Gene and Cell Therapy Commercialization Advances, Challenges, and the Path to Success

September 23, 2024

Cell and gene therapy appear poised to revolutionize drug and vaccine discovery, with the potential to address diseases that have been untouchable, and treat others with more successful therapies. But the road to success has been rocky, and many obstacles remain for both gene and cell therapy commercialization.

Challenges in Gene and Cell therapy commercialization

A Look Back

Therapeutic Targets

Gene therapy involves the replacement, insertion, editing and or deletion of a gene that is either non functioning or expressing pathological proteins, while cell therapy involves the insertion/replacement of cells that can treat or possibly prevent disease.  As of August 2024, the US Food and Drug Administration (FDA) listed 38 approved cell and gene therapies—more than double from 2023. Eight of those are umbilical cord blood-based therapies, another eight treat cancers, while other treatments are for severe hemophilia A and B, type 1 diabetes, sickle cell disease, beta-thalassemia, Duchenne muscular dystrophy, wound healing and knee cartilage defects. Another subset treats a range of rare diseases, including leukodystrophy, congenital athymia, nasolabial fold wrinkles and spinal muscular atrophy. Most cell and gene therapies for more common diseases are designed for patients who have not responded to other therapies or have specific mutations that exacerbate their disorders.

Advancements in R&D

Gene therapy effectively began in the 1970s with the introduction of recombinant DNA research and its potential for therapies. At the same time, advances in engineering retroviruses for gene transfer and autologous cell transfer research helped set the stage for advances in gene and cell therapies. Early gene therapies were largely aimed at single-gene disorders, such as SCID (severe combined immunodeficiency disorders). In the 1990s, the development of DNA vaccines showed the usefulness of genetic modification in the design of more efficient immunogens and vaccines. The 1999 death of 18-year-old Jesse Gelsinger during a clinical trial of an adenoviral vector carrying the ornithine decarboxylase gene was a turning point in gene therapy research, halting clinical trials temporarily but forcing a re-evaluation of how trials were conducted. On the cell therapy side, the 2008 announcement of the derivation of human induced pluripotent stem cells opened the door to designing specific cellular therapies with stem cells. These basic science and early clinical studies have paved the way for a virtual explosion in pre-clinical and clinical trials—currently, more than 2,000 gene therapy products (including CAR-T cell therapies, pluripotent stem cells and genetically modified cells) in development and more than 3,000 in pre-clinical research and development. The types of diseases targeted have also expanded from rare and single-gene disorders to complex diseases including cancers.

Challenges Remain

While gene and cell therapies have taken giant steps forward even in the last 10 or 20 years, significant R&D challenges remain. Transitioning from a “proof-of-concept” stage to long-term strategies in product development have unveiled the need for introducing safety factors and product quality processes that must be included in development, from the bench through chemistry, manufacturing and control, and on to clinical development. Clinical data analysis, risk-benefit studies, and collection of real patient outcomes will ultimately show patterns and principles of gene and cell therapies that can be applied across the industry. Standardization of these processes will also help propel the field beyond rare indications and refractive diseases. The delivery of therapeutic genes (and often cells) to targets remains a research challenge, to maximize efficacy and minimize off-target effects. Researchers that have relied on adeno-associated viruses (AAV) and lentiviruses are starting to look at other vectors, including mRNA.

Moving from laboratory to clinic also reveals gaps in our knowledge that need to be filled. Speed to market is imperative for cell and gene therapy companies. But markets in this area are so far very different from small molecule, or even monoclonal antibody therapies. For gene and cell therapies, their target diseases have very small patient populations. These therapies can be dramatically curative, but the tiny markets will likely not support multiple competitors, and even single manufacturers will struggle to stay economically healthy. Scalability is also an issue as a therapy moves from research into actual product production.

Manufacturing Hurdles

Overcoming Cost Hurdles

Cell and gene therapies constitute some of the most expensive therapies on the market, some costing millions of dollars per dose. While many therapies only require one dose, million-dollar therapies remain out of reach for most people, and even payors such as Medicare, Medicaid or private insurance. Where do these high costs arise? They start with the complexity of developing such treatments, but the process of applying these therapies is long, often taking weeks to complete. Simpler in vivo treatments are still costly, requiring multiple steps, engineering viruses and processing and creating synthetic genetic materials. Vector design, process optimization and improving cell production systems (for both gene and cell therapies) are not standardized, lack automation and so far, are resisting scale up. This all contributes heavily to costs.

More Reliable Processes

Reducing these costs will involve taking strategies already in place with small-molecule and established biological therapies: automation, footprint reduction, automated quality control. Fully understanding the biology of the therapy in the beginning will also help with scaling up, allowing manufacturers to identify challenges to scaling up cell function, integrating analytics, and connecting to data management. Ensure the purity and efficacy of viral and other vectors and making all processes more transparent and reliable will also help overcoming current cost issues. New innovations that specifically address making biological processes more efficient will help manage costs, as well.

Scalability Challenges

Scalability is a key obstacle to cost-effective, successful cell and gene therapies. Much of the manufacturing process (unlike small-molecule therapeutics) still involves manual labor, which adds significant time and expense. In addition, adherent systems (as opposed to cells in suspension) are a significant obstacle to high batch yields. Mass manufacturing tools that provide more automation and smaller footprints at every step of the process—from fermentation to fill and finish and QC—are needed to boost productivity. Switching from autologous treatments to off-the-shelf products will also decrease costs. Larger volume stirred tank reactors can also help boost scale.

Enhancing Vector Purity

Gene and cell therapies present purity issues, due to the manual nature of processing and the fact that there is not yet a “one way to rule them all” approach to developing these new therapeutics. Regulatory expectations have increased on product purity, with the FDA and USP requiring that final products be nearly free of aggregates, and other contaminants. Vector manufacturing is still using different production systems and downstream processes. Current improvement methods include using serotype-specific tissue tropism or modifying surface proteins to make cell targeting more precise. This can also reduce the dosage needed per patient, in turn lowering costs.

The ability to purify cell therapies and gene therapies in a rapid, automated fashion is another challenge. Unlike traditional methods that cannot tell cells apart from protein aggregates or harm-causing particles, Aura CL® is the first system that can identify them quickly while providing all required cytometric capabilities—counting cells, identifying types, and measuring viability in one simple assay. For gene therapies, Halo’s Aura® GT is the first and only system designed to detect, count, and characterize AAV particles and aggregates with just 5 µL. Combining Backgrounded Membrane Imaging (BMI) with Fluorescence Membrane Microscopy (FMM) multi-channel technology, you can now make confident decisions earlier, so you are one step closer to success.

Automation in the Digital Era

For much of this, automation is key. Removing the errors, time and labor involved in manual processes can significantly reduce the processing materials needed and bring down costs, just as they have in other sectors of the pharmaceutical industry. Instruments like the Halo Labs’ Aura CL and GT help automate the process of characterizing particle presence and formation in cells and gene therapies, by incorporating automated sampling processes as well as data management.

Capacity and Workforce Shortages

The capacity shortage for cell and gene therapies is acute—it is estimated there is currently a shortage of 500 percent in capacity for manufacturing. This is due to increasing demand in the face of current scalability and process obstacles. New facilities and expansion of existing plants help meet demand, while larger companies are turning to in-house manufacturing. Smaller companies, meanwhile, can turn to contract development and manufacturing organizations (CDMOs), which can handle practically every aspect of development, from pre-clinical development, through clinical trials all the way to final manufacturing and even distribution, in some cases.

Finding trained workers is also a challenge. Positions in quality control, analytical development, and manufacturing are considered the most difficult to fill. Education needs to be expanded, to include universities and academic institutions, in particular more training curricula in addition to traditional basic science. It will be more necessary to institute formal training and move away from the “on the job” training common among current manufacturers.

Current Regulations

Regulatory agencies—the US FDA, in particular—are gearing up to meet the increased pipeline of gene and cell therapies. The FDA’s new Office of Therapeutic Products was set up in 2023 at the agency’s Center for Biologics Evaluation and Research (CBER).  The FDA has set up Breakthrough Therapy Designations, Regenerative Medicine Advanced Therapy Designations and Priority Review to address the unique properties and issues around cell and gene therapies, especially those that address rare diseases and/or have an “n of one.” These may bypass the traditional reviews of chemistry, manufacturing and controls (CMC).

Ensuring Long-Term Success: Business Sustainability and Affordability

What Does the Future of Gene/Cell Thearpy Commercialization Look Like?

It’s uncertain that the current business model of gene and cell therapy—very expensive, minimal dose treatments for rare diseases—will last. This model raises questions about how much revenue companies will be able to gain from developing and delivering these treatments. However, moving into treating more common diseases like cancer, diabetes or even sickle cell and beta thalassemia could result in more profitable models, while still reserving space for rare disease treatments. More clinical trials and developing diagnostic tools will also be necessary for expanding the industry. Meanwhile, developers are looking at different price models to help make their therapies more affordable. Value-based agreements with insurance and other payers, partnerships and novel funding models are all on the table.

Key Challenges of Gene Therapies

Currently, more than 2,000 gene and cell therapies are in clinical trials, with another 3,000 in pre-clinical development. As therapies aim toward more common diseases such as cancer, the number of trials for these therapies will only grow faster. Currently, moving from clinical testing to regulatory approval at least appears to be the same process as other therapies (three stages of clinical trials, followed by New Drug Applications to the FDA). However, the FDA (and, somewhat, its counterpart organizations in Europe and Asia) is looking at breakthrough designations, and other fast track processes to account for the orphan status of many of these therapies, and the fact that clinical trials for these therapies do not—and cannot—include as many participants as traditional drugs.

Getting Gene Therapies Paid For

Scalability challenges, the long, slow process of completing a round of patient therapies and the complexity of development all add up to a lag in commercial success of gene and cell therapies—simply put, they take a long time to develop and they are too costly to implement, even after regulatory approval. Insurers are also reluctant to reimburse health care providers for these therapies, at least so far.

Getting Treatments to Patients

The more expensive a drug, the less available it will be. People in developing countries would not be able to afford the price tag of drugs that treat diseases like beta-thalassemia or sickle cell disease, for example. Even poorer areas of industrialized countries like in North America and Western Europe would not have access, and many areas would not have the specialized medical expertise necessary to deliver these therapies. However, more innovation in streamlining processes could go a long way toward bringing prices down and making therapy delivery easier. Moving to off-the-shelf treatments (from customized autologous treatments) will also boost access.

For cell therapies, which are significantly more perishable and less stable than other large molecule therapeutics, delivering drugs right off the manufacturing line directly to patients for administration without delay is critical. Having decentralized manufacturing and logistics of these types of therapies would increase the success of treatment to patients.

 

 

 

The rate of manufacturing failure in cell therapy appears to range from 1 to 13 percent, which can be quite high compared to small molecule manufacturing. However, this is largely due to the great variety of manufacturing techniques, the use of autologous therapies that defy standardized, scaled up processing and even the definition of “out of specification” properties with CAR-T and other such therapies. Still, other therapies have seen success rates of about 5 percent. 

Current barriers are the complexity of developing and delivering these therapies, and their extremely high cost of development. Also, the time needed for therapy delivery presents obstacles, as does the need for specialized laboratories to create autologous treatments. The current commercial model of pharmaceutical firms—blockbuster drugs manufactured in high volumes—is not the right match for one-time treatment therapies, often for rare disorders. 

Demand for cell and gene therapy is high, and growing. Many of these therapies have been designed to treat rare and ultra rare diseases for which there is no existing treatment, and which can be devastating if not fatal to patients. Currently, 2,000 drugs are undergoing clinical trials, with another 3,000 in pre-clinical testing. Many startup companies are also entering the industry, with the possibility of developing a new therapy on their own, as well as possibly partnering with a larger-capacity pharmaceutical firm. 

The cell therapy market is growing quickly. Estimates are that the market will reach more than $32 billion by 2033, with an annual growth rate of about 18 percent. Much of that growth will come from therapies in oncology and cardiovascular diseases. For the moment, autologous therapies dominate with about 90 percent of the market, but that may change over the years. While this is a promising revenue stream, there are headwinds that could eat into earnings, including the capital and labor costs of developing and delivering therapies, interest rates, and geopolitical stability of supply chains for raw materials and instrumentation. 

REFERENCES

External References

https://www.asgct.org/about/timeline-history

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296588/

https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products

https://www.nhlbi.nih.gov/health/genetic-therapies/benefits-risks#:~:text=In%20the%20future%2C%20genetic%20therapies,thalassemia%2C%20and%20sickle%20cell%20disease.

Footnotes: 

Gene Therapies Require Advanced Capabilities to Succeed

Wu, G. Cell and bene therapy manufacturing: the next generation of startups. BioPharma Dive.

Gene Therapies Getting Approved, But Major Challenges Remain

Cohen, J. Cell and gene therapies face persistent manufacturing capacity constraints. Forbes.

Capra, E. et al. Viral-vector therapies at scale: Today’s challenges and future opportunities. McKinsey and Company.

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