The cell and gene therapy (CGT) landscape has grown significantly in the past year. Between the 24 therapies already approved by the FDA1 and a marked increase in clinical trials, widespread accessibility to precision medicine feels within reach. Lauren Collison, PhD, Senior VP, Operations & Site Head, KBI Biopharma, reflects.
The individual successes within the CGT market are impressive, but this therapeutic class remains unattainable to the vast majority of the world. One example: Zynteglo, a newly approved gene therapy priced at a record-breaking $2.8M2. While there is no silver bullet for increasing the availability of CGTs, improving manufacturing processes that enable their development at scale can help reduce the cost of these treatments and get them to those who need them most.
Repercussions of the Covid-19 pandemic
The idea that the Covid-19 pandemic dramatically affected the CGT supply chain and upturned CGT manufacturing has dominated the conversation in the biotech sector3. In reality, the situation revealed that, before the pandemic, many in the industry failed to plan well. Before 2019, CGT drug developers still had a young, academic mindset, ordering reagents, materials, and equipment haphazardly and assuming they would show up when needed. This approach meant that when the supply chain temporarily shifted due to the global crisis, companies could not get the resources they needed when they needed them.
The lesson taught by this predicament: All parties in CGT development and manufacturing should hold themselves to the highest level of accountability. Planning—without hoarding resources—is everything. Being open to new approaches and tools will ultimately strengthen drug development processes.
Beyond revealing weaknesses in the supply chain, the Covid-19 pandemic taught another transformative lesson: that drug discovery researchers, developers, and contract development and manufacturing organisations (CDMOs) can work remotely and benefit from it. CDMOs that integrate digital solutions into their business processes minimise the amount of hands-on work in their operations. As a result, workflows and review times can be accelerated, improving overall efficiency4.
Without the disruptive force of Covid-19, the field may have adopted these technological approaches more gradually. But now, the increased efficiency is likely making drug development cheaper. So what bottlenecks are making CGT so inaccessible?
Challenges driving CGT costs up
Several factors limit how easily a CGT can be produced, including manufacturing capacity, the complexity of the product, and the ability of those involved to navigate the regulatory landscape. Drug discovery researchers usually partner with a CDMO to provide support through the development, manufacturing, and clinical supply required to bring a drug to market. However, identifying a trusted CDMO that meets their needs can be a struggle for developers.
CGT drug discovery researchers must determine if CDMOs have sufficient process development expertise to develop their drug and the capacity to see it through. Facilities for CGT development require a high level of maintenance, specialised equipment, and a fill/finish facility to produce sterile drug products. Because these companies are proceeding cautiously in opening facilities with enough space, staff, and equipment to accommodate several CGT programs simultaneously, CDMO capacity is at a premium.
Additionally, the complexity of these drugs remains vastly under appreciated. Whereas mature manufacturing systems for biologic drugs start with a consistent source material and use established platform processes, equipment, and analytics, cell therapy development represents just the opposite.
Consider a mature protein therapeutic that’s existed for 30-plus years. Manufacturers have a consistent cell line to start the manufacturing process and reliable platform equipment that varies only based on the scale of their operations. They can manufacture the drug substance and then pass it to a specialised fill-finish facility that will load it into its final sterile packaging.
Conversely, cell therapy manufacturing starts with a highly heterogeneous source material: human blood. Sometimes the blood comes from healthy individuals, but often the blood will be used to make autologous therapies and therefore comes from patients who are very sick, have other co-morbidities, and may be taking medications that interfere with their blood cell levels. Platform processes have not yet been established to develop manufacturing processes for different cell therapies, leaving independent researchers to focus primarily on searching for new, more effective ways to make these drugs. The complexity of the drug production and manufacturing processes drive up cost.
Finally, the complexity and novelty of CGT modalities can make it difficult, if not murky, for developers and CDMOs to navigate the regulatory scene. The diversity between different CGTs creates many challenges as developers seek regulatory approval in a field that, until recently, felt like the Wild West. Now, regulatory agencies are trying to impart knowledge from more mature modalities onto regulatory policies for cell therapies; some fit, and some don’t. While the field is working out these kinks, drug developers must keep pace with a rapidly changing regulatory landscape and seek guidance from experienced CDMOs who can help.
Partnering to overcome drug development bottlenecks
Drug discovery researchers can overcome these bottlenecks by planning carefully, enlisting people with technical, clinical, and regulatory expertise, and partnering with an experienced CDMO. The earlier they start these activities, the better– while there is a small chance that their new therapy will be ready to be used in clinical trials in a year or so, most require multiple years of development. Additionally, developers must be willing to reduce complexity in their manufacturing process as much as possible. Simple processes that draw on numerous materials suppliers are the recipe for robust manufacturing that delivers a high-quality drug every time. At the end of the day, this is what will best help the patients they’re trying to reach.
To set their partnership up for success, developers should approach CDMOs with a clear idea of their desired timeline. At the same time, a CDMO should ask new partners key questions to gauge their goals and priorities. Subsequently, the CDMO should collaborate with researchers to establish a drug development strategy, providing several options that reflect their restrictions and plans. For example, some developers may prioritise developing a drug product as quickly as possible with the knowledge that the manufacturing process or analytical assays may require reworking at a later stage. Other developers may prioritise establishing fully mature processes and analytics over a longer period of time, with the knowledge that once complete, the drug will be ready for rapid succession through clinical trial phases.
A CDMO’s resources can help reduce CGT development costs
CDMOs can help make CGTs more accessible by ensuring that all resources, equipment, and processes they offer increase drug development efficiency.
There have been few recent technological breakthroughs in equipment, so those unafraid to explore new technology platforms will be instrumental in pushing the field forward. CDMOs that prioritise acquiring the best technological platforms not only have better tools to develop new CGTs but are also helping to advance the field as a whole. Because CDMOs forge connections with clients across the drug development sector, they are uniquely positioned to identify and partner with technology manufacturers poised to improve the industry, from large, established organisations to small companies with groundbreaking ideas. The cell therapy field will mature through more mutually beneficial partnerships that pay off for stakeholders and, ultimately, future patients.
CDMOs can further streamline CGT drug development by employing the most sensitive, accurate, and creative new analytics techniques—ideally in-house, where analytics can proceed faster and more efficiently. CDMOs that offer a wide range of analytical techniques are set up to rapidly deliver safe, effective, and consistent products. Over the last two decades, developers have largely relied on analytical tools including flow cytometry, immunoassays (i.e., ELISA, ELISpot), and cytotoxicity assays, single cell and whole genome sequencing, SNP analysis, and rapid sterility methods to characterise cell therapies. New and innovative methods are on the horizon, including residuals analysis using mass spectroscopy, artificial intelligence, and machine learning to find better targeting constructs for genetically modified therapies, and sophisticated cell-based assays for defining cell-cell interactions. In general, this new generation of analytical tools benefits cell therapy development by providing greater functional insight into a CGT product and insight into how to increase yields.
That said, maximum drug production requires sufficient materials. CDMOs that have strengthened their supply chains during the pandemic are well-prepared to maintain efficiency despite challenges. But even when the supply chain is robust, and developers have the resources necessary to produce large volumes of a new drug product, a lack of sufficient blood supply can often limit the development of allogeneic cell therapies. To maximise progress, drug developers need to broaden the networks of blood donors they work with and strengthen their screening process to ensure that they always have a sufficient blood supply. Simultaneously, the average citizen may not fully understand how badly donations are needed and may benefit from awareness programs that convey the importance of donating blood to clinical trials to support the development and manufacturing of medicine. By getting more people on board with this concept, developers can better help humankind.
Improving access will require a concerted effort
To achieve industry success, developers must price a new drug at a level that reflects its medicinal value and the time and resources poured into its development. But as long as the expenses of CGTs remain astronomically high, they remain a last resort for terminal patients with no other options, not the general public. Patients need access to lifesaving medications earlier when they have a better chance of working. So, what are the most promising tactics for increasing public access to CGTs?
Reducing manufacturing costs may help significantly in bringing drug costs down. By collaborating to simplify processes, CDMOs and drug researchers reduce the cost of resources used during manufacturing, minimise waste, and ensure that every batch of drug product is of high quality. At the same time, CDMOs can maximise efficiency and drive the industry forward in two key ways: by sourcing from multiple suppliers throughout the process to strengthen their supply chain and by using the most innovative technologies and analytics tools during the development of any drug.
But this kind of change can’t happen in a bubble. To complement streamlining the manufacturing process, broader strategies reaching additional stakeholders can help bring the vision of more affordable cell and gene therapies to reality. For example, CDMOs, developers, and government agencies may find great benefits in working with insurance companies and providers to reduce drug costs. In parallel, efforts to educate the general public on the importance of donating to clinical trials will help reduce manufacturing limitations caused by limited blood supply.
It has taken a concerted effort to evolve cell and gene therapies into what they are today, and the technology is advancing faster than ever. Continued innovation, process optimisation, and collaboration between stakeholders will give more patients access to these life-changing drugs.
About the author
Lauren Collison is an established scientist and researcher with over 15 years of experience in cellular immunology. Collison is currently the Senior VP of Operations and Site Head at The Woodlands, TX for KBI Biopharma. Prior to joining KBI, she was Director of Immunology at Opexa Therapeutics. Previously, she also worked at St. Jude Children’s Research Hospital where she researched mechanisms of immune regulation. Her work here led to the identification of a novel regulatory T cell cytokine—IL-35. Lauren obtained both her Ph.D. and Bachelor’s degree from the University of Texas at Austin.
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