Read the related sidebar article, "Optimizing Vectors to Standardize Success," in the Feb. 1, 2023 issue of BioPharm International.
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A slew of late-stage clinical trials is expected to push new regenerative medicines onto the market in the next few years.
Regenerative medicines have the attention of investors, industry players, and regulatory authorities. Prompted by an influx of funding in the regenerative medicines sector, drug developers have jumped forward with clinical development of product candidates. Factors that remain critical to the successful development of regenerative medicines include raw material sourcing and overcoming manufacturing bottlenecks.
Read the related sidebar article, "Optimizing Vectors to Standardize Success," in the Feb. 1, 2023 issue of BioPharm International.
Going into the 2023 year, the biopharmaceutical industry saw 2220 active clinical trials worldwide for regenerative medicines, primarily cell and gene therapy product candidates, and of those, 202 trials are in Phase III (1). These Phase III clinical trials are expected to fuel more regenerative medicine approvals in the next few years, according to Tim Hunt, CEO, Alliance for Regenerative Medicine (ARM) in ARM’s state of the industry address (1).
Hunt further emphasized that the industry saw an 11% growth year-over-year in the number of developers working on cell and gene therapy therapies. This increase brings the total number of cell and gene therapy developers to 1457, currently.
Among the more critical factors in the development of new regenerative medicines, and specifically cell and gene therapies, is the quality of raw materials. Yet, the impact that starting materials have on the end-product quality remains ambiguous in the case of cell and gene therapies.
“To be fair,” says John Lee, senior vice-president, Head of Cell Therapy, Center for Breakthrough Medicines (CBM), “the jury is (mostly) still out on this question. Until the field is able to connect aspects of the manufacturing process to clinical readouts, it will be difficult to truly answer this question with any degree of confidence.”
Lee explains that cell selection is arguably the most important component of these types of therapies, however, since clinical efficacy is “assuredly linked to the therapeutic capacity of the source material,” which he points out the field has learned from lessons taken from the development autologous chimeric antigen receptor-T cell (CAR-T) therapies.
Regarding cell selection—in the case of cell therapies, for instance—autologous cells will have the same concerns as currently exist with FDA-approved CAR-T therapies, such as the fact that patient-to-patient variability will continue to hamper manufacturers’ abilities to standardize processes and define critical process attributes that allow streamlined production of reproducible drug product(s), Lee emphasizes. Allogeneic cells derived from healthy donors, however, offer an ability to bypass many of those concerns via donor screening and the creation of master cell banks, he explains.
“In line with this reality, the identification of ‘super donors’ who can yield cell-based products whose human leukocyte antigen (HLA) phenotype is tolerated by many recipients is an area of active investigation across the field. Likewise, induced pluripotent stem cells (iPSCs) represent an alternative allogeneic option to create a desired cellular phenotype with gene-edits that avoids immunogenic rejection or graft-versus-host response,” Lee states.
According to Randy Yerden, CEO of BioSpherix, a US-based company focused on the design and manufacture of cell culture, processing, and production equipment, the old adage of “bad protoplasm in yields bad protoplasm out” has been seen when starting cells for cell therapies are sourced from patients who have had multiple rounds of cytotoxic therapy in autologous immunotherapies. New strategies for sourcing and storing the patient’s cells before the cytotoxic therapy may improve end product quality and consistency, he notes. Other patient-specific factors, such as age or comorbidities, however, may also adversely affect autologous end-product quality.
In contrast, Yerden explains, a major allure of allogeneic therapies is sourcing starting cells from prime young healthy donors, which are then expanded and banked (i.e., stored) as a uniform, high quality end product, or as an intermediate starting cell for further processing and production. “In either case, if universal histocompatibility can’t be achieved, even a uniform high quality allogeneic end product may exhibit variable safety and efficacy due to patient immune reactivity differences,” Yerden cautions.
“Regardless of the starting cells,” Yerden continues, “innovators in the live cell industry are relentlessly finding and eliminating more and more sources of end-product variability in the production process. For example, one source of variability and end-product quality degradation has been under our noses for decades.” Yerden explains that short fluctuations in the three universal critical cell process parameters (CPPs) of temperature, carbon dioxide (CO2), and oxygen (O2) when cells are taken out of the incubator or bioreactor and exposed to room air are now known to be harmful (2). However, technology exists today that can now eliminate these fluctuations over the entire cell production process (3), he notes.
Sourcing starting material for regenative medicines overall is moderately easier than sourcing starting material for other cell-based therapies, says Lee.The reason being that most regenerative medicines are created from healthy material, he notes.
“While some platforms utilize somatic cells, the majority of products in development are derived from different types of stem cells, including embryonic, iPSC, hematopoietic, mesenchymal, and endothelial progenitor stem cells. Each of these cell types has unique differentiation and proliferation profiles that guide their respective utility for therapeutic usage,” Lee adds.
With 2220 regenerative medicine clinical trials actively in progress worldwide, the types and categories of therapies are broad and varied. Yerden points out, however, that as certain categories prove successful, more and more developers will move into these categories. “For example, with the success of CAR-T cell therapies, there might be more developers focusing on CAR-Ts than most other categories put together,” he states.
As for Lee, he notes that some of the most promising categories of clinical candidates include engineered skin grafts to treat burn patients; customized bone grafts for implants, joint replacements, and injuries; restoration of heart function in cardiomyopathy patients; restoration of muscle function in patients with urinary incontinence, rotator cuff surgery rehabilitation, etc.; restoration of eye function in disorders such as retinitis pigmentosa and/or macular degeneration; grafts to repair tears in connective tissues (i.e., tendons and cartilage); and restoration of kidney function in diabetic patients with chronic kidney disease.
As evidenced by both the number of active clinical trials currently in the industry pipeline and the growth in the number of developers, the advancement of regenerative medicines is progressing well on all fronts.
The successful development of regenerative medicine products has had its own hurdles on the road toward market approval. According to Yerden, the first obstruction happened early, at the time when the regenerative medicines industry first started to form.
Yerden recalls that virtually all discovery and intellectual property (IP) was developed in medical universities, as was the similar path of medical devices and new drugs. Unlike medical devices and drugs, however, there was no pre-existing big industry infrastructure to license the cell-based products. “Big medical device companies usually license and commercialize new devices developed in the universities. Big drug companies usually license and commercialize new drugs developed in the universities. When the first cell therapies were developed, there were no big industrial companies to license and commercialize the new cell therapies,” he explains.
In response to that vacuum in the United States, the US government built, staffed, and supported a handful of good manufacturing practice (GMP)-compliant cleanroom production facilities for cells with therapeutic potential, Yerden states. “They saw the tremendous potential and figured it would be well worth taxpayer money to place these around the country to provide a mechanism for the IP to advance beyond the typical limitations of universities just short of clinical trials. They would enable a pathway further down the development cycle through Phase I and Phase II clinical trials. Shortly thereafter, the big medical universities decided to build their own GMP-compliant cleanrooms for the same reason,” Yerden explains.
Yet, for years, there was no industry infrastructure to license and commercialize the cell products, despite the fact that many were advancing through early stage clinical trials, Yerden continues. A few high profile venture-funded companies were formed. Afew of the big drug companies were starting to dabble in their own skunkworks-style cell development labs.
However, it all changed when a cell therapy started to cure childhood leukemias (CAR-T). Fast forward to present time, and the industry now has a robust infrastructure, Yerden emphasizes.
The second big obstruction occurred when, instead of cell biologists making cell manufacturing decisions, it was a flood of pharmaceutical engineers making these decisions, Yerden adds. “Money was no object. They didn’t understand the significant difference between cells-as-substrate and cells-as-product. A massive amount of money and effort is still getting wasted on legacy biotech manufacturing technologies, which will never be able to produce high quality therapeutic cells. Even today, many manufactured cells are treated without regard to the science of cells,” he states.
For example, Yerden reiterates those fluctuations in the three critical cell process parameters of temperature, O2, and CO2 (universal for all cells) are routinely ignored in steps of production upstream and downstream of the incubation step.Modern science-based closed production technology eliminates these fluctuations, says Yerden, and improves cell quality.
Another example he includes is that most cell production processes in cleanrooms and traditional isolators are dependent on the heavy use of biocides to establish and maintain aseptic conditions; but he cautions that nothing is more dangerous to therapeutic cells than the biocides used for microbial contamination risk mitigation. Modern science-based closed production technologies enable aseptic production without biocides, he points outs.
A third example lays in the fact that large-scale batch production ignores the critical paracrine role in well differentiated, highly functional phenotype and results in poorly differentiated, minimally functioning phenotypes. For this challenge, modern science-based closed production technologies now enable paracrine-friendly small batch production, which can be run in parallel for large scale. Alternatively, new microencapsulation strategies may satisfy the paracrine need and result in better therapeutic cells from big vats, Yerden concludes.
“Tying the manufacturing process to clinical outcomes remains an opportunity for significant growth,” Lee adds. “The identification of critical process parameters (CPPs) and critical quality attributes (CQAs) is essential for the successful en masse establishment of regenerative medicines in the clinic.”
In regards to CPPs, Lee explains that a dedicated focus on identifying CPPs during manufacturing is merited to achieve the goal of consistency between efficacious batches of drug product. “The field is in need of automation that is capable of closing the manufacturing process while also enabling inline testing across a panel of biological readouts. By minimizing manual manipulation, variability within manufacturing can be lessened such that CPPs can be better assessed and identified,” he states.
Through the identification of CPPs, Lee further states, manufacturers can subsequently better understand how those CPPs impact the CQAs of these therapies.
Meanwhile, the absence of CQAs that are directly correlated with patient outcomes is another area that still requires substantial attention, Lee points out. “Because a portion of the manufacturing process literally occurs within the patient, researchers and manufacturers will need to prospectively derive datasets that can be retrospectively analyzed alongside patient outcomes to better define these CQAs,” he notes.
While the field collectively awaits more substantial clinical data, there may be non-human in-vivo models that can help bridge the gap in the interim, Lee posits. However, he cautions that the extraneous limitations of such models (i.e., xenograft-based biology) likely impairs their predictive utility for such applications.
Another area that Lee expects will require additional attention is how the field of regenerative medicines will address questions surrounding product-specific logistics for administration. For instance, some drug products will need to be administered within hours of completion of manufacturing, which creates hurdles around release testing and shipping conditions that must be navigated. Lee says that cryopreservation is a potential solution in some instances, but such a solution comes with other issues, including the maintenance of functionally post-thaw, and ensuring the proper handling of these valuable therapies upon receipt.
1. ARM. 2023 Cell & Gene State of the Industry Briefing. Alliancerm.org/arm-event/sotibriefing. Jan. 9, 2023.
2. BioSpherix Medical. BioSpherix CEO Speaks at Perinatal Stem Cell Society. Youtube.com/BioSpherix. April 17, 2020.
3. Manufacturing Chemist. Modernising Therapeutic Cell Production. Manufacturingchemist.com/Manufacturing. Dec. 9, 2022.
Feliza Mirasol is the science editor for BioPharm International.
Vol. 36, No. 2
When referring to this article, please cite it as Mirasol, F. Robust Development Fuels Drive to Finish Line. BioPharm International 2023, 36 (2), 10–13.