An attentive audience at Phacilitate 2020
(www.phacilitate.com)

Presenters in the three main program tracks at the Phacilitate Leaders World conference in Miami, FL, this past January represented sponsor-developers of cell/gene-therapy (CGT) products, contract service providers, and technology suppliers to the industry. Topics include process and product development strategies for advanced therapies, regulatory and inspector expectations, automation and closed-system processing, the choice between in-house and outsourced manufacturing, quality assurance and control, analytical methods, viral vectors, and artificial intelligence and Industry 4.0. At the end of each session, presenters gathered for a short roundtable discussion and questions from the audience.

Biotech Bootcamp
Even as large amounts of money are pouring into the industry, the arena of financing and commercialization presents a daunting labyrinth to many young companies working on CGT candidates. Often founded by scientists and physicians rather than entrepreneurs, these small organizations seldom have regulatory affairs or business experts on staff. That made the “Biotech Bootcamp” concept a valuable addition to the Phacilitate program and the place to be for managers and executives during Advanced Therapies Week this year.

Follow the Money: In “Investing in Regenerative Medicine: State of the Capital Markets,” Reni Benjamin (managing director of biotechnology equity research, JMP Securities) presented a mixed-bag of information, the highlight of which was a more than doubling of biopharmaceutical venture financing from 2014 to 2019. The total gross proceeds of US$21.1 billion in 2018 is nearly an all-time high for venture capital in the industry. But money raised from initial public stock offerings, which was likewise impressive in 2018, was down by about a third in 2019, with only three-quarters as many IPOs. However, key players such as Genmab, BridgeBio, Adaptive Biotechnologies, Gossamer Bio, and Turning Point Therapeutics all did well.

Benjamin listed a number of factors that drive investment in biotechnology: an aging population, an associated increase in life expectancy, and related rises in chronic disease; commercial opportunities in orphan-disease development; and improvements in clinical-trial design helping more product candidates make it to market than in the past. Collaborations, mergers, and acquisitions, he said, are providing greater access to capital than ever before. With breakthrough therapy and fast-track designations as well as accelerated approvals and priority reviews, the regulatory environment generally is seen as friendlier these days than in the past. But he pointed to the “patent cliff” problem as one that has yet to be solved. The pharmaceutical industry, he said, is a “major R&D burning machine.”

“While worldwide R&D spending is expected to increase every year, the average annual proportion of R&D spending to pharmaceutical revenue actually is expected to decrease over time — from a high of 21.7% in 2019 to 18.4% in 2024. There are $159 billion of sales at risk between 2020 and 2024, with more than 36% of these in 2023, which is when key patents of biologics (including Humira and Stelara) will expire.” Benjamin also showed how the latest news, whether positive or negative, can make a big difference in the capital markets — so timing of IPOs and follow-on financing is key. Major drug approvals in 2018 and 2019 have shone a spotlight on the CGT industry, and with all the attention has come an influx of cash.

He concluded with some investor perspectives on regenerative medicine (generally positive, with a focus on data and M&A), stem cells (generally negative, with a focus on poor performance), cellular immunotherapy (generally positive, with some caveats related to manufacturing costs and timelines), and gene therapy (again positive, with impressive performance despite commercial worries).

One of many panel discussions at Phacilitate 2020 (www.phacilitate.com)

In “Assessing the Potential for Return on Investment of Cell and Gene Therapy Assets,” Delfi Krishna (director of cell and gene therapy platform R&D strategy, portfolio, and operations at GlaxoSmithKline) offered an insider’s view of a large pharmaceutical company’s approach to investments in CGT. Amid this flurry of interest overall, with exciting clinical data and landmark approvals, questions remain over the cost and complexity of manufacturing, reimbursement challenges, and patient access. Krisha showed how that makes it necessary to define R&D costs and value drivers to enable data-driven decision-making about CGT assets.

Early commercial input is vital for developing a competitive profile to make candidates more competitive, she said. The potential size of commercial opportunity should determine a development strategy (e.g., timeline and budget). A competitive timeline takes a product from lead to launch in five years. “Clinical development plans should minimize the time and cost to a positive efficacy signal through creative trial design,” she suggested. That could include “basket trials” covering multiple indications and simultaneous interrogation of multiple assets in the same indication.

On the manufacturing side, she said that platform processes for chemistry, manufacturing, and controls (CMC) methods and formulations can accelerate development. “Process intensification for viral vectors and automation in cell processing and analytics will reduce overall cost of goods sold (CoGS).” Krishna suggested that shortening cell processes and selecting for healthier, stem-like T cells (for example), could reduce CoGS and even enhance efficacy. She looks for genetic constructs design to enhance drug-safety profiles and provide for outpatient treatment.

Krishna highlighted the importance of good manufacturing practice (GMP) compliance, with early investment in manufacturing and testing as keys to success. “Investment and partnerships for experienced supply chain, logistics, and tracking systems [are] crucial,” she said, as is “creating a deep talent pipeline and strong training program.”

Developing an Eye for Business: Band Loncar (CEO, Loncar Investments) also spoke of such partnerships in “M&A in Biotech and How It Might Affect You.” He highlighted major deals between Gilead Sciences and Kite Pharma, Novartis and Avexis, Astellas and Audentes Therapeutics, Roche and Spark Therapeutics, and Sanofi and Synthorx as ideal case studies to follow. Kimberly Noonan (EVP/CSO/founder, WindMIL Therapeutics) provided her own business case study worth examining in “Fostering Successful Working Relationships: Thinking Commercially in Academic Settings.” Her company’s adoptive cell therapy uses marrow-infiltrating lymphocytes (MILs) for autologous cancer treatments.

Noonan showed a timeline from early MIL studies in an academic setting to the company’s 2016 founding roughly a decade later. She described three primary considerations that mattered along the way:

• including clinicians, scientists, regulatory specialists, and technical specialists on the team
• considering real-world manufacturing and costs in the business strategy
• attracting investment through creative relationship building
• learning about intellectual property (IP) and technology transfer early on.

She also described pitfalls that academics need to be looking out for in their entrepreneurial journeys. These range from institutional competition for support and resources (including grant money) to confusion over IP. Few academics are trained and knowledgeable about the difference between what is publishable science and what is protectable IP. Conflicts of interest can arise over licensing and technology ownership.

Also helpful to many in the bootcamp audience was “Who Are You and Why Should I Care? The Importance of Identity in a Crowded Market,” by Matt Trudeau (vice president of marketing at bluebird bio). Marketing is a concept that is foreign to most scientists and clinicians, as well as technical specialists. But the competition for money, talent, and attention in an increasingly crowded segment such as CGT can be fierce. Trudeau described the difference between brand equity (value as seen through the eyes of customers) and brand identity (the essence of what a brand stands for). The equity comes from high awareness of that perceived value: the words, thoughts, and images associated with a given brand on the market. “A great brand story captures stakeholders’ attention and encourages them to tell a story,” said Trudeau.

Manufacturing
For several years, the main question for CGT developers was whether their therapeutic concepts were “manufacturable.” Could they be made safely at scale, with reproducible quality, and efficiently enough to be affordable both for the companies tasked with making them and the insurers, patients, and other payers expected to buy them? The answer is still unclear: Yes, the technologies are available for scaling up and out — and increasingly so all the time. Yes, the analytics are available for assessing safety and efficacy — again, with improvements ever in progress. But can companies make enough money from these products to stay afloat, and can the market bear the prices they have to charge to do so? The answer to that may depend at least somewhat on technical advancements. And all these are underlying concerns that drove discussions in the manufacturing track at Phacilitate 2020.

Approaches to Project Management: In “Working with CMOs on Closed-System Cell Therapy Manufacturing for Phase 1 Clinical Trials: An Academic Perspective,” Shabnum Patel (process development and manufacturing scientist at Stanford University) provided practical suggestions for academic researchers setting up relationships with contract manufacturing organizations (CMOs). She emphasized identifying knowledge gaps, potential risks, and differences in priorities between such organizations, then establishing an operational infrastructure that can serve to bridge their quality systems approaches.

“Be proactive in addressing concerns on both ends,” she advised. That requires continuous communication and “some level of insight into CMO operations and clinical manufacturing.” A good business/quality agreement will detail these things in writing from the start.

In her case study, Patel showed how necessary changes to the original manufacturing process ultimately required full-scale runs using clinical-grade materials and reagents. So updates had to be made to related CMO documentation — batch record formats, process-flow diagrams, and sampling plans — in addition to rescheduling of personnel.

Stanford University’s own regulatory team was able to file an amendment to the investigational new drug (IND) application with the US Food and Drug Administration (FDA). All this had to happen within timelines (and using both academic and company resources) that could minimize the consequences of clinical manufacturing on patients. Comparability studies were needed both for the cell product and quality control (QC) assays required for testing it.

In “Roles, Responsibilities, and Project Management Concerns,” James Brown (vice president of corporate development at Aldevron) provided the CMO’s perspective on CGT outsourcing. He characterized early discussions in terms of three main questions: How are we going to interact? What are we going to make? How will we execute the project? Statements of work (SoWs) spell out the specifics in service agreements — but Brown cautioned the audience to watch out for IP and access to technologies, to make sure terms and deadlines are defined, and to reserve quality-related concerns for the quality agreement itself. For that, the FDA offers help in the form of a guidance document (1). Issues that can arise with quality agreements can include change control and who controls what, auditing (scheduled and for-cause), consistency and security amid staffing changes, and what constitutes “notification.”

Communication is always important in outsourcing. But Brown highlighted details such as different technologies and software (e.g., groupware, collaboration cloud sites, and project management programs) for staying in touch, expectations for turnaround times and meeting schedules, press releases and public statements, and just knowing who is supposed to do what. He emphasized the importance of regulatory communications as well.

Release specifications should be set before manufacturing even begins, and their specifics should fill in whatever gaps the original proposal left open. In a plasmid-DNA example, Brown showed how these specifications might be categorized as performance, safety, and process related. He also pointed out that technology transfer goes both ways, not just from client to CMO — and that IP, reports, and documents should not be overlooked. Having a sponsor-company “person in plant” at the CMO can help prevent confusion or delays when changes need to be made or approved.

Getting it right the first time (GIRFT) was the focus of Mark Lowdell (director of cellular therapeutics at University College London) in his talk, “GIRFT: Achieving the Balance Between Short-Term Solutions and Long-Term Strategy.” He said that advanced therapeutic medicinal products (ATMPs) will become successful only if they can be cost-effective and deliverable at scale, using technologies that are easy to transfer. To emphasize this point, he highlighted three approved products that have been withdrawn (and one suspended) from the EU market since 2015. “Were these drugs ready for market?” he asked.

Although we refer to advanced therapies as an industry, roughly nine out of 10 cell and gene therapy products in development still are part of investigator-led programs. Physicians do not approach these projects as product development, but rather as specialized treatment approaches to known patients. Quoting Phil Vanek (general manager of cell-therapy technologies at GE Healthcare), Lowdell showed how it would be a mistake to automate current processes fully because “the process today is . . . 2010 technology” that’s “fine for academic centers that handle 5–10 patients per year. But we have to figure out a process for tens of thousands.”

Lowdell said that accelerated approvals for advanced therapies often make the time from phase 1–2 trials to product approval too fast for a good manufacturing process to be developed. Investors push for (and respond to) clinical data, not validation and product characterization studies. Under regulatory guidelines, process validation progress is determined by the stage of product development: By phase 1, mere verification is acceptable — with validation efforts increasing from phase 2 to 3 — and by the time a product achieves market authorization, its manufacturing process should be fully validated. But at the time of application, full data aren’t always yet available.
“Technical challenges for ATMPs are considerable, but solvable,” Lowdell said. Academic developers need to plan early for success, with the principles of process validation in mind:

• Understand the sources of variation.
• Detect the presence and degree of variation.
• Understand its impact on process and product attributes.
• Control variation in a way that is commensurate with its risk.

Ideally, phase 1 products should be made using validatable processes that can become good manufacturing practice (GMP) compliant. Studying the basic biology of cell and gene products should facilitate comparability studies as that process evolves over time. QC assays should be developed and qualified during clinical testing.

Advancing Technologies: In “Scaling Out Using a Digitized Supply Chain,” Obay Alchorbaji (product manager, Werum IT Solutions America) offered a means for managing raw materials and final products, a critical aspect of time-sensitive CGTs. He highlighted the complexity of the supply chain, especially for autologous products, and said that traditional biopharmaceutical IT solutions weren’t up to the task. In a case study of a chimeric antigen receptor (CAR) T-cell therapy, he showed how implementation of a Werum manufacturing execution system (MES) shortened batch-release times from 30 hours to four — primarily by reducing the number of manual entries from over a thousand to less than 200.

In “Implementation of Automated Equipment: Key Considerations,” Patrick Hanley (director of the cellular therapy laboratory at Children’s Research Institute) described how advanced instrumentation gave his group the capability to provide mesenchymal stem cell (MSC) treatments. “Automation literally enabled us to have an MSC program.”

The institute worked with two suppliers — Intellicyte for its iQue system, and Terumo BCT for its Quantum platform — to implement their technologies. Hanley said the partnerships were vital to project success. Another enabling instrument that came up in several talks was the CliniMACS Prodigy system from Miltenyi Biotec.

In “Radically Shortening Process Development and Clinical Translation Timelines for hMSC and EV-Based Products,” Jon Rowley (founder, chief product officer, RoosterBio) also touted the value of automation. He described his company’s goal of radically simplifying production of human MSCs to make it easy to establish new programs, scale up, and translate processes for supplying clinical trials. By banking robustly characterized cells and using microcarriers with automated, single-use bioreactor systems, RoosterBio improved exosome productivity and yields while shortening timelines from seven to 11 years for first-in-human testing down to three to four years.

Pascale Belguise (director of business development at Polyplus Transfection) focused on gene therapies in “Viral Vector Manufacturing: Securing Raw Material Quality and Supply.” Adenoassociated viruses and lentiviruses are the most common vectors for gene delivery, he reported, and new regulatory guidelines are increasing the need for high-quality and sustainable supplies as raw materials for cell and gene therapy products. His company developed its efficient and versatile PEIpro transfection reagent — GMP manufactured through controlled and documented processes — to help fulfill that need. It can be used with both adherent and suspension-adapted cells, and the company is building a new GMP manufacturing facility to support the worldwide demand for this virus-manufacturing raw material.

In “AAV Manufacture and Drug Delivery: Gene Therapy Moving from Small to Large Patient Populations,” Ian Pitfield (VP CMC, Gyroscope Therapeutics) presented a gene-therapy case study for age-related macular degeneration, the leading cause of irreversible blindness in the developed world. First, the small company had to make the basic decision of whether to “go virtual” and outsource all development and manufacturing, build an expensive GMP plant to keep everything in house, or do something between those two extremes. The leadership team chose to keep process development, assay development, and QC in house while outsourcing the manufacturing itself. With technology transfer and scale-up ongoing, the current manufacturing platform is based on suspension cell culture.

Pitfield said that even the process of finding, selecting, and contracting with a CMO can be a substantial investment. His company began screening 16 candidates and chose one of those after a year-long process that involved site visits, requests for proposal (RfPs), and multifunction team reviews and approvals. In the current business environment, he said, it’s worth paying to reserve resources and time early in contract negotiations. And a “person in plant” is crucial to success of scale-up and engineering batch runs. “Do not underestimate timelines,” he said. “There will be delays from starting materials, scale-up data, and scheduling complexities.”

Quality By Design (QbD): Few if any speakers at Phacilitate 2020 brought it up by name, probably at least partly because most cell and gene therapy products remain in early development phases. But some tenets of QbD made their way into manufacturing discussions here. Lowdell’s talk described above is one example. Two other speakers elaborated on the validation theme: Michael Brewer (director and global principal regulatory consultant at Thermo Fisher Scientific) and Shashi Murthy (founder and chief technology officer of Flashworks).

In “Update on Validation Considerations for Rapid Mycoplasma Detection Using qPCR: Regulatory Queries and Responses,” Brewer focused on a specific analytical method. He highlighted recent FDA thinking on mycoplasma testing, which is required for all biologics. Until recently, the only test accepted by regulatory agencies was culture based and took about a month to get results — leading to delays in lot disposition. This became a problem especially for cell and gene therapy products, which suffer from short shelf lives. The test also required specialized expertise to perform using live control organisms, so it often was outsourced to contract testing laboratories at fairly significant expense.

Last year, regulatory agencies began accepting results from nucleic-acid test methods as an alternative to the 28-day culture test for detecting mycoplasma. Brewer highlighted his company’s Applied Biosystems MycoSEQ kit as one example. Based on quantitative polymerase chain reaction (qPCR) analysis, it provides rapid results that enable same-day product lot release: At harvest following cell expansion, spent media can be used for testing.

Murthy gave more of an overview in “Operational and Performance Validation,” using as an example his company’s MicroDEN and EDEN automated systems for generating dendritic cells (both commercialized through a partnership with Corning). He described the difference between a therapeutic manufacturer’s view and a tool provider’s perspective of validation. For the former, it is part of commercial process development, when a process is defined and evaluated for reproducibility. For the latter, it is more about system function and driven by quality-systems thinking. For both, the complexity of the exercise increases with the number of steps and unit operations involved.

At the level of a single unit operation, Murthy explained, considerations related to starting materials, protocols, and pass–fail criteria can affect speed and robustness of product development. He suggested that CGT developers identify a minimum set of critical quality attributes (CQAs) and use them to optimize performance of any new tool or technology using design of experiments (DoE) techniques to compare results with those of an existing standard. Then he showed how platform scalability can help to smooth that process.

Joanne Kurtzberg (director of The Carolinas Cord Blood Bank at Duke University, and president of the Cord Blood Association) took the discussion of CQAs further in “Successfully Establishing In-Process Controls, Product Parameters, and CQAs: A Case Study of the CCBB at Duke.” She leads a public umbilical-cord blood bank with a current inventory of around 45,000 units from nine collection sites. Because they are used in creation of human stem-cell therapies, those units must be collected, handled, and maintained under GMP conditions. Kurtzberg showed how important electronic records management is to that. Banking is a multistep process: from donor recruitment, education, and consent through screening, testing, and qualification; cord-blood collection, processing, cryopreservation, and storage; and thawing, washing, and administration with in-process and release testing primarily focused on stability. Procedures are validated and documented, with results that must conform to specifications, and automated processing has been beneficial even though much of the work must be done by hand. Standard operating procedures are essential.

Finally, Amandine Breton (EU manager of cell therapy operations at Orchard Therapeutics) offered advice on a critical aspect of product characterization to support QbD in “Potency Assay Development: Life-Cycle Approach for Cell and Gene Therapy Products.” The ideal such assay, she explained, reflects a product’s mechanism of action (MoA); predicts its clinical response; provides information on all product constituents; is easy to perform and provides fast read-outs; and can be robust, consistent, and accurate. Product release must be based on established acceptance criteria.

Potency assays are key to all stages of a CGT product’s life cycle. As knowledge and understanding of the product improves over time, that can and should feed back to help fine-tune the potency-testing approach. Such testing is a legal requirement for releasing each batch of a licensed product, and potency is considered to be a CQA for all biologics. Regulators expect defined acceptance criteria to be in place before the start of pivotal clinical trials — and that the method will be validated before submission of a market authorization application. “In early development, however,” Breton said, “defined acceptance criteria — although desirable — are not required for potency testing.”

She went on to show a number of obstacles that CGT developers face in developing potency assays, especially for autologous products: e.g., limitations on MoA and other knowledge, small batches with short shelf lives, product variability, and limited process controls. And she advised a stepwise and continuous effort toward building a fit-for-purpose potency assay. “A steady, continuous improvement of potency-assay development needs to be considered,” she concluded. “Use the increasing product knowledge to support assay development — especially when MoA is not always well defined to start with. Potency is key to controlling the process, to maintaining quality and consistency of a product, and to assessing stability. Consider matrix assays and surrogate assays based on clinical responses.”

Future Trends
What does the future hold for the CGT industry? Where will all the impressive investment take it? And what trends are defining the direction it can go? The answers from speakers in this track pointed to gene therapies, allogeneic approaches, and increasing attention on GMPs and QbD as more products move through the development pipeline. And of course, money will make all the difference as advanced therapies mature.

Manufacturing Trends: Damian Marshall (director of new technologies at the Cell and Gene Therapy Catapult) focused on what artificial intelligence (AI) can do for CGT developers with “In-Process Control and Product Parameter Monitoring.” He highlighted dozens of AI companies in the United Kingdom alone that address “all stages of product development, from biomarker discovery through patient stratification, clinical trials, and patient monitoring.” Because cell and gene therapies are the most complex drugs ever attempted, manufacturing them at high levels of consistency is a challenge, he said, and current equipment in use tends to be “information poor.”

After pointing out how “digital biomanufacturing” is changing biopharmaceutical production, Marshall described how it can enable data-driven decision- making for advanced therapies as well. Self-organizing maps (SOMs), for example, use neural networks to visualize metabolite data graphically — making it possible for process developers to observe gradual changes in the complex metabolism of cultured cells over time. Integrating metabolomics and transcriptomics could lead to real-time process monitoring.

“AI applications are starting to be explored by cell and gene therapy companies,” said Marshall. He pointed to examples such as Oxford Biomedical’s R&D collaboration with Microsoft Research for lentiviral manufacturing; Celixir’s 2018 acquisition of Desktop Genetics for modeling CRISPR-based gene editing; Moorfields Eye Hospital’s work with Google DeepMind on ocular imaging and diagnostics; and bluebird bio’s partnership with Gritstone Oncology for immunotherapy development.

In “A Scalable Lentiviral Vector Process Platform for Early to Late-Phase Development,” Lucas Chan (cofounder and CSO, CellVec) described his company’s R&D services and GMP manufacturing capabilities from vector design through process optimization and production scale-up. He touted a six-month timeline from pilot-scale runs to release of GMP lentiviral vectors.

Gene-therapy technologies were prominent throughout the Phacilitate 2020 program — understandable considering that many cell therapies are also gene therapies. Tony Khoury (vice president of client services at Project Farma) presented on manufacturing experience alongside Greg Gara (vice president of pharmaceutical engineering at Sarepta Therapeutics): “Gene-Therapy Case Study: Using Advanced Therapeutic Manufacturing Playbook.” To decide whether to build its own facility, Sarepta worked with Project Farma on the “make-or-buy” analysis. Khoury and Gara emphasized the importance of a good company infrastructure and quality management system. They highlighted the difference between mere business relationships (short-term associations) and true partnerships (long-term commitments) with key suppliers. And they brought up the engineering axiom of the three-legged stool: Making safe and high-quality products depends on the scope, schedule, and budget of a project. “If you remove one leg, the stool falls over. The key is figuring out which leg is prominent. Projects can have two prominent legs, but never all three at one time.” Risk assessment and management are key.

The aggressive project schedules that come with today’s drive for speed to market make it necessary to make scheduling a priority. When some parts of a project require a zero tolerance for risk, Khoury and Gara advised looking for other areas where some risk is acceptable. “Sometimes putting something in place to get started is good enough. One can always circle back later and optimize.” Sarepta found modular cleanrooms to be a helpful option. Similarly, a phased approach to commissioning and qualification helped to keep things moving. Sarepta recommended following Project Farma’s Advanced Therapy Manufacturing Playbook for these types of projects, an approach that has provided assistance in over a dozen similar facility projects around the world.

Future Therapeutic Directions: Infectious disease may be the next big target for CGTs. Judd Hultquist (assistant professor in the department of medicine at Northwestern University) focused on the human immunodeficiency virus (HIV) in “High-Throughput Gene Editing in Primary Human Cells to Understand HIV,” as did Dimiter Dimitrov (director of the Center for Antibody Therapeutics, CAT, at the University of Pittsburgh) in “Antibody and Cell Therapies for HIV-1.” Hultquist explained that the current antiretroviral approach to treatment is not enough to prevent millions of new infections from arising every year.

“To improve patient health and provide a lasting solution to the HIV epidemic,” he said, “we need to invest in curative and improved therapeutic interventions. They need to account for the host as much as for the pathogen.” Viruses depend on their hosts to replicate and survive, so biologists have spent decades searching for the host genes that are necessary for HIV replication. Hultquist described a high-throughput screening array platform for doing so using the CRISPR-Cas9 system. In a case study, the approach was able to identify 86 genes in primary CD4+ T cells that affected HIV replication significantly — half of which were not previously reported as such.

Dimitrov’s laboratory has found human antibody domain scaffolds to use for constructing large libraries for screening. The team found potent engineered human antibody domains to cancer- and HIV-related proteins — and engineered a single-domain CD4 with potential as a tool for HIV-1 eradication. Next, they developed Fc fusion proteins and CARs with therapeutic potential (both highly effective in mice and monkeys). CAT now is working on new VH, scFV, and Fab libraries as well as new antibodies. And a company called Abound Bio is licensing IP from CAT for developing novel therapeutics.

Other forward-looking therapeutic strategies presented at Phacilitate 2020 included those for inflammation-mediated degenerative disease (Bonghee Lee, Nsage and Ngene Therapeutics chief executive officer) and exosomes (Pete Gagnon, chief scientific officer of BIA Separations). For more on the latter, please see the article by BPI editorial advisor Gagnon in this month’s regular issue.

Allogeneic Cell Therapies: As sponsors of autologous cell therapies learn through experience just how complex an endeavor they’ve attempted to undertake, many companies are turning their attention toward allogeneic approaches instead. Several presenters in the future-trends track had experiences and advice to share.

For example, Chris Gemmiti (vice president of operations at Sentien Biotechnologies) described his company’s work with MSCs in “Ex Vivo Allogeneic MSC Therapy for Treatment of Systemic, Immune-Mediated Inflammation.” He showed how the product candidate SBI-101 treats systemic inflammation in acute organ failure by enabling extended exposure to MSC-secreted factors. “Allogeneic cells are key to meeting on-demand requirements,” he explained. “CoGs allow for significant pricing flexibility.” Clinical data already are supporting the therapeutic hypothesis, and additional acute and chronic indications are under investigation.

In “Scaling Up an Allogeneic Cell Therapy for Commercial Success,” Isaac Erickson (director of bioprocess engineering at DiscGenics) recounted his company’s journey in developing cell-based regenerative therapies for patients with degenerative disease of the spine. Lead candidate IDCT is an allogeneic, homologous, injectable discogenic cell therapy currently under clinical evaluation. From its first patent filing in 2007, the company moved through exploratory research and animal models to the first patients treated with GMP material in 2018 and fast-track designation in 2019.

Key considerations toward commercialization, Erickson said, are GMP compliance, product efficacy, and manufacturing issues (including scale-up). The better the proven clinical efficacy for a product, the higher its reimbursement value will be. But cost-effective manufacturing requires scalable systems, and compliance requires well-understood and documented raw materials, processes, and test methods. Erickson pointed out the value of serialization in tracking CGT materials. He also touted the importance of automation and integration of closed systems in manufacturing.

Sean Kevlahan (senior director of cell and gene therapy at Bio-Techne) echoed some of those points in “Addressing Challenges in Allogeneic Cell Therapy Manufacturing.” After illustrating the general workflow of an allogeneic process — whether it begins with induced pluripotent stem cells (iPSCs), natural killer (NK) cells, or T cells — he described a number of challenges that must be addressed. In scale-up, large culture volumes require more efficient media exchange and more vectors for transfection/transduction. Feeder cells are a common inclusion in small-scale stem-cell cultures and must be removed from the process as the cells get transitioned to serum-free conditions. Kevlahan pointed to the need for flexible and scalable closed-system platforms with efficient and defined expansion conditions compatible with automation. Raw material and supply security are critical, and sensitive quality-control assays are key to success.

Coming Full Circle
As can be expected, the subject of money overshadowed most discussions at Phacilitate 2020, whether the general topic was manufacturing or product development or business. It became clear that investment is key not only to success but also to survival — and that clinical results are major drivers for getting access to financing. Two future-trends presentations brought these considerations full-circle from the plenary session’s overview approach that had kicked off the conference: “The Latest Data on Cell Therapy Clinical Trials: Overview and Trends,” by Frances Verter (president and founder of the Parent’s Guide to Cord Blood and Celltrials organization) and “Financing for Advanced Therapies: Future Trends,” by Greg Bonfiglio (founder and managing partner, Proteus).

Verter introduced an online resource called CellTrials.org and used it to provide an overview of trends in clinical-trial cell types and sponsors. “Only worldwide trials data can reveal global trends,” she said. And the information she shared showed that growth of CGT trials has stabilized to about 740 trials initiated around the world each year. By the third quarter of 2019, over 1,000 trials were under way, and over half of those were in phase 2. Gene therapies and gene-modified cell therapies made up the bulk of products in the regenerative-medicine pipeline (over 3× the number of pure cell therapies, which were themselves over twice the number of tissue therapies). Verter showed that the majority (66%) of those trials are USA-based, but that a significant minority (22%) are proceeding in China, with the remaining 12% divided among the rest of the world.

She also illustrated a major difference between the two main countries: 70% of CGT clinical trials in China are academically driven, whereas 63% of those in the United States are industry-driven. Around the world, she said, the industry dominates in funding immunotherapies. And she highlighted two major growth areas: gene therapies for inherited disorders and the quest for a universal donor to enable allogeneic CAR T-cell therapies.

That brings us back to money — and Bonfiglio’s analysis. He referred to the current funding environment foQr CGTs as “the best of times. Large pools of capital are available. Venture funding is near all-time highs. Public markets are receptive.” And, he said, significant M&A activity reflects that both “big pharma” and the wider biotechnology industries are both fully engaged in this field of endeavor. However, he forecasted “clouds on the horizon” related to manufacturing and pricing, even though advanced therapies have made great progress so far. He pointed to manufacturing as the main near-term concern. “CoGs are too high, and capacity is constrained.” As processes are optimized and allogeneic approaches begin to dominate, it could take a few years for new facilities to come on line. Meanwhile, drug-pricing limitations have bipartisan support in the United States and are already a reality in many other developed nations. CGT companies are exploring the ideas of extended payments and performance-based pricing, but neither idea has fully caught on yet. The ultimate solution is likely to come from both technological and business considerations.

Reference
1 CBER/CDER/CVM. Contract Manufacturing Arrangements for Drugs: Quality Agreements — Guidance for Industry. US Food and Drug Administration: Rockville, MD, November 2016; www.fda.gov/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry.

Cheryl Scott is cofounder and senior technical editor of BioProcess International, part of Informa Connect, PO Box 70, Dexter, OR 97431; 1-646-957-8879; cheryl.scott@informa.com.