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The concept of gene therapy arose initially during the 1960s and early 1970s. Turning that concept into a therapeutic reality has taken a tremendous amount of scientific discovery and pioneering manufacturing efforts. Today, nearly half a century later, gene and cell therapies are slowly beginning to be approved by regulatory bodies for clinical application.
Unlike many other medicinal approaches, cell and gene therapies have the potential to cure a disease. One drawback to a broader application of these novel techniques is the high cost of goods that is partly due to the complexity of manufacturing. A number of different components, including cells, viral vectors, and plasmids, comprise the final cell and gene therapy products. Over time, costs of goods will decrease in a manner similar to other new technologies with additional effort and inventive approaches.
GEN spoke to four thought leaders to get their input on the status of the field, the challenges in manufacturing, and the innovations needed to make a wider array of cell and gene therapies available to address more diseases in larger populations.
GEN: As we learn more about cell and gene therapies, and we see a number of these therapeutics receiving regulatory approval, has the range of targeted indications increased? How large are these patient populations?
Cacia: The field of cell and gene therapies is still in relatively early stages compared to other modalities. Currently, only six cell and gene therapies are approved. A lot of the cumulative industry effort has focused on the use of CAR T cells for oncology indications. Now, many companies are working with hematopoietic stem cells, and, when you add in gene-editing capabilities, new potential therapeutic areas open up, including hematological, neurological, and ocular indications. Luxturna for an ocular indication was the first U.S.-approved gene therapy. This has led to more diversification in terms of patient populations, modalities, and indications. I expect this trend to continue.
Patel: As a field, gene therapy is maturing. The increase in studies across the industry and academia, many of which are targeting broader indications and patient populations, continues to provide valuable insights into the safety and efficacy of gene therapy.
Rocket’s mission is to seek gene therapy cures, and we are the only pure-play gene therapy company with both an ex vivo lentiviral platform and an in vivo AAV platform. We currently have three lentiviral-based gene therapies and one AAV-based gene therapy in clinical development.
Two of our gene therapies are in Phase II pivotal clinical trials and nearing top line data readouts—leukocyte adhesion deficiency type I (LAD-I; this quarter) and Fanconi anemia (FA; Q3). In addition, the four programs represent the first wave of our pipeline, and we are completing IND-enabling studies to bring our second wave of assets to the clinic.
The addressable market across Rocket’s clinical programs is: LVV-Pyruvate Kinase Deficiency (PKD): 3,000 to 8,000 patients (United States, Europe, and Rest of World); FA: 4,000 patients (United States and Europe); LAD-I: Estimated 2,550 patients treatable per year for severe population and up to 100 for potential expansion into moderate population; AAV-Danon Disease: 15,000 to 30,000 patients (United States and Europe).
Chang: As we understand more about genetic diseases, and the promise of advanced therapies to treat them, the industry has become understandably more ambitious. Gene therapies are still an extremely important avenue of investigation for treating rare genetic diseases, and I don’t think that’s likely to change. However, as we understand more about the underlying genetic causes of disease, get better at developing safe but potent viral vectors (or nonviral-based approaches) for gene transfer, at targeting delivery of these vectors to the right cells, and at controlling the expression level of the therapeutic transgene once it arrives, we can more confidently design cell or gene therapies to treat systemic disease, or diseases with a larger patient population.
In the case of cell therapies, CAR T-cell therapies are a wonderful example of this. The initial breakthroughs came from pediatric patients with blood-borne cancers who had exhausted all other treatment options. Now the field has expanded to developing CAR-T and other immune cell–based therapies to not only treat more patients with blood cancers, but also those with solid tumors, significantly expanding the number of patients who may one day benefit from these treatments.
Loggia: Cell and gene therapies are innovative new medicines and have shown the potential to address a wide range of indications. As they are deployed in clinical trials and commercial settings, they continue to show their potential to transform the lives of patients. At Orchard Therapeutics, we have collected data from more than 160 patients across seven different diseases in our current and former programs with over a decade of follow up in the earliest treated. Today, we are utilizing the insights gleaned from these data to apply our hematopoietic stem cell gene therapy platform to more prevalent diseases.
We have shown the ability of using our approach to enable broad distribution of gene-corrected cells and localized delivery of therapeutic enzymes and proteins in the brain. Now, we are exploring this approach to treat genetic subsets of frontotemporal dementia. Similarly, we observed our platform’s potential to correct colitis in a rare disease. We are investigating the same technology and concept for a subset of Crohn’s disease, which affects an estimated 7–10% of all individuals with Crohn’s disease, which is approximately 200,000 patients in the United States and European Union.
By showing clinical proof-of-concept of our approach in various rare diseases, we have the confidence to move into other disease areas in larger populations.
GEN: What vectors are best suited as a delivery mechanism and why?
Loggia: When it comes to gene therapy there are two major approaches—adeno-associated virus and lentivirus vectors. There is no one-size-fits-all approach and it is important to select the vector technology that is best suited for the specific modality and target indication.
Importantly, even within the same technology, there are different ways to define your vector construct. It is very important is to make sure your construct shows a favorable safety profile. At Orchard, we use vectors to modify a person’s own hematopoietic stem cells, which is the end therapeutic product. Autologous cells that are transduced with ex vivo lentiviral vectors are not administering the virus per se as is often the case with AAV therapies.
Patel: For bone marrow–derived diseases, lentiviral vectors are particularly effective because they can easily transduce stem cells and other types of cells in the blood and bone marrow compartments of the body. This delivery into stem cells can occur outside the body, ex vivo, in a lab.
For AAV, selecting the appropriate serotype ultimately comes down to the target tissue. Different AAV serotypes preferentially bind to specific receptors, which enables researchers to utilize specific serotypes to increase the likelihood of successful targeting of particular cell types.
In the case of Rocket’s Danon Disease program, which is the first clinical program in the field to show proof of concept for a gene therapy targeting the heart, AAV9 (which has been shown to have a particular propensity for heart muscle cells) was chosen.
Chang: This is a tricky question because the answer completely depends on the application. Delivery vectors can be viral or nonviral, and different types of viral vectors are commonly used depending on the therapeutic. For example, AAV vectors are often used for in vivo indications, where the goal is long-term transgene expression without integration of the viral DNA into the host genome. This is often considered safer for in vivo applications because there is no risk of insertional mutagenesis from nonspecific integration into host DNA.
On the other hand, lentiviral vectors, which do integrate into the host genome, have an excellent safety record as a gene transfer vector for ex vivo cell therapies, including CAR T-cell therapies. Here, integration into the host genome is a distinct advantage because it brings the potential for persistent expression of the therapeutic gene. Lentiviral vectors have the additional advantages of being able to transduce nondividing cells and to incorporate a larger transgene. Development of nonintegrative lentiviral vectors means that these are increasingly being explored for in vivo applications, too.
Cacia: Lentiviral vectors are commonly used in CAR T cells. They are good because they can carry a large amount of genetic information and have been used to an extent that we are confident they can deliver genes to target locations with good fidelity, although there are some limitations, drawbacks, and safety questions.
AAV vectors are also commonly used. Different serotypes allow you to minimize risk of patient rejection and off-target effects. AAV vectors carry genes with good fidelity, and in some cases, there is less concern about off-target integration. Insertional oncogenesis is a risk we as a field have to be mindful of as we think about our delivery mechanism. The drawback is the carrying capacity. At Graphite Bio, our lead indication is in sickle-cell disease, and AAV is an ideal vector for us to deliver the donor DNA template to correct the single point mutation.
Looking ahead, there is a lot of R&D in nonviral vector delivery, such as lipid nanoparticles (LNPs) to deliver genes to organs. These approaches have their benefits because they can be safe. The complexity comes in getting the integration levels you want for any gene editing or gene correction.
GEN: When using vector-based delivery systems, what are the largest challenges when scaling up from clinical-trial capacity to commercial-scale manufacturing? What is lacking with the current techniques and approaches?
Chang: One of the big challenges for anyone scaling up their viral vector manufacturing is the current reliance on plasmids as an integral part of the manufacturing process. This causes multiple challenges. Plasmid supply is a widely recognized industry bottleneck, frequently causing cell and gene therapy developers supply chain headaches. That’s why we established research to GMP-grade plasmid manufacturing facilities, where we hold stocks of both AAV and lentiviral packaging plasmids ready for immediate shipping, and invested in molecular biology and process development expertise to ensure that we can design, build, and ship custom plasmids as fast as possible—currently within 20 weeks for commercial GMP-grade plasmids.
The other challenges can’t be easily addressed through capacity increases. These include cost of goods; plasmid-based commercial processes are expensive due to the cost of plasmids. In addition, plasmid-based viral vector production hits a scalability limit at around several hundred liters due to the lack of transfection efficiency beyond this scale. Finally, the design of plasmids could significantly impact the yields of viral vector manufacturing as well. Using high-quality, high-performance plasmids in conjunction with extensive process development and standardizing the vector manufacturing platform could mitigate these challenges, but this will always be an inherent challenge of plasmid-based viral vector manufacturing.
Cacia: Cell and gene therapy companies rely on a number of complex materials that have to undergo specific manufacturing processes to suit the desired medicine. Viral vectors and guide RNA plasmids are among the critical components needed to make a gene edited therapy. For the viral vector, this must be manufactured in a GMP-compliant manner, and the manufacturers may be subject to regulatory inspections as part of the licensure process. While the regulatory landscape in cell and gene therapies continues to evolve, we as an industry rely on the manufacturers of these critical components to produce high-quality products in a reliable and reproducible manner.
The manufacturing processes are involved and take time to develop and execute. As suppliers of critical cell and gene therapy components continue to mature, the most successful will be those that combine their deep technical expertise to produce these complex products in a reliable, reproducible, and cost-effective manner, irrespective of where the cGMP regulatory boundaries are ultimately drawn. When you are at commercial scale and treating large numbers of patients, suppliers must be reliable. These are complex processes, and a lot needs to come together. We cannot make our products without their products.
The companies we work with must have deep scientific and technical understanding of their products. Often that expertise is deeper than what the innovator company has internally. This is somewhat unique to cell and gene therapy. For commercial scale, we care a lot about suppliers that are technically competent and have a good track record for producing GMP materials in a reliable way.
We make autologous therapies, so with every patient their cells are their own treatment. The components that go into making the treatment may not be individualized, but the cells that are used come from the patient. At this time, the components and the individualized nature of these treatments result in these therapies costing much more compared to conventional medicines that are mass produced. We also need our suppliers to be cost effective, which will become an increased focus. Over time, as we refine our processes and become more efficient at manufacturing not only the needed gene editing components but also the treatments, we hope to make these individualized therapies widely available to anyone who wants them.
Loggia: This question is close to my heart since I work in the manufacturing field. In the very early stages of development, it is very important to have a process that I define as “fit for purpose” to treat patients in clinical trials. This process needs to be robust enough and have all the characteristics to be able to withstand regulatory review to show safety. Clearly, when you are moving into commercialization to treat larger patient populations, you need to start upgrading manufacturing processes.
One of the bottlenecks is the manufacturing of your viral vector. What we can do as process development experts is to leverage as much as possible processes already available and have been used for years for the manufacturing of other biologic modalities; although some modifications are necessary to adapt them to the particular viral vector. For example, moving from cell adherent to cell suspension processes is the way the industry seems to be going.
When it comes to the actual drug product, it is very important to move from a manual operation to automation. This allows you to process, in limited time, different specific batches for patients. You can achieve scale through automation.
Patel: Vector manufacturing capacity is limited based on factors including the rapid pace of gene therapy research, limited space at CDMOs, and technical expertise required, among other factors.
Rocket’s differentiation is that we have planned our manufacturing thoughtfully from the beginning for both LV and AAV. Our three lentiviral-based gene therapy programs rely on external manufacturing through CDMOs, which minimized time to bring manufacturing online and emphasized speed-to-patient in Rocket’s early years as a company. To manufacture our AAV-based gene therapies, which right now is our largest program in Danon Disease, Rocket previously made the decision to build our own state-of-the-art manufacturing facility in Cranbury, NJ.
GEN: To facilitate delivery of these therapies, and enable them to address more indications and larger patient populations, how can scaleup manufacturing challenges be addressed?
Patel: Building our state-of-the-art manufacturing facility will give us greater control of supply, cost, quality, and timing and facilitate a smoother path toward commercialization. The facility is in the final stages of coming online and will enable in-house manufacturing of our AAV gene therapies to ensure future patients will have reliable access to therapy.
Loggia: We need to deliver processes that can allow us to leverage cell and gene therapies for a large number of diseases to treat as many patients as possible. Besides the viral vector development from cell adherent to suspension culture, we need to start focusing on creating stable cell line producers that would allow us to remove plasmid DNA that are expensive and add an additional step in the process unlike the manufacture of other biologic modalities. This is an area we are focusing on at Orchard and would allow us to reduce manufacturing costs. The other aspect that is extremely important is automation to create significant efficiencies and closed processes, which in turn provide additional adherence to GMP standards.
Orchard works on autologous therapies, so you have to take into account viral vector manufacturing as well as the final manufacturing of your drug product. Ultimately, we modify patient’s cells that will be administered. Safety elements are different than for certain applications of AAV where you are introducing a foreign element.
Cacia: We need to industrialize gene and cell therapy to reach as many patients as possible. If we look at biotech 35 years ago it was at a stage that cell and gene therapies are today, and COGS of the first products were high. Components were difficult to attain, complex to make, and not necessarily GMP-grade. Over time, these costs have decreased significantly.
For example, 35 years ago, a recombinant protein could cost as much as $4,000/g to manufacture and today companies can do it for $50/g because of industrialization-scale and process and cell line optimization. In cell and gene therapy today, we should feel confident that in time we can move toward industrialization, and make our technologies more robust, commercially viable, cost effective, and better in general.
One of the goals of the cell and gene therapy industry is to cure disease. That’s especially true for my company, Graphite Bio. For autologous therapies, one of the features of industrialization will be to make these treatments more predictable and reliable. The patients themselves are the largest source of variability and present a unique challenge to developing a process that will work for all. Each patient comes with their own genotype, phenotype, and disease presentation.
An important element of facilitating treatment with these therapies is the translational science aspect. This requires looking at and capturing the disease state of each patient, and analyzing all that data to hone treatments and ensure they are going to work for each individual.
Chang: Here, I can speak predominantly to the work that we’re doing at WuXi Advanced Therapies. Since reliance on plasmids is the root cause of many of the challenges associated with scaling up viral vector manufacture, we’re implementing novel plasmid-free manufacturing strategies that we’ve developed at OXGENE in the United Kingdom to overcome them.
TESSA technology, which we recently published in Nature Communications, is a method for manufacturing rAAV using gene modified adenoviral vectors. Instead of plasmids, all the genetic elements needed to produce rAAV encoding the gene of interest are integrated into two separate adenoviral vectors. These have been modified so that they can provide all the help necessary for AAV replication but can’t produce adenoviral structural proteins. This results in high yields of infectious rAAV.
At the same manufacturing scale, TESSA technology produces significantly higher yields of more infectious rAAV than plasmid- based manufacturing processes. The exact fold change depends on serotype, but in most cases, the yield is at least 10-fold higher than using standard AAV plasmids. However, the additional scalability advantage is that as well as producing higher yields, TESSA technology doesn’t limit rAAV manufacture to hundreds of liters. In fact, we believe it will be possible to manufacturer AAV at thousands of liters or more using TESSA technology, which will greatly amplify the number of patients that can be treated with a single batch of rAAV.
Meanwhile, for scalable lentiviral production, we are developing lentiviral producer cell lines, which have all the genetic elements needed to produce a gene-of-interest-expressing lentiviral vector stably integrated into the cells’ genome. This system requires nothing more than cell culture and expansion prior to harvesting the lentiviral vectors. Our GFP-expressing cell lines produce similar yields of lentiviral vectors to the transient system prior to any process development, and we expect similarly positive results from a producer cell line we’re currently developing with a therapeutically relevant transgene.
GEN: Ideally, what is needed to advance the future of cell and gene therapy manufacturing to further facilitate the development of cell and gene vector–enabled therapies?
Cacia: I expect innovation to continue in all areas of cell and gene therapy and that will enable better and more effective treatments. For autologous products, we do not have inventory. If a batch goes wrong in manufacturing, a patient does not get their medicine. That weighs heavily on every person involved in that process. We must ensure robustness, and we have to be right the first time, every time. That is the next level of rigor, and to accomplish that, we need innovative approaches.
Cryopreservation is one area of interest. We work with live cells from the patients and need to keep those cells viable to cultivate them. If patients are in geographically diverse locations, we will need to transport the cells to our manufacturing site. Sounds simple, but it is not. In the manufacturing process for our lead product, this involves freezing the cells to increase robustness and reliability. Other key areas for innovation are the technologies involved in gene delivery as well as the equipment used to manufacture the treatments.
For autologous therapies, often the same products used in manufacturing are used in a process development lab because it is the same or similar scale. That is unique. Innovation targets for manufacturing equipment include more automation and recording of data in a cGMP-compliant manner.
Chang: Anything that can improve the quality, speed to clinic or commercialization, and/or cost effectiveness of cell and gene therapies will be positive developments for the field. Technologies like TESSA and the lentiviral-stable producer systems will go a long way toward ultimately making these therapeutics more accessible to patients. Standardizing manufacturing processes and equipment and adopting a platform-base, “plug and play” approach will also reduce manufacturing costs and accelerate manufacturing timelines. Additional vector optimization steps like promoter engineering or custom capsid design that can improve the specificity of transgene expression and/or vector delivery will also improve the quality and safety of the viral vector–based therapeutics we can develop.
Patel: In a future state, the fruits of ongoing and future gene therapy research and approvals will generate standardized approaches to manufacturing at scale in a manner that is cost-effective for all relevant parties.
Loggia: Delivering on the promise of gene therapy requires continuous innovation. When we think about the viral vector manufacturing process, it makes sense to utilize technologies that are out there for other modalities, and we have to move to the next level of innovation, such as stable producer cell lines. There are other approaches that can be used, such as transfection, but for me, the potential to make a substantial difference is our ability to create processes that are more efficient and at scale.
GEN: Many companies outsource their manufacturing development to a CDMO. What key elements do you require in a partnership?
Loggia: The field of cell and gene therapy has created an original need and strategy to build all manufacturing abilities internally. It is a strategic option. I personally believe working closely with CDMOs is a suitable alternative and partnerships remain a relevant and important approach for manufacturing. There are some key elements that make that collaboration a true partnership. For a partnership to be successful and deliver reliably to both clinical trial and commercial patients, it is important to select partners that have the relevant expertise and to establish a strategic collaboration by aligning capabilities and service offerings.
Establishing a strategic collaboration is key at times for co-development, and complimentary abilities can support a faster transfer. But it is also important that you communicate a clear understanding of what you are trying to accomplish, engage your partner on the value of the therapies, and create a level of excitement at the CDMO so they become an extended capability of your company.
Chang: When developers outsource the manufacturing of their cell or gene therapy to a CDMO, they’re placing a huge amount of trust in their manufacturing partner to deliver the best possible version of their groundbreaking new therapeutic. As CEO of a Contract, Testing, Development and Manufacturing Organization (a CTDMO), I can tell you that we do not take that trust lightly. We want to build a relationship with the organizations we partner with that goes beyond purely transactional. This is—in the best-case scenario—a long-term partnership that can span discovery, development, manufacturing, testing, and regulatory support to make sure that every therapeutic we work with has the best possible chance of getting over the finish line of regulatory approval to patient benefit.
To achieve that, it’s important that we listen to what our partners need and pre-build the capacity and capability to meet the need, and are flexible to meet their requirements at different phases of their product development, but also that we can use the lessons we’ve learned through experience, as well as our in-house scientific expertise, to their benefit.
Patel: Rocket manufactures externally through CDMOs in the United States and Europe for our three lentiviral-based gene therapy programs. In these collaborations, we greatly value transparency, timeliness, and, most importantly, quality in the process and product.
Cacia: I think about this in two buckets. Companies can manufacture themselves to enter human clinical studies on a small scale. When you get into later stages of development and treating larger patient populations with higher manufacturing hurdles, you have more cGMP requirements such as process validation and qualification, and developing cGMP QC systems. It can be advantageous, especially for smaller companies, to look for a partner when entering later stages of development in preparation for commercialization. A top priority in the partner selection process is that they have proven capabilities, including a GMP manufacturing inspection history, to ensure a strong compliance record and the ability to work through the global regulatory agencies.
Other critical elements include technical competency such as process development capabilities and the ability to develop and provide strong analytical capabilities for product characterization and QC testing. We must ensure that the products we give to the patients are of the right quality.
For autologous products, we also look at scaling out. The footprint to manufacture for an individual patient is not huge, but you need to scale out to treat dozens or hundreds or thousands of patients. A number of companies have made the investments to realize this need. The companies that we work with must have the wherewithal, resources, and capacity available when we need it. We also look for a high level of service, including adapting manufacturing schedules to meet the variability intrinsic to treating patients with autologous products. We need the suite available and the staff ready to process in alignment with the patient treatment schedule.
COVID taught us the fragility of our global supply chain. Working with reputable CDMOs that have the footprint to purchase materials on our behalf is important to make sure we have the necessary robustness in terms of inventory when we are ready to manufacture.
At the end of the day, if we produce reliably and do it right the first time, then manufacturing will become cost effective. If treatments work to cure in the clinic, we will want to reach as many patients as possible. Our CDMOs and partners need to work on our behalf. Our success is tied to their success; it is a partnership. Making autologous medicines accessible in a cost-effective way is no small feat. CDMO partners are a key piece of the industrialization of cell and gene therapies.
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