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The growing interest in developing cell and gene therapies has prompted industry investment to grow manufacturing capacity.
With the hard-fought road to commercialization won by cell and gene therapies in the past few years, biopharmaceutical companies have stepped up their interests in developing these emerging therapies. Some biopharma companies are also building capacity by investing in expansions and/or new facilities. In anticipation of growing demand for capacity and services, contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs) have also been investing in expanding manufacturing capacity and capabilities for cell and gene therapies.
One such example is biopharmaceutical company Gilead Sciences, which acquired Kite Pharma in October 2017 for approximately $11.9 billion. That same month, Kite’s cell therapy product, Yescarta (axicabtagene ciloleucel) for large B-cell lymphoma, was approved by FDA. Through Kite, Gilead has established a global manufacturing network to meet patients’ needs for cell therapies today and in the future. “Outside of California, key investments include the opening of a manufacturing site in Amsterdam later this year  and ongoing construction of our newest automated facility in Frederick County, MD, that will significantly expand our ability to manufacture a variety of chimeric antigen receptor T (CAR T) therapies, and our new clinical manufacturing facility in Gaithersburg, MD will produce investigational T-cell receptor (TCR) cell therapies being evaluated in solid tumors,” says Charles Calderaro, Kite’s global head of Technical Operations.
In addition, in July 2019 the company announced the development of a new facility in Oceanside, CA (1) that will be dedicated to the development and manufacturing of viral vectors. Viral vectors are a critical starting material in the production of cell therapies, Calderaro notes.
Also looking to leverage itself with capacity for now and in the future, Orchard Therapeutics, a London-headquartered biopharmaceutical company, has been organizing its CDMO network as well as its in-house capabilities. “In anticipation of a potential launch, we will be leveraging our existing CDMO infrastructure to produce the required vector and drug product. At the same time, we understand that we must invest in our own, in-house manufacturing capabilities given the depth of our clinical-stage pipeline,” says Ran Zheng, chief technical officer, Orchard Therapeutics. “We are beginning construction of a manufacturing facility in Fremont, CA, in order to meet the need for greater capacity, and expect it to be operational in 2021. In addition to vector and drug product manufacturing, the Fremont facility will house process development, quality control, and other support functions.”
Meanwhile, CDMO Catalent made a significant investment with its $1.2-billion acquisition in May 2019 of Paragon Bioservices, a CDMO specializing in viral vector development and manufacturing for gene therapies (2). Paragon had just opened its second good manufacturing practices (GMP) gene therapy manufacturing facility in Harmans, MD, in April 2019, notes Colleen Floreck, senior director of Marketing and Communications at Catalent’s Paragon Gene Therapy. “The 425,000-ft2 facility offers individualized manufacturing suites specially designed to handle the unique needs of gene therapy products,” Floreck says.
Soon after the acquisition, Catalent Biologics and Novavax partnered in a strategic deal under which Paragon Gene Therapy would assume the leases to two of Novavax’s product development and manufacturing facilities in Gaithersburg and Rockville, MD. The deal gave Paragon immediate access to state-of-the-art manufacturing equipment and a further 54,000 ft2 of current good manufacturing practice (CGMP) space that the company needs to grow its gene therapy development and manufacturing business. One hundred of Novavax’s employees transferred to Paragon.
“Each of these announcements included commitments from customers for dedicated capacity for their programs, but also provides additional capacity for technology expansion and new development customers. Since then, Catalent’s Paragon Gene Therapy business has announced further collaborations, validating its proactive investment strategy,” Floreck says.
In addition to building up capacity for cell and gene therapies, companies are also making strategic investments to support advancing product candidates through the pipeline. “We are investing across a number of areas to support the advancement of our investigational ex vivo autologous gene therapy programs for rare, inherited diseases,” says Zheng.
Orchard Therapeutics’ additional investments include research and development for new indications; technological innovations, such as stable cell lines for vector production and hematopoietic stem cell transduction enhancers; automated cell processing; and initiatives to identify metachromatic leukodystrophy (MLD) patients, including diagnostic testing and newborn screening pilot programs. “We view all of these activities as crucial to our long-term success,” Zheng emphasizes.
Catalent’s additional investments include its February 2020 acquisition of MaSTherCell Global, a cell therapy CDMO, for $315 million. “This creates an industry-leading platform spanning both cell and gene therapy and complementing Catalent’s cell line, analytical, and biologics fill/finish capabilities,” Floreck says.
MaSTherCell has a 25,000-ft2 facility in Gosselies, Belgium, that provides clinical services and a 32,000-ft2 facility in Houston, TX, which is currently undergoing validation activities to undertake development-scale projects before the end of 2020, Floreck explains. “Like Paragon, MaSTherCell already has expansion plans in progress and construction is underway on a dedicated 60,000-ft2 commercial-scale production and fill/finish facility adjacent to its existing Belgian facility, which is scheduled to open in the fall of 2021. MaSTherCell adds a unique portfolio of capabilities and technologies to Catalent that include the development and manufacture of autologous and allogeneic cell therapies and related analytical services,” Floreck adds.
MaSTherCell’s expertise includes therapies based on CAR-T cells, TCR, tumor-infiltrating lymphocytes (TIL), and mesenchymal stem cells (MSC).
Gilead’s investments beyond building capacity is based on Kite’s commitment to continuous innovation in platform services and logistics support, both necessary to improve the cell therapy experience for patients and healthcare professionals. “We have a customized program, Kite Konnect, which is designed to help enable rapid and reliable delivery of Yescarta to treatment centers. Kite Konnect uses an integrated technology platform to provide real-time status updates to patients and doctors throughout treatment,” explains Calderaro.
The increased focus on developing cell and gene therapies and the significant number of product candidates in the clinical pipeline means that there is need for capacity upgrades on the market. “With so many cell and gene therapy companies looking to bring products through clinical trials to the market, capacity is tight,” Zheng concurs. “We’re increasingly seeing companies adjusting to this dynamic by securing supply agreements with CDMOs, building internal manufacturing capabilities, and improving manufacturing processes and efficiency by exploring new technologies.”
In gene therapy manufacturing, Catalent focuses on growing with its clients. “It is critical that we can support our customers’ pipelines and increasing asset portfolio with GMP viral facilities,” says Floreck.
With the number of gene therapy clinical trials on the increase and many gene therapy programs carrying expedited status, it is additionally important to Catalent that the company offers not only dedicated space for clinical trial and commercial production, but also scale-up expertise to support increased manufacturing efficiency, Floreck explains.
“It should be the goal of any successful gene therapy CDMO to offer an end-to-end solution for its customers. From the raw materials through to development, scale-up, manufacturing, and fill/finish, we want to be able to guide our customers through the process and increase their chances of final approval and patient material. At Catalent, we are committed to expanding capacity to meet industry demand; however, without the viral vector expertise, it is just empty space. Early phase clients need to lock-in early with manufacturing partners, to not only secure the production suite but also to have the necessary technical expertise in place to optimize their program,” Floreck stresses.
On the cell therapy front, the constraint isn’t so much about capacity but more about getting into the field early. Floreck points out that the barrier to entry in the cell therapy field is low, but the real challenge involves the people and expertise. “There are many manufacturers who can build upstream and downstream cell culture suites, especially without the challenges of virus production, but it takes a minimum of six months to effectively train personnel across various platforms,” say says.
“Additionally, you are so close to the end user (i.e., the patient) that the cell production and the need to lock down a process early is even more critical. Knowledge and expertise across a variety of cell types and modalities are important to offer customers the speed they need to get to the clinic faster. Many cell therapy indications and products are similar, making speed to market of paramount importance to customers,” Floreck says.
In the field of autologous cell therapy, in particular, there is no option but to build out. “Since you are treating one patient at a time, clients often do not even know how many patients they will have during each month of the trial. With enrollment being the biggest unknown, the numbers also challenge the affordability of the treatment,” Floreck explains.
In comparison, for allogeneic cell therapy, it is not known yet what the final bioproduction process will be. “At Catalent’s most recent acquisition, MaSTherCell, we are designing the processes, including stirred-tank reactors all the way through to fill and finish. We are working with clinically advanced companies like CRISPR Therapeutics and Servier as they navigate the defining of the allogeneic production process,” Floreck says.
Furthermore, unlike traditional biomanufacturing, current CAR T therapies require a complex and carefully controlled, multi-step process that can be difficult to optimize, adds Calderaro. “Manufacturing speed and quality in cell therapy is critical because people waiting for these medicines are typically very ill and have the potential for rapid disease progression. In addition to our global, industry-leading manufacturing network, Kite continues to explore ways to optimize the quality of manufacturing and has currently set the bar for the industry with a rapid and reliable median 16-day turnaround time in the United States,” Calderaro states.
Calderaro goes on to say that the progress of cell therapy is closely tied to innovation in manufacturing and technical operations. “In addition to our US and European locations, we are investing in other areas around the globe to ensure our operational footprint allows us to meet the needs of potential patients worldwide. We are actively advancing cell therapy technology across all aspects of the manufacturing process, including technologies such as next-generation autologous and allogeneic development platforms.”
Because Kite’s singular focus is cell therapy, it’s strategic drive into the future is also very focused. Today, the company is exploring cell therapies in more than 10 cancers, including hematologic malignancies and solid tumors, and is also exploring varied technologies. “As we advance our industry-leading cell therapy pipeline, expanding and investing in our capabilities is essential to ensuring we are able to improve outcomes for people with cancer now and in the future,” says Calderaro.
Catalent is taking its cue from its customers and intends to build a future with them. “It is critical for Catalent to grow with its customers. We are committed to developing the capacity needed to support their programs as they grow and expand,” Floreck says.
Meanwhile, Orchard Therapeutics is considering several factors looking toward the future as it develops and executes its manufacturing strategy. “Our first consideration is about patients and our ability to produce and deliver products to them reliably. With the construction of our facility in Fremont, we will work to ensure increased manufacturing capacity to make products for these patients. Given the nature of our investigational products-ex-vivo autologous gene therapies, which use a gene-corrected version of a patient’s own cells-reliable supply chain management is also necessary to ensure quality and timely delivery of our products. We are committed to working closely with regulators in the European Union, the US, and globally to ensure compliance and efficient product approvals,” Zheng says.
1. Gilead Sciences, “Kite Announces Plans to Bolster Industry-Leading Cell Therapy Manufacturing Capabilities with New Viral Vector Facility,” Press Release, July 16, 2019.
2. Catalent, “Catalent Completes Acquisition of Gene Therapy Leader Paragon Bioservices, Inc. for $1.2 Billion,” Press Release, May 20, 2019.
Vol. 44, No. 3
When referring to this article, please cite it as F. Mirasol, “Investments Inject Growth in Cell and Gene Therapies,” Pharmaceutical Technology 44 (3) 2020.