In 2017, the first two commercial CAR-T therapies – Kymriah™ and Yescarta™ – received FDA approval. However, this does not mean CAR-T advancement stops. In contrast, the CAR-T manufacturing process is getting longer and longer. At the CAR-TCR Summit held in Boston last September, experts convened to discuss the long production times and high manufacturing costs being faced by CAR-T developers. Fully 68% of CAR-T experts at the Summit believed that automation would play a key role in reducing CAR-T therapy costs.
Kymriah and Yescarta therapies cost $475,000 and 373,000, respectively, and are manufactured via semiautomated cell manufacturing processes, a key factor which is contributing to the high price of these medications. An effective way to reduce costs is by increasing the use of CAR-T automated manufacturing, which is a goal of all CAR-T developers. Boyalife has recently made significant investments in the area of automated cell processing, first with its majority investment in US-based Cesca Therapeutics in 2016, and then again with Cesca’s acquisition of SynGen, Inc. in 2017. Together, Cesca and SynGen are working to develop a scaled CAR-T, CMC automated manufacturing technique.
In November 2017, Xiaochun Xu, who was at Cesca’s California headquarters, was interviewed via video conference by a reporter from Pharmcube in Wuxi City, China. Despite getting just four hours of sleep per night, Xiaochun Xu was still energetic at 5:00 p.m. local time, while discussing Cesca’s plan to develop an automated CAR-T cell manufacturing and control (CMC) solution.
The Cell Therapy Industry Faces Significant Challenges
Pharmcube: Boyalife started as a stem cell storage business but is transforming into regenerative medicine, animal cloning and tumor immunotherapy. What is the basis for pursuing these different businesses?
Xiaochun Xu: Since its establishment, Boyalife has been focused on the whole life science field. The development of life sciences takes a significant amount of time, and it is not like other industries where things can be accomplished very quickly. We plan to enter a business with significant barriers to entry instead of participating in very fierce market competition. The world has entered the cell therapy era, and cell therapy will become the new pillar of medical treatment in the future.
Stem cell therapy and CAR-T cell therapy are related in terms of their basic principles and their essence is to modify living cells by isolating them using special functions. Then, they undergo in vitro multiplication before being sent back to the human body in order to exert the corresponding treatment function. Different from the traditional drug development mode, cell therapy is an individual treatment method. The traditional “big pharma” manufacturing model is not suitable for the development of cell therapy products.
Considering the above, we were involved in stem cell storage first, and we have made significant progress adapting our stem cell learnings since our establishment eight years ago to the CAR-T cell therapy industry. We made all these layouts with long-term consideration because we are very clear about the technique and solution needed by the industry in the future.
Pharmcube: What do you think is the biggest challenge facing the cell therapy industry?
Xiaochun Xu: We have known for some time that the industrial bottleneck of cell therapy lies in the biomanufacturing process, and automation will evolve into a key part of the equation. In addition to R&D costs in the early stages of CAR-T drug development, it costs Novartis $100,000 to produce a single dose of Kymriah using the current “semi-automated” production technique. That’s why the therapy costs are so high. The cell manufacturing process is the main technical barrier for CAR-T therapy, and China’s cell therapy industry must undergo the process of automation and standardization.
It is critically important that drug manufacturers comply with GMP standards. Drugs simply cannot be manufactured in a plant without these important and rigid quality standards. And these standards apply to CAR-T therapies as well – the manufacturing process MUST comply with GMP standards. The FDA’s guidelines and China’s Measures for the Administration of Drug Registration both specify that clinical test drugs must comply with Good Manufacturing Practices for Pharmaceutical Products and the manufacturing process must conform to the requirements contained therein. This means that the product to be tested in a clinical trial must conform to GMP specifications before entering the human body. This is totally different from regulations governing the development and testing of medical technology.
Pharmcube: Many companies in the world have entered CAR-T field, including many companies in China. What’s your vision for this significant opportunity?
Xiaochun Xu: The US has more than 700 companies in this industry, and China has more than 1,000. Most of them are focused on early stage development, like identifying biological targets. They are very homogeneous so competition among them is very fierce. It is unfortunate that China does not yet have the capacity to produce automated clinical-grade CAR-T cells.
But, in my opinion, a single biological target cannot be demonstrated to be better than others without clinical testing. The preclinical study involving a mouse can yield different results from an actual clinical trial. We plan to provide one enabling target so as to transform products very quickly. This is very much like the “Gold Rush” of last century. All the people believe that CAR-T is the next gold mine of tumor immunotherapy but where is the gold? It is buried beneath the earth? You need good tools.
Currently, China’s regulation of CAR-T developers is loose. Enterprises and medical organizations still submit their therapeutic techniques to the National Health and Family Planning Commission as they have always done, and the threshold is relatively low. If it is based on the drug standard, drug developers must acquire CFDA clinical test approval documents only. In China, we must have more firm regulations when it comes to the human body.
I believe that such strict supervision will give rise to a powerful new industry. The death of Wei Zexi, which was caused by an experimental treatment, also reflects the reality that some medical organizations provide dangerous and ineffective treatments to hopeless patients while collecting extremely high fees. Meanwhile, important regulations are ignored, as are warnings from the medical and scientific communities. Without stricter regulations, this will have an adverse effect on the development and evolution of China’s drug development industry.
Pharmcube: What are your reference standards in cell therapy field?
Xiaochun Xu: Taking Boyalife stem cell as an example, we are still China’s exclusive clinical stem cell library, meeting three sets of rigid international standards, including AABB, NRL and the American CAP capacity test. We strive to keep pace with top international organizations such as Harvard Medical School, Johns Hopkins Hospital, Mayo Clinic and the National Institutes of Health (NIH).
By strictly abiding by these standards, I believe our cell therapy products can enter US Phase 1 clinical testing smoothly. In my opinion, all of life sciences must be governed by rigid standards and thresholds. Not standards that are influenced by administrative power, but those that are judged by the quality standard system. The quality standard should be applied to the fully-automated process of CAR-T manufacturing. This is the key to good quality control of the clinical application of CAR-T therapy.
A majority of CAR-T developers are pursuing a fully-automated and standardized process, but few of them succeed. Cell pre-treatment and frozen storage are ongoing challenges: developers need to treat cells from different medical centers before conveying them to different sites. In the process, developers are under a rigid time constraint and must ensure the activity, stability and consistency of cell products. BLA clinical products conforming to FDA requirements cannot be produced without automated, standardized cell separation, purification and culture processes.
Provide an integral cell therapy solution
Pharmcube: What techniques (technical storage) are used by Boyalife to achieve full CAR-T process automation? What is your core competitive strength?
Xiaochun Xu: We have many different components to our system. For our CAR-T automated technique and our stem cell automated technique, we use a combination of internal research and external observations. Strictly speaking, we provide automated bio-banking, point-of-care solutions for the operating room and fully automated technical systems or CAR-T. Our goal is to be the leading supplier of these tools, globally.
The automated separation system, AXP®, and automated storage system, BioArchive®, were developed by Cesca, which continues to be the market leader with this equipment ins use in six out of 10 cell libraries, worldwide. Our notable customers include New York Blood Center, CBR and Hong Kong Red Cross; Beijing Cord Blood Bank, Zhejiang Cord Blood Bank, Guangdong Cored Blood Bank and Beike Biotechnology.
In July of 2017, Cesca acquired the cell processing assets of SynGen, Inc. SynGen has recently been issued two patents that are key to the CAR-TXpress platform, specifically the pre-treatment of cells such as CD3+, CD4+, CD235a, CD14+, CD19+, CD56+, CD34+, CD117+, KDR+ and SIRPA+ . CAR-TXpress in based upon a critical method for cell sorting known as Buoyancy-Activated Cell Separation, or X-BACS™ for short. It is used to separate specific target cells from the complicated cell mixture using microvesicle. The surface of each microvesicle is paired with an antibody which combines to target a specific cell. When combined with microvesicles, target cells will float by buoyancy while non-target cells will sink; the target cell layer can be separated by centrifugal force. The collected target cell layer can then be separated from the microvesicles in order to obtain highly purified target cells. The patents are also applicable to the automated separation of low-density surface antigen cells. This is the main challenge faced by cell manufacturers at present. With CAR-TXpress, it takes just two hours to separate the specific cell population from blood products. This is four to eight hours faster than FCM (flow cytometry)/magnetic beads separation (MACS).
Pharmcube: What commercial model will Boyalife use to provide this service? What level of resources will Boyalife deploy in the CAR-T field in the future? Can you share your development plans?
Xiaochun Xu: We have a Chinese company called IncoCell that mainly specializes in CAR-T development. It is a CDMO enterprise, which means they do contract development and manufacturing. The company provides the integral parts of the CAR-T cell manufacturing process, including biomanufacturing, clinical biobanking, and the operating room solution. It is not unlike companies that are integrating in other industries, such as Cisco or Huawei. The goal is to become an integral solution service provider. These GMP systems reside not only within drug developers but also in medical organizations such as hospitals. In the future, hospitals will not only treat patients, but also establish their own GMP production line, including the capacity to generate fully-automated cell production and high-end clinical storage. We plan to help them prepare clinical cells based on FDA standards.
In other words, we are providing the tools for the gold miners instead of exploring for gold ourselves. For the powerful drug developers, such as Novartis, they can purchase the tools directly while for the small and medium-sized enterprises, we can lend them our equipment through a co-development arrangement. We are building China’s first, fully-automated CAR-T production line in Tianjin, which will include eight sets of automated equipment. It will run parallel to our production line in California. It will be built according to FDA standards, and all equipment will be supplied by Boyalife.
Benefiting the society by taking father as an example
Pharmcube: Frankly speaking, it is more challenging for you than common people to achieve greater success because of your father’s achievements. Why did you and your wife choose to run a business by quitting your job as a senior manager of a foreign enterprise? What does your father think of your decision?
Xiaochun Xu: All of China’s industry is transforming and upgrading from traditional industry to high-tech industry. When viewing it from a very professional perspective, drug development has been experiencing the transformation from small molecule drugs to large ones. The future will be the era of cell therapy. With my experience in drug development at a multinational company, and my knowledge of the clinical development process in Europe and America, we are able to establish an international team in China. We believe we can do better in China.
For Academician Xu, he is mainly focusing on vegetation while I work on medicine. We are actually in the same general industry. Ever since my brother and I were young, he seldom interfered with us because he believes that everyone has his unique way of development. When we started our business, he neither said yes or no. His only requirement was for us to benefit society. We must benefit society, whether doing scientific research or running a company. My father has done this for so many years. He donated all his bonuses and allowances to the Peking University Education Committee. I am very proud of his deeds, regardless of not having so much money growing up.
In the last several years, Boyalife has also developed a series of stem cell clinical applications. The treatment costs for difficult-to-treat diseases are as expensive as CAR-T. Taking the case of Cockayne Syndrome, developed together with Peking University Third Hospital, besides the stem cell treatment fees, we also bear all the inspection and auxiliary treatment fees, which have been $475,000 to $633,000. It means a heavy burden for an enterprise that is just starting out. Of course, we hope that we can do better as we develop.
Pharmcube: Over the past eight years since establishment, Boyalife has developed different businesses in many cities of China and even the US, Korea and India. As you and your wife are involved in so many ventures, how do you balance work and life?
Xiaochun Xu: I established Boyalife after coming back to China in 2009 and my wife Yishu Li came back six months later to assist me. She is now the director of Boyalife Stem Cell. I am very grateful to have her with me when we started this business because she had to put in more effort than common people. We were prepared for all the difficulties we might face, but we remained determined. It is always difficult to start a business, but when thinking from another aspect, it is worthwhile creating higher quality standards for the industry.
In small molecule drugs and the small molecule drug development field, it is hard for us to imagine how to enter clinical development without any standard quality systems in place. However, the reality is that traditional biochemistry techniques are not suitable for developing individual cell therapy products. For enterprises with cell therapy products such as Novartis and Kite, they face the challenge of increasing output. In the face of the huge market demand, all cell therapy companies need to realize the benefits of a fully-automated and standardized cell manufacturing process.
The development of policies, standards and techniques will change the drug development industry substantially, and companies with no qualification or techniques will be quickly eliminated. In contrast, enterprises with great technical and development potential will succeed and thrive in the cell therapy industry. Will Boyalife become the winner in the CAR-T field after all these painstaking efforts? We must wait and see.