By mid-2022, there were eight cell and gene therapies approved by the U.S. FDA. Six regenerative medicine products were approved globally in 2021 alone — a year in which investments in regenerative medicine developers set a new record, led by gene therapy (including gene editing) and cell-based immuno-oncology (IO) companies (including adoptive cell therapies).1 One new gene therapy product has already been approved in 2022, and four more are up for regulatory decisions this year, along with five other regenerative medicines.2 Eleven companies are expected to file biologics license applications (BLAs) for cell and gene therapy products in 2022, and up to 70 approvals could be issued in the next five to eight years.3 In fact, more than 50 new in vivo and ex vivo cell and gene therapy launches are already planned for the next few years.4
Early data readouts from clinical trials could drive more M&A, financing, and collaborative activities.1 Indeed, the successes achieved with approved gene and gene-modified cell therapies and the potential for these products to cure — rather than just treat — serious conditions have driven significant investment in the sector.
According to Pharma Intelligence, approximately 55% of pipeline candidates are in vivo or gene therapies, and most of the ex vivo investigative therapies (largely chimeric antigen receptor (CAR)-T cell therapies) are autologous.5 It should also be noted that some gene therapies regulate the expression of genes through the delivery of RNA, which can also be in vivo or ex vivo.6
Growing Clinical Trial Space
According to the Alliance for Regenerative Medicine (ARM), there are over 2,400 regenerative medicine clinical trials underway globally, with 1,129 industry-sponsored, 222 of which are in phase III.2 Nearly 1,200 cellular therapies and more than 1,240 gene therapies were at the preclinical development stage in 2021, with an additional 625 and 520, respectively, in clinical studies.4
Slightly more than half of all trials target cancer, with cell-based IO studies representing the largest percentage (41%), half of which target solid tumors.2 Central nervous system (CNS) disorders are the second largest target (6%) for regenerative medicines and include Parkinson’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer’s disease.
Notably, nearly 60% of trials (largely in phase I and II) target prevalent conditions (rather than rare diseases), such as musculoskeletal disorders, diabetes, CNS disorders, and cardiovascular diseases, and several are in phase III, suggesting that approval of a gene therapy for a widespread disease could come in the next few years.2 The top targeted rare diseases include sickle cell disease, hemophilia, retinitis pigmentosa, ALS (a complex, polygenic disease), and thalassemia.
The trial landscape suggests a shift in focus from rare monogenic diseases and liquid tumors to more complex diseases and solid-tumor cancers, as well as more prevalent conditions. Data readouts suggest new opportunities for regenerative medicines.1 Some study results also suggest that gene therapies could be applicable as earlier-line treatments and not just as a last hope. Modification of cells in vivo has potential as well. Additionally, readouts in 2022 will shed light on trials targeting hemophilia, Duchenne muscular dystrophy, diabetes (a stem cell therapy), and more. Early results of the diabetes trial and a trial in AADC deficiency suggest as well that damage may be reversed, thus potentially widening the treatment window.
Thriving Contract Services Sector
Of the nearly 2,500 cell and gene therapy candidates at the preclinical development stage and more than 1,000 in the clinic, many are being developed by startups. These firms need assistance with everything from process and analytical development to manufacturing and regulatory filing, driving demand for outsourcing services. Contract development and manufacturing organizations (CDMOs) are challenged to meet customer needs, given that cell and gene therapies are an emerging treatment area supported by a limited (but growing) body of science that lacks platform manufacturing processes and clear regulatory pathways to approval.7
Some CDMOs are responding with unique service offerings. ElevateBio has startups work at its facilities using its scientific experts. Discovery Labs currently offers traditional fee-for-services CDMO services but also has plans for a business incubator and an accelerator or manufacturing support service in conjunction with an academic partner. BioCentriq operates a clinical production site and training facility on the campus of New Jersey Institute of Technology (NJIT) in Newark and a pilot plant in South Brunswick, New Jersey, where customers come to work onsite. Center for Advanced Biological Innovation and Manufacturing (CABIM), a partnership between FUJIFILM Diosynth Biotechnologies, Cytiva, the Massachusetts Institute of Technology, Harvard University, and Alexandria Real Estate Equities and located in Watertown, Massachusetts, operates as an incubator for cell and gene therapy process development researchers.
Big players in the space include Lonza, WuXi Advanced Therapies, Thermo Fisher Scientific, and Catalent.
A survey of 101 respondents from cell and gene therapy developers in North America and Europe conducted by Industry Standard Research (ISR) in Q3 2021 found that nearly two-thirds (62%) of respondents planned to outsource viral vector manufacturing to CDMOs over the next 18 months, while just under half (46%) intended to outsource plasmid DNA production, with both numbers rising over five years (to 68% and 50%, respectively).8 Allogeneic and autologous cell therapy manufacturing would be outsourced by 33% and 37% of respondents over the next 18 months, both increasing to 42% within the next five years.
Capacity Shortages a Major Challenge
One of the biggest issues facing developers of new gene therapies is the limited availability of manufacturing capacity. The explosive growth of startup companies with candidates at the preclinical stage and the growing numbers of developers reaching commercialization stage have created gaps in capacity and capabilities. The industry growth rate is greater than the rate at which new capacity is being added.9 Wait times for manufacturing suites at CDMOs, for instance, can be as long as 12–18 months.8
A further challenge is the lack of availability of many important raw materials, including plasmid DNA, media, and single-use components and assemblies, as well as the inability of drug makers to easily switch from one supplier to another.
While additional capacity is needed across the supply chain, other steps must be taken to address the capacity shortage, including the development of more efficient manufacturing processes that can be readily and cost-effectively scaled up rather than out.9 Finding a mechanism for allowing bridging between materials and SU components that do not impact efficacy, dosing, or product identity is another. Certainly, collaboration between drug developers, CDMOs, and regulatory agencies is needed. Even so, it is likely that capacity will remain limited for the next several years.
Manufacturing Efficiency Issues
Manufacturing issues for cell and gene therapies are a top concern for the FDA. Processes are complex. The BLA for Luxturna was nearly 60,000 pages long, with most of the information related to manufacturing,10 and 80% of FDA review times for gene therapies are spent on manufacturing and quality issues.11
The first major development that is needed is widespread access to fully closed and automated manufacturing solutions, which will afford greater robustness with reduced labor requirements and lower risk of batch failures due to human error. Standardization of manufacturing platforms is also needed, but that will first require more advances in technology, ideally through collaborative efforts between suppliers and drug developers. Overall, cell and gene therapy developers need to shift from a first-to-clinic-at-all-cost mentality to a right-first-time philosophy in order to ensure the development of optimum manufacturing processes and product formulations from the outset.
First steps have been taken toward templating parts of the upstream and downstream production processes for cell and gene therapies. Closed and automated units have been introduced for cell therapy manufacturing, for instance, while fixed-bed bioreactor technology is improving the scalability of adherent viral vector production. In addition, fit-for-purpose plasmid and transfection reagents are improving vector yields, while tailored filtration and separation materials are boosting the performance of downstream purification steps. Autologous therapy developers are also exploring more compact and efficient approaches for scaling out, rather than simply running many entire processes in parallel.
Rapid Analytical Testing Capabilities Essential
Raw material release, in-process and final product release, and biosafety testing can all be complicated for cell and gene therapies and currently involve advanced cell-based methods, typically with long turnaround times (up to 60 days). Streamlining testing methods and processes while still ensuring sufficient sensitivity, precision, and consistency will be essential. Doing so can be achieved by implementing automated solutions and converting cell- and cultivation-based assays to rapid alternatives, such as quantitative polymerase chain reaction (qPCR)-based methods.
Application of such advanced analytical technologies that can be used through the development cycle from preclinical to commercial is needed to help reduce time to market. Sensitive, rapid, and accurate methods can provide more valuable data to enable informed decision-making earlier in development, allowing drug developers to halt questionable projects and focus on candidates with a high likelihood of success.
Viral Vector Focus
Many different carriers have been used as delivery vehicles for genetic material, such as DNA nanoparticles, naked DNA, liposomes (DNA and cationic), polyplexes, and non-viral solutions, but viral vectors are most widely used. Lentiviral vectors (LV) are currently used for ex vivo transduction of cells. They can carry large genes, but because they are so large, they are attacked by the immune system so have not yet been developed for direct gene delivery. Adeno-associated viral (AAV) are smaller, making them ideal for in vivo treatments. However, they are not integrated, so the longevity of these therapies is not yet known, but subsequent treatments have generated strong immune responses.
Improvement of LV vectors may be achieved by developing other envelopes beyond the widely used VSVG envelope to reduce the immune response. There is also work underway on AAV vectors to enable multiple administrations. One company working in this area is Chameleon Biosciences with its EVADER™ next-generation, AAV-based technology. Some researchers are investigating completely different viruses, such as foamy viruses and bocavirus as a vector platform.9
There are safety concerns with the use of viruses as delivery vehicles, and some of the failures of recent clinical trials have been due to safety issues, particularly for AAV vectors. Significant attention is therefore also being paid to the development of nonviral delivery technologies that eliminate the safety concerns associated with viral vectors. Examples include injection of naked DNA, electroporation, sonoporation, magnetofection, and the use of oligonucleotides, lipoplexes, dendrimers, or inorganic nanoparticles, which may also be more amenable to large-scale production.12 Most of these approaches exhibit lower transfection efficiencies, but progress is being achieved.
CMC and Regulatory Challenges
One of the key challenges facing cell and gene therapy developers is the lack of clarity on regulatory pathways, particularly around chemistry, manufacturing, and controls (CMC) requirements.1 Much of these issues relate to the nascent nature of the sector. There are frameworks for approval of advanced therapy medicinal products in Europe, the United States, and other nations. The FDA also implemented the accelerated regenerative medicine advanced therapy (RMAT) designation in 2016. Regulatory agencies have and continue to work with researchers in academia and industry to understand the best approaches for evaluating safety and efficacy of these novel medicines.
Much has been learned through the approval processes for products on the market, and additional formal and informal guidelines have been issued.9 Rapid evolution within the cell and gene therapy field, however, requires constant updating of regulatory requirements, and continued collaboration between industry and regulatory authorities is essential to enable further development of safety and effective cell and gene therapies.
Industry is keeping a close eye on the Cures 2.0 Act (H.R. 6000) introduced by Reps. Diana DeGette (D-Colo.) and Fred Upton (R-Mich.) in November 2021, which could provide more clarity on CMC requirements.
Limited Availability of Talent
In addition to limited physical capacity, the rapid growth of the cell and gene therapy field has resulted in elevated demand for workers with the requisite talent and skills. Given that companies in this sector have been established in a few centralized locations, there is fierce competition for people with relevant experience and expertise.9 Developers of cell and gene therapies must hire appropriate people and invest in their training. New entrants should consider newer locales with improved talent markets. Governments on all levels should fund educational programs at universities and institutes that will provide a workforce with skills needed to support cell and gene therapy development and manufacturing.
Need to Reduce Costs
There is no question that the very high cost of cell and gene therapies is limiting access to patients in need because they are not affordable for most patients. Adoptive cell therapies are introduced with prices in the $400,000-$500,000 range, while direct gene therapy prices have been more than $2 million per dose. Reducing their costs is paramount to the continued success of the field, including manufacturing, distribution, and indirect costs related to patient care.
The cost of goods for manufacturing a gene therapy (not including R&D, clinical trials, and infrastructure-related costs) ranges from $500,000 to $1 million.13 Part of the reason is that developers do not always take time to optimize processes in the race to get to market, leading to lower yields and potency.14 Costs for plasmid DNA and other raw materials are also climbing. Capacity shortages are another contributor.
Right now, manufacturing of viral vectors for use in gene and gene-modified cell therapies presents one of the biggest issues. There is still a significant need to boost production efficiencies and improve yields in order to achieve a truly cost-effective supply of viral vectors in the quantities needed to enable the commercialization of the candidates in the pipeline.
For autologous cell therapies, the main manufacturing challenge relates to scaling of processes. Scaling out assures that no cross-contamination or crossover occurs between batches within the same manufacturing site. It is also essential to ensure that the chain of identity is maintained throughout the entire manufacturing process. Cell therapy developers are actively working to develop allogeneic, off-the-shelf versions of patient-specific products to eliminate the logistics issues associated with autologous therapies.
The lack of proper infrastructure within the healthcare system and the indirect costs of treatment must also be addressed. Existing systems are designed for the delivery of conventional small molecule drugs and biologics and therefore do not meet the different needs of cell and gene therapies.15,16 In fact, the second largest contributor to the cost of gene and gene-modified cell therapies is hospital services, which can be quite high for patients that experience strong side effects.17 Other ancillary costs include bridging therapies before treatment, travel costs for the patient, out-of-pocket costs for family members, and regulatory requirements for long-term follow-up for up to 15 years.18
Better therapeutic designs will be needed as well; increased specificity with a concomitant reduction in serious side effects would contribute to lower costs.
It is comforting to realize that monoclonal antibodies today have manufacturing costs of just a few dollars per gram, which is much lower than the more than $30,000 per gram for the first few mAbs bought to market.19 Similar progress will be made with cell and gene therapies, and the costs of manufacturing gene and adoptive cell therapies will eventually be reduced to a sustainable level.
Policy and Reimbursement Hurdles
With their curative potential after one or a limited number of treatments and high prices, cell and gene therapies present a new approach to medicine for which current reimbursement models are not suited.2 Manufacturing efficiency and logistics complexities will be addressed, and innovation in therapeutic design will continue to afford ever more safe and effective treatments. Reimbursement challenge may well be the greatest impediment to the continued success of cell and gene therapies.1 Barriers to innovative payment models must be removed. A shift from cost-based to value-based pricing will also be essential.3
Transformative Treatments for Patients and the Pharma Industry
In 2021, the value of the global cell and gene therapy market was approximately $5 billion.26,27 It is projected to expand at a compound annual growth rate of nearly 40% to reach $36.92 billion by 2027.27 The excitement generated by gene and cell therapies is warranted. The technology has the potential to be transformative for countless patients.
However, emerging safety issues must be resolved and new technologies and solutions implemented to dramatically reduce the cost of gene and adoptive cell therapies. Rapid introduction of gene therapies to the market requires the development of facilities; supply chains; novel, efficient, and robust manufacturing and analytical technologies; and a well-defined global regulatory framework.
All members of the value chain are committed to overcoming the hurdles facing cell and gene therapies, and the sector has made tremendous progress toward meeting these development needs. In addition, significant advances have been made in therapeutic designs. New viral-vector and non-viral delivery solutions are not the only therapies to show promise. Next-generation CAR-T, CAR-NK (natural killer), and CAR-M (macrophage) therapies are in development that are safer and better able to attack both liquid and solid tumors.20 Gamma delta (γδ) T cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR) therapies also show potential to overcome the limitations of first-generation CAR-T therapies.
New technologies for 3D cell growth,21 whole ecosystems to support the development of cell therapies based on mesenchymal stem cells (MECs), including gene-edited cells and extracellular vesicles, such as exosomes22-24 and solutions enabling the use of iPSCs,25 are additional examples of important developments. Gene therapies based on gene editing using CRISPR and other editing technologies are also advancing in the clinic.1,2
Collaboration between all stakeholders — raw material and equipment suppliers, contract manufacturers, drug developers, regulators, physicians, healthcare institutions, patient advocate organizations, patients, and caregivers — will be essential to rapidly developing and deploying these technologies and solutions. If the pharmaceutical industry’s history of innovation is any indication, solutions will be found and not only will people suffering from rare genetic diseases have new hope, but patients with all types of cancer and cardiac diseases and those diagnosed with Alzheimer’s, diabetes, and other challenging disorders could benefit from novel regenerative medicines.
