May 27, 2021 PAO-05-21-CL-05
Well, 2020 was a very difficult year for the cell and gene therapy industry. Many companies saw their commercial license applications delayed, and some of those that received late complete responses were denied. Of course, this type of activity represents the typical growing pains experienced by any new therapeutic modality heading toward the finish line. The last big hurdle is achieving alignment with the regulators to ensure that only safe and efficacious products reach the market and patients.
As we gain a better understanding of the science involved in cell and gene therapy development — and thus better control over both manufacturing processes and products via advanced characterization — the types of challenges faced in 2020 will be greatly reduced, and approval rates will increase, possibly even in an exponential manner.
Cell and gene therapies are new modalities that likely will not be considered mature for at least another five years. Over the next decade, we can expect the industry to grow at 15–20% annually. Much of that growth will be driven by startup companies translating promising research into clinical applications and one by one reaching the commercialization stage. Ultimately, as a result, approvals will also increase exponentially.
There are definitely gaps in capacity and capabilities, given the exploding growth of startup companies and the increasing number of developers that are reaching the point of commercialization. Efforts to catch up and build capacity and capabilities to the necessary levels, which have already been going on during the past few years, will continue for the near future.
What is required is a concerted effort from both innovator companies and their service providers — contract testing, development, and manufacturing organizations (CTDMOs) in particular — to collaborate to address these deficiencies collectively.
Right now, optimizing manufacturing of viral vectors for use in gene and gene-modified cell therapies presents one of the biggest issues. There is still significant need to boost production efficiencies and to improve yields in order to achieve truly cost-effective supply of viral vectors in the quantities needed to enable commercialization of the large number of therapeutic candidates in the pipeline.
For cell therapies, particularly autologous treatments, such as chimeric antigen receptor (CAR) T cell therapies, the primary manufacturing challenge relates to the scaling of processes. Because these are highly personalized, even patient-specific therapies, one batch often treats one patient. Scaling is currently achieved by scaling out rather than scaling up, and this requires assurance that no cross-contamination or crossover occurs between batches within the same manufacturing suites. It is also essential to ensure that the chain of identity is maintained throughout the entire manufacturing and transportation processes.
The logistics for both cell and gene therapies are complex. These products require cryopreservation and must be maintained at temperatures as low as –80 °C during storage and shipment. Some shipments have very short turnaround times as well — particularly autologous CAR-T cell therapies, which must be transported from the manufacturing facility to the patient within 48 hours in cold and non-cryopreserved state. The cold chain and rapid delivery requirements combine to create truly unprecedented logistics challenges.
For cell and gene therapies, there are three main types of testing that must be conducted to enable products to move into the clinic and onto commercialization: raw material release, in-process control and final product release, and biosafety testing. All three types of testing are complicated and currently require advanced cell-based testing methods, which typically require long turnaround times. For instance, it can take up to 60 days when testing lentiviral vectors, to receive the results needed to confirm that no replication-competent lentivirus (LV) is present.
As a result, one of the main challenges facing the industry with respect to testing is streamlining testing methods and processes. Those shortened turnaround times, however, must be achieved while still ensuring sufficient sensitivity, precision, and reproducibility.
There are two approaches to realize this goal: implementing automation and converting cell- and cultivation-based assays to rapid alternatives, such as quantitative polymerase chain reaction (qPCR)-based methods. Automation is important to reduce error, time, and labor costs, particularly around sample preparation and manipulation. Many non-cell-based assays can be completed in hours to a few days, which will have a tremendous impact. Adoption of qPCR, digital droplet PCR (ddPCR), and similar methods is taking place rather slowly, but there have been some promising precedents.
With some effort, the combined use of automation and more rapid testing methods will enable the industry to overcome the very, very challenging testing requirements for cell and gene therapies.
I have been in the industry for more than 30 years and never seen such a “war” for talent as exists today within the cell and gene therapy field. This situation has arisen partly as a result of the exploding growth of the industry and partly due to the complicated competency training required to bring new employees on board.
Companies exploring cell and gene therapies must not only hire the right people, but train, develop, and engage employees so they can begin to contribute as quickly as possible but also maintain a commitment to stay with the company that hired them. Different firms are taking different approaches.
At WuXi ATU, we attract talent by not only offering competitive employment packages but also enacting intense engagement efforts that include career development opportunities and cross-functional training programs. This is helping us to build a winning, employee-centric culture. In addition, we have developed a unique onboarding training program that allows us to reduce the time required for new employees to gain proficiency in expected tasks, including special programs for training manufacturing technicians in a holistic manner and analytic technicians in advanced methods, such as flow cytometry.
This really depends on which processes you are considering. For more established viral vectors, such as adeno-associated virus (AAV) and LV, that have been used for years, the industry is more or less converging on a common platform that resembles the approach used for traditional biologic manufacturing. Similarly, for more established cell therapy modalities, most notably CAR-T cell therapies, the industry is mostly converging on one or two types of platforms in wide use.
The same cannot be said for newer cell therapies, such as those based on stem cells and induced pluripotent stem cells (iPSCs). These therapies are still at the earliest stages, and translation from research into clinical development has just begun. As a result, significant customization and individual manufacturing solutions are needed at this point. Once several of these candidates have progressed through the development cycle and been fortunate to receive approval and undergo commercialization, we can expect platform technologies to be established for them as well.
The current high cost is unquestionably limiting accessibility to these lifesaving or life-changing treatments for patients. Innovators — and the industry as a whole — must work on reducing costs. There are several places to look for these needed changes.
First, as mentioned, it is absolutely necessary to increase the yield and efficiency of production processes for cell and gene therapies. Raw material and labor costs both need to be reduced. These issues can likely be addressed on an industry-wide basis.
In addition, developers of cell and gene therapies need to focus on drug products that allow treatment with a lower dose and that have improved safety profiles, such as no undesired adverse events, so that patients do not require extensive monitoring and management during treatment.
We classify innovators into two groups: early-stage companies with new product ideas and mature companies that are close to (or have just realized) commercialization. Each has its own priorities.
Early-stage companies are focused on advancing their products into the clinic as quickly as possible. These companies can benefit from a partnership with a service provider, such as WuXi ATU, WuXi AppTec's cell and gene therapy Contract Testing, Development, and Manufacturing Organization (CTDMO) business unit.
WuXi ATU strives to provide a turnkey solution that supports rapid development of innovative gene and cell therapies from the earliest stages into the clinic with a full range of process and formulation development, analytical testing, and clinical trial material production services.
For companies close to or at the commercialization stage, a CTDMO like WuXi ATU provides agile, flexible capacity and capabilities to help meet evolving demands as companies move from the clinic to the market.
One key to successful development in the cell and gene therapy space for both innovators and CTDMOs like WuXi ATU is for both to share the risk associated with the development of these new, somewhat volatile modalities. There is room for greater alignment and agreement in this area.
OXYGENE’s state-of-the-art, industry-leading plasmid technology for viral vector manufacturing piqued our interest, and talks began approximately one year ago. Initially, we were interested in in-licensing the plasmid technology in order to be able to manufacture and supply these products to the industry, as well as to use them internally.
During those discussions, we discovered that OXGENE has an ongoing, intense, and advanced effort to develop a next-generation production system for AAV and LV vectors in addition to its industrially leading plasmids. That type of technology was one key element that had been absent in WuXi ATU’s service offering. Concurrently, OXGENE realized that WuXi ATU has the mature GMP development, manufacturing, and testing capabilities needed to take their technologies to the next level.
This mutual recognition of our complementary capabilities quickly resulted in the dialogue advancing from an in-licensing deal to an M&A discussion. After constructive and pleasant negotiations, we reach the conclusion to acquire OXGENE and make it a WuXi ATU company on March 2, 2021.
OXGENE is a spinoff company from Oxford University, one of the most reputed universities engaged in gene therapy and viral vector development. Having a physical location near the university allows us to attract local talent and thus enrich our talent pool, which will definitely give us an edge in that war on talent we discussed. A presence in the EU also allows us to establish local cell therapy manufacturing capability for the European market. Local production is absolutely essential for autologous cell therapies given the short turnaround times for these products.
With its advanced technologies in genetic modification and development of plasmids, viral vectors, and cell lines, OXGENE helps WuXi ATU to further establish itself as a turnkey solution for cell and gene therapy developers — from discovery to clinical and commercial production.
We will be fully integrating OXGENE’s manufacturing technology platform into the global WuXi ATU business. Its discovery and research technology platform will remain in OXGENE’s UK facility and continue to serve its existing clients, as well as support both existing and new global WuXi ATU clients.
At WuXi ATU, we believe that “every drug can be made and every disease can be treated” by building an open-access platform with the most comprehensive capability and technology in the global healthcare industry. We have developed WuXi ATU as a fully integrated CTDMO with capabilities in testing, development, and manufacturing, which allows us to provide a true turnkey solution.
With information on a client’s gene of interest, we can provide GMP product for clinical and commercial phases. And now, following the acquisition of OXYGENE, we have even greater capabilities with respect to the development and optimization of plasmid DNA, viral vectors, viruses, and cell lines, and importantly the ability to leverage next-generation viral vector production using helper-free, plasmid-free systems, which we believe will revolutionize industrial viral vector–based gene therapy services.
A decade from now, WuXi ATU will be widely recognized as a leading turnkey solution provider in the cell and gene therapy space with the ability to provide end-to-end support for clients. Early-stage companies will look to partner with us for assistance with building their gene delivery vehicles and cell therapy products, developing efficient and cost-effective manufacturing processes and producing their products for clinical and commercial use, including all of the necessary analytical testing throughout the life cycle. More mature companies will leverage our commercial-ready capability and capacity to help them cross the finish line and get these life-changing products to patients.
WuXi ATU will also be seen as a technology leader as we continue to develop more robust and efficient manufacturing and analytical methods and even next-generation solutions that address the key challenges facing cell and gene therapy developers today.
Dr. David Chang has more than 30 years of industrial experience. Before his current role, he was Corporate VP and Head of Cell Therapy Global Manufacturing, of Celgene Corporation; the Global Head of Engineering and Strategy at Roche based in Basel, Switzerland; the VP/Site Head of Roche Shanghai Technical Operations in China. Earlier in his career, Dr. Chang worked at Genentech as the Senior Director of Global Manufacturing Science and Technology and as the Director of Process Development in its Oceanside, CA site. He was also formerly at Biogen Idec as Director of Cell Culture R&D, at BASF Bioresearch as a cell culture group leader, and at Schering-Plough Research Institute as a process development engineer. Dr. David Chang obtained his bachelor’s degree in chemical engineering from National Taiwan University in Taiwan and Master’s and Ph.D. degrees in biochemical engineering from Massachusetts Institute of Technology.