other regulatory related services, further helping pharmaceutical companies accelerate their research and development progress.
In general, cell therapy CDMO can complete the standardized production of target products "more, faster, better and more economical", while meeting the customized needs of pharmaceutical customers, helping pharmaceutical companies complete the declaration of cell drugs and achieve stable supply.
However, many of the advantages of cell therapy CDMO mentioned above can only be established under the premise that cell therapy CDMO is very mature and professional. If a cell therapy CDMO is not mature and professional, then pharmaceutical companies must have many worries and doubts when entrusting their own cell drugs to CDMO. So, how is the development of the domestic cell therapy CDMO track? In the cell therapy industry, which dark horse will be the first to rush out of the "water sales" team?
The domestic cell therapy CDMO industry is still in the early stage of development, and very few enterprises can provide mature services
Arterial Network has previously done a relevant inventory of the field of gene cell therapy CDMO, and found that there are very few companies specializing in cell therapy CDMO services in China, and most CDMO companies will carry out gene and cell therapy CDMO services at the same time. Spectral Biotech may be the only provider in China that focuses on the overall solution of CDMO for cell therapy, and the company has just recently completed a Pre-A round of financing of nearly 100 million yuan, led by PwC Capital.
As an emerging development track in the medical field, cell therapy undoubtedly requires a certain strength and courage for start-ups to bet on such a segment, because the risk is really not small. In order to gain a deeper understanding of such a company that chose to take the "path of a few companies" - focusing on the CDMO segment of cell therapy, we had a conversation with Dr. Yi Zhu, CEO of Pranex Biotech.
Why did you choose to focus on cell therapy CDMO services? Dr. Zhu Yi said that making such a choice is entirely based on the strength and advantages of the company's team - the company's team has developed relevant cell therapy products in the early stage and accumulated a lot of experience in the development and production of cell drugs. Based on its own understanding and development capabilities of cell drugs, Spectral Bio can help customers avoid the "pits" that may be encountered in the development and production of cell drugs and successfully solve many problems that may be encountered in the process, thereby helping customers "take fewer detours".
"Compared with CDMO services in the field of antibodies and small molecules, the CDMO service for cytopharmaceuticals has its own uniqueness, and the process and production standards are very different. Therefore, in addition to the conventional requirements of cGMP, production capacity, and quality, CDMO also puts forward higher, newer, and more important requirements for cytopharmaceutical CDMO companies - a deep understanding of cytopharmaceuticals and the ability to transform the industry. Dr. Zhu Yi said that it is a challenging problem to look at CDMO services from the perspective of making drugs, especially for cell drugs, its research and development and production are closely linked.
Novartis, a leader in cell therapy, has repeatedly chosen to cooperate with Oxford Biomedica (OXB) in the production of cell drugs, which is a good example. Founded in 1995 and launched in 2001, Oxford Biomedica is known as a pioneer in the field of lentiVector gene therapy, with patented LentiVector gene delivery platform, and based on this, it has developed a variety of gene therapy products, while providing gene and cell therapy CDMO services. Because of Oxford's unique experience in the development and production of gene therapy products, Novartis has been working closely with Oxford since 2013, repeatedly choosing Oxford to provide lentiviral vector clinical supply services for the company's CAR-T candidates.
Novartis has had several strategic collaborations with Oxford Biomedica
(Arterial network mapping after public information collation)
Similarly, Based on drug development standards for order delivery, Spectral Biotech will provide customers with a truly feasible rectification plan, even at the product design level, on the basis of timely discovery of problems. "This places high demands on our team, but it greatly reduces the barriers to subsequent development of the product. To ensure the speed of each stage while ensuring the success rate of product development, is the added value that Spectral Services can give to customers. We believe that such a service is very valuable to our customers. ”
The first registered clinical production project undertaken by Spectral Biotech is a Phase I/II CAR-T cell drug project. Based on the full-process experience of early research and development of this cytomycle, IND declaration, registered clinical production, etc., Spectral Has established a perfect, three-dimensional and mature full-process service capability.
The current situation of domestic cytopharmaceutical CDMO companies is that most companies are still in the process of crossing the river by feeling the stones and growing together with customers, and few companies have experience in the delivery of mature cytopharmaceutical projects. Spectral Bio is one of the very few CDMO companies in China with practical experience and ability to undertake such projects, which is an important reason why it can still develop well in the industry despite the layout of cell therapy business in many leading and start-up companies.
As one of the earliest companies in China to lay out cell drug CDMO services, the number of industrial customers of Spectral Biotech has exceeded 100. The company operated independently at the end of 2020 and received orders of RMB 120 million for the whole year of 2021. In August 2021, Prancorp and Pumis Biotechnology reached a comprehensive strategic cooperation on the commissioned development and production of cell therapy drugs, providing CDMO services for a number of new CAR-T cell drugs of Pumis with its process development capabilities and GMP production capacity of cell drugs.
"The trust that customers have in Spectrum is the best evidence of our capabilities." Dr. Zhu Yi said happily.
The release of new documents on stricter GMP cell therapy products is a good thing for companies that build factories with high standards
Focusing on the field of cell drugs, Spectral Has built a unique innovation platform in the industry , including the HiLenti lenti lenti lenti lenvirus platform and the HiCellx cell technology platform , which is the first CDMO manufacturer to produce cell therapy drugs under the MAH system. With experience in the development and pilot production of multiple plasmid processes, Andrchen has mastered the production process of safely amplified suspended serum-free cells and disposable reactor lentivirus, and has supported multiple partners to successfully incubate a variety of CAR-T, TCR-T, stem cell and other drugs.
Layout of various technology platforms of Spectral New Biology
(Source: Frost & Sullivan)
"Spectral Bio is the first company in China to realize the serum-free suspension culture process, and it is also one of the few CDMO companies that currently has projects to use the suspension serum-free lentivirus process and obtained indulner license." Dr. Zhu Yi said that as the cytopharmaceutical industry enters the late stage of industrialization, higher requirements are put forward for the yield, quality and stability of viral vectors. From a technical point of view, the production capacity of virus adherent cells is sufficient for small-scale research use, but for commercial production, suspension culture systems can provide higher yield and quality.
The HiCellx Cell Technology Platform is equipped with all internationally recognized closed cell production equipment recognized by health regulators, and has a mature closed cell production platform process, which has supported the production of cells for multiple projects. "To fundamentally solve the problem of production stability, the premise is to reduce human intervention and use more automated fully enclosed culture systems for product production, which is the future development trend of the cell therapy industry." Dr. Zhu Yi said.
In terms of production capacity construction, Spectral Bio currently has a 10,000-square-meter GMP plant in Suzhou headquarters and an 8,000-square-meter GMP plant under construction in the Shenzhen base, which has initially formed a national layout of the production base network. In addition, the North Carolina base in the United States is also under construction to synchronize the company's global production capacity layout. "At present, Spectral Biotech has the same level of production capacity and quality system as the listed enterprises of cell drug products, and all production facilities and overall construction standards are established for the commercial production of cell and gene therapy in the future."
On January 6, 2022, the General Department of the State Food and Drug Administration publicly solicited opinions on the "Good Manufacturing Practice for Drugs - Appendix to Cell Therapy Products (Draft for Comment)", which is the second edition of the GMP Cell Therapy Products Appendix for Comments. This document considers the actual situation of the production management process of cell products, a special drug, and also puts forward higher management requirements and stricter requirements for content involving all aspects of safety.
"The document raises the entry threshold of the industry and puts forward higher requirements for production management." All of our plants are built in accordance with the high regulatory standards of Chinese regulators for cell drugs, and the domestic standards even exceed the regulatory standards of the US FDA in some details. Therefore, the landing of this document of the Food and Drug Administration is a good thing for the company, and Spectral Bio always looks at various issues that need to be considered in the development process from the perspective of making drugs. ”
"Let cell drugs write a new chapter of life" is the vision of the new spectrum people. Based on their own team ability, it is their style to take advantage of their focus to the extreme. In the cell therapy CDMO, which seems to be a very small subdivision track, there is no small dream of the new people.