Cell and gene therapies (CGTs) are poised to revolutionize the landscape of biologic drugs that treat diseases and offer hope in areas where there was previously none. There are 20 FDA-approved CGTs, and this number is expected to grow significantly. Regulators predict that by 2025, they will approve 10 to 20 CGT products a year, based on an assessment of the current pipeline and the clinical success rates of these products. Pharma and biotech companies clearly recognize the potential of CGTs, with 16 out of 20 of the world's largest (by revenue) biopharma companies adding CGT assets to their product portfolios. Valuable insights into what drives progress, to new innovations on the horizon, and the critical challenges that sponsor companies face in developing these treatments were provided by Thomas VanCott, Ph.D., Vice President and Global Head of Product Development, Catalent Cell and Gene therapy. VanCott has over 15 years of experience bringing vaccines and many different therapies from clinical stages to the commercial marketplace, therefore providing a deep understanding of how to successfully navigate the CGT arena.
Q. What are the drivers behind the immense progress in the CGT industry?
VanCott: Advancements in technology is a huge accelerator. Currently, the availability of manufacturing platforms and pathways can move these CGTs from the lab to the clinic in a reasonable time frame. Meanwhile, adeno-associated virus has proved to be a safe and flexible gene-delivery mechanism, and with the emergence of other suitable viral vectors and non-viral delivery methods, there are many viable options out there.
Another significant driver has been the early successes with products such as Kite's Yescarta® and Novartis' Kymriah®. Cell therapy is generating a lot of excitement, and it is not just limited to CART T-cells, but to widely divergent cell types, such as natural killer cells, macrophages and stem cells that are broadening CGT applications.
We have flexibility of viral and non-viral vectors for gene therapies, and different cell types to adapt for cell therapies. We have manufacturing processes in place that can get us into the clinic. Success generates excitement across the board, from scientists, patients and advocacy groups to investors. We have a lot of companies in the space, a lot of investment and a deep pipeline, which is making the future look very promising.
Q. To realize the full potential of CGTs, what do you expect will be some of the greatest challenges along the way?
VanCott: Developing scalable manufacturing processes for CGTs within a reasonable cost is a critical challenge. The public is probably willing to pay more for some of these early therapies, but if these really become a staple in doctors' medical arsenals, we will need to work to get these prices down, and the best way to do that is to have more efficient and more scalable processes.
CGTs are so varied and complex that fully characterizing each product's activity is no trivial matter. Consequently, the development of better analytics will be a formidable challenge for this industry.
A lack of effective preclinical models to predict the safety of CGTs is another challenging area for sponsor companies. Safety issues with CGTs get a lot of attention; we need to strive to develop better models that can predict problems before moving these treatments to patients and commencing clinical trials.
The COVID-19 pandemic exacerbated a major problem for the CGT industry, that of supply chain shortages. We have only limited resources and raw materials, and so keeping your supply chain intact to continue manufacturing has definitely been one of the biggest challenges recently.
Q. What are some innovations shaping the CGT landscape, and what effect may they have on curing diseases?
VanCott: I predict that future innovative therapies will be created using induced pluripotent stem cells. Even though these cells are really difficult to work with, they have almost unlimited applications because they can differentiate into any cell type.
Continued innovation in non-viral gene-delivery methods that will facilitate methods such as tissue-targeting and repeat dosing will propel CGT products forward. There's always been a lot of work in non-viral delivery, but we're seeing an acceleration of that because of the success of the Moderna and Pfizer COVID-19 vaccines that use lipid nanoparticles (LNPs) for effective delivery of mRNA. In fact, without these LNPs, there would be no mRNA vaccines for COVID-19.
Innovations in the field will lead to treatment of other diseases, such as diabetes, Parkinson's and macular degeneration, that affect much larger populations. Historically, CGT has been mostly reserved for treating rare diseases, but I am confident this will change in the near future. Higher-yield CGTs are needed for this to become a reality, and I foresee a surge in allogeneic cell therapies, which could mean having off-the-shelf types of products on the market. In addition, coupling cell therapies with some of these new gene-editing technologies, such as CRISPR/Cas9, you can start to further engineer cells to address countless therapeutic needs.
Data from clinical efficacy and safety of CGTs will unquestionably shape the field. There is great promise that ten years from now, we're going to have many new gene therapy treatments for monogenic diseases and certainly more cell therapies. CGTs are here to stay, and they're going to become an important part of a doctor's arsenal for treating patients.
Q. Any expert advice or words of wisdom?
VanCott: My advice to sponsor companies is to develop more robust processes early on to analyze the critical quality attributes of their products, to formulate their target product profile and to get their manufacturing process commercial-ready all within an earlier time frame. Typically, the development pathway for CGTs is much faster than with more conventional therapies. Instead of taking ten years to develop a product, you're cutting that time in half. Sponsor companies too often underestimate the importance and the time it takes to get the analytics optimized. Spending a significant time at the beginning of the development process to optimize each step and avoid moving forward in a rush with a process that is not rigorous and reproducible is very important.
Seek out CDMO partners that can handle accelerated timelines and give preference to those CDMOs with a fully integrated service offering. In the past, it was pretty standard for sponsor companies to work with a CDMO for the early-stage development, including tech transfer and process development, and maybe clinical Phase 1 and 2, then switch to another CDMO that had the larger-scale capacity and could handle Phase 3 and commercial stages of development. In today's CGT field, you do not have those long timelines, and clients do not have the luxury of switching CDMOs. Successful CDMOs need to offer everything from that initial tech transfer all the way up through commercial production.
Detailed and long-term planning is needed for establishing a reliable supply chain for CGT development. With the COVID-19 pandemic creating a strain on resources, it has not been easy recently to maintain a steady supply chain. However, there is some good news, in that the market will respond to increasing demands. As more companies start producing larger amounts of the needed supplies, and once we get through this initial high demand, there will be more supply making the scarcity of resources a temporary issue. As CGTs become approved for larger indications in the future, the ability of the supply chain to be ramped up, as it was for COVID-19 vaccines, will be a valuable element in the future success of these therapies for the wider population.
To hear from more of the industry's leading CGT specialists, register for the BioPharma Dive webinar, Gene Therapy at a Crossroads: The Challenges and Opportunities Ahead