published 16 Mar 2021 at
written by Amanda Micklus
reproduced with permission
PDF available for download, here
Regenerative medicines have made significant advancements in patient care, especially for rare diseases and small patient populations who no longer have to fear being told there are no other options. Unlike small molecules and even some biologics, cell and gene therapies have a more challenging road to commercialization and success for many reasons, including the nature of the modality – the promise that some therapies are one-time cures – and the price of such therapies – how do you simultaneously enable patients to access these expensive treatments, but also reward developers for innovation and investment in an arduous research process. These are all critical considerations as predictions have put 40-60 product launches in the US and over 500k patients treated by 2030, according to Peter Marks, the director of FDA’s Center for Biologics Evaluation and Research, and global sales forecasted at $13.23bn by 2023, based on estimates from market research agency ResearchAndMarkets.
Arguably, one of the biggest hurdles in getting cell and gene therapies over the finish line to becoming a sustainable modality on the market is manufacturing. One of the key reasons manufacturing has remained an obstacle is because of the rapid pace of development of cell and gene therapies over the last 10-15 years. “Cell and gene therapy in general is going through this transition from, ‘Is it possible? Is it feasible to?,’ to now, ‘How can it how do we do it?’ That is happening across all of the modalities from the AAV field to even CRISPR/Cas editing, both ex vivo and in vivo, to the cell therapies that we may make, both engineered and un-engineered. I think you're seeing across the board that the realization that it's now about how to do it, not can it be done,” Emile Nuwaysir, president and CEO of BlueRock Therapeutics, told In Vivo. Bayer AG acquired BlueRock in August 2019 for $600m, becoming one of Bayer’s bigger investments in the cell and gene therapy field alongside its October 2020 acquisition of Asklepios BioPharmaceutical, Inc. and December 2020 partnership with Atara Biotherapeutics, Inc. Increased dealmaking and investment in this area resulted in Bayer launching a cell and gene therapy platform in December 2020 operating within the big pharma's pharmaceutical division.
In Vivo spoke with Nuwaysir and several other cell and gene therapy manufacturing experts about what they believe are the biggest hurdles for manufacturing in the sector and solutions to those challenges.
Manufacturing has been such a pain point mainly because there was a lack of investment early on in the field, due to wariness about the viability and safety of cell and gene therapies following the death of Jesse Gelsinger, a patient with partial OTC deficiency who received a gene therapy in a clinical trial, in 1999, and cases of leukemia resulting from gene therapy studies in the early 2000s. Even though R&D progressed, manufacturing infrastructure in the sector did not. “Manufacturing technology has lagged so far behind therapeutic development because in the early days of cell therapy, they had a couple clinical trials where patients unfortunately died. And in the early days, the investment community and others got a little bit scared of the potential implications,” Jason C. Foster, the CEO and executive director of Ori Biotech, told In Vivo. Ori was founded in 2015 to provide a bespoke manufacturing platform for cell and gene therapy developers.
In recent years, investment in cell and gene therapy has exploded, with financing for companies in this sector totaling $19.9bn in 2020 according to the Alliance for Regenerative Medicine.
Because of the nature and complexity of these products, cost of goods in cell and gene therapy is extremely high. “The best estimates in the industry is that for the first-generation CAR-T products, cost of goods costs between $150,000 to $200,000 per patient,” said Foster. To reduce this cost, Foster believes the industry needs high throughput, high quality, low cost manufacturing processes, which can be achieved through improvements in automation, robotics and technology.
Cost of goods is central to cell and gene manufacturing, according to Katy Spink, COO and managing partner at Dark Horse Consulting, which specializes in cell and gene therapy products. “It is a near universal issue in my view across the whole field, because the cost of goods of making these things is so high that there's only a business case for the product if it can sustain a pretty high price point,” Spink told In Vivo.
Spink also believes there needs to be automation of manufacturing, and automation in lot release testing for autologous cell therapy manufacturing. “One of the challenges for these patient-specific autologous products is that you have to do individual testing and release of the product for every patient. You don't get to divide that testing cost across the thousands, or tens of thousands of patients per lot the way that you do for traditional small molecule or antibody therapeutics for example.”
Lowering manufacturing costs has a downstream effect on pricing of and access to cell and gene therapies. Enabling and expanding patient access to these medicines will be helped by reducing cost of goods in manufacturing, leading to less expensive methods to make these therapies. The goal is to still allow sponsors to recoup R&D expenses but make medicines affordable for patients. Bringing down cost of goods is also critical if the sector wants to start addressing larger, primary care indications with autologous cell therapy where the value proposition is less extreme. “If we can't figure out how to get cost of goods down, we're just not going to be able to price these therapies at levels that are going to be both affordable and value-based,” said Spink.
Driving down cost of goods could also move cell and gene therapy earlier up in the treatment paradigm, but pricing will still need to validate that investment for a developer, according to Spink. “I'm not advocating for cost-based pricing. I think we're always going to be in a value-based pricing model. But whatever we are pricing the therapy based on value has to have an attractive business proposition for the sponsor.” Spink believes there are certain indications where the value proposition exists to move cell and gene therapy into first-line, but this depends largely on the strength of the safety and efficacy data package.
In the area of gene-modified cell therapies, the shift from autologous to allogeneic has great potential to drive down costs. “Moving to allogeneic allows you to have those economies of scale. You can only eke out so much economy of scale while you’re still in an autologous platform,” said Spink.
Allogeneic therapies have advanced into human testing across a range of oncology indications, and manufacturing experts believe the industry will have a better understanding of the viability of this class soon. “We are reasonably close on [allogeneic]. Actually there are a lot of different approaches being taken – engineering of T cells to make them universal, using gamma delta T cells or NK cells or other approaches – where the underlying immune specificity of the cell is more amenable to an allogeneic approach. I think we've got so many shots on goal right now that are all reasonable from an underlying biology perspective that I'm optimistic that we will get there relatively soon,” Spink stated.
Nuwaysir agrees that availability of allogeneic therapies will make a big impact, and that we should expect to see proof of concept in the near future. “I think [allogeneic therapies] will first be used in places where you don't need stable engraftment, where a transient effect is okay, and the rejection effectively of that therapeutic is okay. BlueRock represents the first in an entirely new category of allogeneic cell therapy where you will see stable engraftment, meaning we've changed the paradigm from a transplant to a biologic. It's one of the biggest sea changes that's happening right now. There's others doing the same sort of thing. I think we'll have the proof point for those in the next few years.”
Centralized manufacturing, in which cells undergo unit operations including genetic engineering at an external location from where the patient is located, is the model for the first generation of autologous cell therapies. There have been reasons for this model, namely to be able to control the process, conducting the process under a quality management system, and having operations and oversight by qualified/skilled personnel.
Centralized manufacturing also increases vein to vein time, though, which is a key consideration for patients who are very sick. “The patients that today have access to some of these therapies are often late-stage, refractory patients. They've failed all the other treatments before, and they've got maybe weeks, not months, to live. And so every day is precious,” said Foster.
Quick View: Cell And Gene Therapy Manufacturing Challenges And Potential Solutions:
Foster believes that decentralized, or distributed, manufacturing is key in solving this the issue. The distributed model can bring manufacturing to the patient and remove variability in the process, but there is a critical need to ensure quality and safety. “You could essentially replicate a centralized model, but in a regional hub and spoke model where it's kind of controlled centrally, but you're just actually delivering the manufacturing process in a remote fashion,” said Foster.
Examples include manufacturing pods that sit outside of certified treatment centers that run on the same hardware and software, instruments, and standardized air handling systems, and are monitored in real time and replicate elements of quality control. They would be pre-built turn-key solutions, according to Foster. “You can then assure the regulator and the people who are interested in these issues that you're delivering the same high quality product, with the same safety profile, no matter where the manufacturing is taking place.” To this end, Ori Biotech has partnerships with G-CON and Germfree Laboratories, which are leading players in the modular cleanroom market.
There are still challenges to a decentralized manufacturing solution, says Spink, due to standardization, ensuring the manufacturing is validated from a regulatory standpoint, and finding physical space for the manufacturing. “It is very difficult to have a truly robust and standardized manufacturing process in a distributed model. And it's not just on the manufacturing, it's also the characterization and release,” says Spink. Instead, Spink believes automation in centralized manufacturing should be fine-tuned first before shifting toward decentralized approaches.
Highly trained and skilled manufacturing professionals are high in demand but low on supply. This is a big concern in the cell and gene therapy sector, especially for early-stage companies that might be inexperienced in the manufacturing component, leading to issues down the road. Yatindra Tirunagari, head of production DSP at Rentschler ATMP Ltd., told In Vivo, “Currently one is witnessing a surge in small and mid-sized drug development companies entering the CGT space and trying to generate phase I, II and III material. While these new entrants may understand the drug, they may not fully understand manufacturing and are inexperienced in CMC requirements, as well as in handling complexities within the projects. This can lead to errors and even ‘small’ errors in this early phase can have ‘huge’ and expensive consequences at a later stage.” In February 2021, Rentschler Biopharma announced it was establishing their ATMP development and manufacturing capabilities at the Cell and Gene Therapy Catapult’s site in Stevenage, UK.
Finding skilled workers is also a concern for niche and early-stage modalities within cell and gene therapy. “There are no pre-trained people in my field. I'm even earlier in development than even the AAV field. So there is none. We effectively have to train that staff for that narrow discipline,” said Nuwaysir.
The solution to this issue is to make a commitment to investing in people, education, and training to find the right operators to staff. “The industry cannot solve [this issue] without investing into education of people. People will not just fall from the sky and not everybody will just be enthusiastic about cell and gene therapy as we are. Investing into people and capabilities, I think personally, is absolutely crucial,” Wolfram Carius, executive vice president and head of Bayer’s Cell & Gene Therapy Unit, told In Vivo.
Tirunagari believes there should be greater partnership between the cell and gene therapy sector and academic institutions. “Talent shortage can only be resolved when academia and industry collaborate and cooperate to this end. Solutions for bridging the talent gap include hands-on training programs for bioprocessing and cell and gene therapy, industry-academia collaborations, and internships or fellowship opportunities to nurture talent.”
Even with qualified and skilled personnel, human intervention can lengthen the time it takes for the genetic programming and the cell expansion steps in autologous cell engineering, and subsequently increases the risk for errors in those steps. According to Foster, this is a big piece of the logistics hurdle that needs to be fixed. Variability is introduced into the process by humans, leading to therapies coming out of specification. “We see a lot of variability because we, as human beings, no matter how skilled we are, introduce variability into manufacturing processes because we just don't do it as reliably as a robot can.”
Foster says the industry needs to remove or reduce human intervention by moving toward automation, not only to improve variability, but also to address the supply issue of experienced manufacturing professionals. “There just aren’t enough of these highly skilled operators that you need. This move to automation has to be done to fill that gap.”
According to Spink, changing manufacturing is a common practice among cell and gene developers. But demonstrating comparability after there are changes to a manufacturing process is a key issue and is closely integrated with other important metrics. “I would tie analytical characterization and measurement of potency as being important, related, and overlapping issues with comparability.”
Problems with comparability have been the cause for many of the setbacks in the cell and gene therapy sector, according to Anthony Davies, founder and CEO at Dark Horse Consulting. “If you look at some of the recent failures and delays, a disproportionate number tracks to asset development, and a disproportionate number of those tracks to potency,” Davies told In Vivo.
To avoid pitfalls with comparability, manufacturing experts who spoke with In Vivo advise planning early on in development to be flexible enough to consider and anticipate future changes to the process. “Begin with the end in mind. Think from day one about what you want your commercial process to look like, plan ahead for future changes you are going to have to make to get there, and make sure that they are ones that will be manageable at that stage of development,” said Spink.
Any type of changes to the manufacturing process should be supported by strong and robust analytics to ensure process changes have not altered the final product, an important consideration not only for the developer, but also for regulators. “When you are dealing with products with complex mechanism mechanisms of action, you have to deal with complex analytical challenges and complex analytical methods,” said Davies.
Spink believes that there will be big developments in analytical technologies. “As our analytical technologies advance, it's going to greatly facilitate that issue. There are things like single cell RNA seq[uencing], for example, that weren't available a decade or so ago that are today, that are still not suitable as validated release assays but that can be used on a product characterization basis to help us think deeply about product comparability.”
Most manufacturing for cell and gene therapies has originated in academic labs, which each have their own processes they have developed at a small scale, or what Foster refers to as their “secret recipe.” Lack of investment in manufacturing has led to processes that end up being difficult to scale for eventual commercialization. “[Academic labs] don't necessarily have the ability or take the time to try to prepare the process for scale. They want to make sure that it's safe for patients, and that it can make it into the clinical trial process. But they're not thinking about hundreds of patients or certainly not thousands of patients at that stage,” said Foster.
Many issues that exist in the cell and gene therapy field currently relate to scalability, according to Tirunagari. “Firstly, separate platform technologies are currently being applied for each individual vector. This obviously translates to added effort and costs. Secondly, one is faced with the challenge of low productivity owing to the very complex nature of the end product. Existing technologies are not yet future proof and transient transfection must be established as a scalable model. Thirdly, limited regulatory guidance and product complexity deepen analytical challenges.”
Spink agrees that scalability has been the core reason for disappointments in the sector. “Many cell and gene therapy products failed – either in late-stage clinically, or just failed to actually be viable commercial products even once they were approved – because they were very academic, unscalable processes, and possibly not reproducible processes as well, that were then sustained throughout development rather than improved because people were so scared to change the process because of concerns about comparability.”
Manufacturing to commercial scale is especially difficult for small biotechs that do not have deep expertise, commitment, and financial resources. “The decision on how to go to the next step, how to manufacture for commercial scale – that’s not something that you can do easily as a standalone biotech. It's not only not easy to finance, but it's also very difficult to staff from an expertise point of view, and to have the vision to do it,” said Nuwaysir.
Addressing the issue of scalability will require marked changes in the industry, stated Tirunagari. “Currently, manufacturing processes are transferred from academia and these are not yet robust for industrial scale up. We need to transform these processes and not just improve them.”
One of the keys to achieving this transformation is through increasing investment in manufacturing at earlier stages to ensure scalability for clinical and commercial manufacturing. This also entails planning for and anticipating changes that may alter the final product. “The process – on the CMC development, on developmentability, on scalability, on manufacturability – determines not only efficiency, but has an impact on safety, and has a clear impact on the quality or reproducibility of a product,” said Carius, who stated that this is a largely different mindset than development of traditional pharmaceuticals. “Thinking through the value chain from the very beginning – thinking about raw materials, of the raw materials of the raw materials, and the impact on the processes as well as the production strategy, the entire part of primary, secondary equipment or even material where you store package freeze – has an extraordinary importance compared to what you classically do in pharma.”
Success in scalability requires a cell and gene therapy developer to have a strong commitment to internal manufacturing. If that is not an option, as Nuwaysir explains, partner with an experienced company that has the resources. “To have the vision to do it, that’s something that’s better suited for a partnership with a little company like BlueRock and a big company like Bayer, who's shown a long history of expertise and commitment in the space…its Bayer providing that other expertise and building that facility with us as the user, helping to direct the specifications. It’s not just about the narrow role of the operator, it's about the entire team,” said Nuwaysir.
In addition to big pharma, there are many advantages for companies to partner with an experienced CDMO, according to Tirunagari. “Working with a CDMO can offer a competitive edge to small and mid-sized companies, for example those that have a limited pipeline catering to rare and ultra-rare diseases. Capacity constraints can be resolved through innovative manufacturing set-up and operations.”
Many companies are working toward addressing key manufacturing challenges in cell and gene therapy with these solutions. Further, long awaited investments in manufacturing have been happening and picking up pace. One clear sign is the uptick in dealmaking activity by cell and gene manufacturers over the last two years. (Also see "Gene Therapy Manufacturers Are Highly Sought Acquisition Targets" - In Vivo, 9 Dec, 2019.) Expanding manufacturing capacity remains an obstacle and is a big driver of these acquisitions. For that reason, consolidation is expected to continue. “I think there will be expansion, there will be carve-outs, there will be buy-outs. From where I sit, it’s increasing, not decreasing,” said Davies.
Nuwaysir agrees there is a capacity crunch that will fuel dealmaking in manufacturing. “For the foreseeable future, as far as we could imagine, demand will outstrip supply. The only question is, is the price the right price for the acquirer? So it makes some acquisitions more or less attractive.”
Some of the largest deals in the cell and gene therapy sector so far in the first quarter of 2021 were for cell and gene therapy manufacturers – Charles River Laboratories International, Inc.'s $875m purchase of Cognate BioServices Inc.; Novasep Holding SAS's €725m sale of Henogen to Thermo Fisher Scientific; and WuXi AppTec Inc.'s completion of a $135m takeover of OXGENE – all positive signs for this industry.