In 1949, Dr Linus Pauling coined the term molecular disease when describing sickle cell anemia in a landmark paper published in Science. Using electrophoresis, Dr Pauling and colleagues demonstrated that sickle cell anemia was caused by an abnormal form of hemoglobin. The results were revolutionary. Even before publishing the paper, newspapers heralded this discovery as the key to cancer research.
More than 70 years after Dr Pauling’s breakthrough, sickle cell disease is at the center of another area of medicine: gene and cell therapy. Approximately 100,000 patients in the United States are affected by sickle cell disease, with 1 of every 365 African Americans and 1 of every 16,300 Hispanic-Americans affected by the disorder, according to the Centers for Disease Control and Prevention.
To date, the US Food and Drug Administration (FDA) has approved more than 15 gene and cell therapy products. The FDA says it expects to see more than 200 new drug applications this year, and anticipates approving between 10 and 20 cell and gene therapies per year by 2025. There are more than two dozen clinical trials for gene therapies that could benefit patients with sickle cell disease alone.
While still falling under the FDA designation of a rare disease, the prospect of gene therapy for sickle cell disease represents a significant challenge for an industry that focuses on personalized, one-off treatments that carry significant cost. While many different payment models for gene therapy have been suggested, not every payer is large enough to weather the cost of an expensive gene therapy treatment, S Russell Spjut, PharmD, clinical pharmacist of formulary management at MagellanRx Management, told First Report Managed Care.
“A single million dollar or more claim for a self-funded employer with 300 employees can feel like a death sentence to their plan’s financial viability,” Dr Spjut said. “While there are potential ways to alleviate the financial burden being spoken of, such as spreading payment out over a period of time or creating larger risk pools for these smaller payers to contribute to, the fear is still real today.”
Optimizing the Manufacturing Process
With many new gene and cell therapies in the clinical pipeline, and a growing number of patients who could benefit from treatment, many stakeholders are looking at new ways to lower the cost of treatments while ramping up production of gene and cell therapy products.
“We have made real progress in the industrialization of gene therapy production, but we are still a long way from seeing gene therapies being manufactured in quantities even close to the level of current demand,” Clive Glover, PhD, strategy director, cell & gene therapy; and Rene Gantier, PhD, director, process research & development at Pall Biotech, said in an interview. “This is arguably one of the biggest challenges in modern medicine manufacture.”
One suggestion is to create efficiencies in manufacturing of gene and cell therapies. “Any innovation to make manufacturing more efficient has a high probability of saving money and potentially reducing the long-term costs associated with gene therapy,” said Ben Isgur, Health Research Institute Leader at PwC.
Continuous biomanufacturing of gene therapies is an umbrella concept that describes several ways to streamline a manufacturing process, explained Dr Spjut. “The basic idea is to minimize holding times and volumes between different steps of the processes needed to create a gene therapy molecule. This can theoretically lead to higher product yields.”
Autologous therapies face an uphill battle in scaling production. In cell therapy, patients undergo multiple processing steps, and samples must be good quality. It can take weeks for companies to receive the sample, produce the therapy and ship it back to the patient for reinfusion, Mr Isgur said. “Taken together with the fact that the approved treatments are limited to rare diseases with small patient numbers, manufacturers will have a limited opportunity to scale up.”
At Pall Biotech, the company is heavily invested in helping companies optimize gene and cell therapy manufacturing, Drs Glover and Gantier said. Pall Biotech’s iCELLis bioreactor is an example of a technology in single-use manufacturing that can automate aspects of cell culturing—improving time spent setting up, cleaning, in-process hold steps, and operator oversight—which can cut down production time by days or weeks. “One main focus of our investment in this area has been to develop an automated, end-to-end integrated, platform solution that is scalable and can address issues that arise when gene therapy products are manufactured using individual manual manufacturing steps,” they said.
A challenge in this area is not speeding up the process of manufacturing, but manufacturing productivity, Drs Glover and Gantier noted. For example, in the case of viral vectors for gene therapies, the number of quality viral vectors produced each month can impact availability of these treatments. “Demand is soaring for the preclinical and clinical-grade viral vectors that allow for the delivery of genes of interest, but the industry has not yet adapted to meet the demand,” they said.
Upscaling production of these viral vectors may seem similar to how the production of monoclonal antibodies (mAbs) were upscaled for cancer treatments, but there are significant differences between the two, Drs Glover and Gantier explained. “There are obviously similarities between the development of mAbs and of gene therapies, and there is no doubt we have taken a great deal of what we learned with mAbs and applied it in our endeavors to scale up gene therapy production.”
However, not all the lessons learned from mAbs apply to gene and cell therapy, and the process is not a copy and paste exercise. There is greater risk and intricacy in the process compared with mAbs because “the use of stable cell lines that you would use for mAbs is challenging,” Drs Glover and Gantier said. “The viral vectors themselves are toxic to the cells that produce them, which can significantly reduce titers.” When you try and scale this process for larger viral batch sizes, it becomes difficult because viral vectors are normally created in academic settings using traditional laboratory-based systems.
There is also a concern with virus safety. Low pH incubation and solvent detergent treatment—traditional methods for making viruses inactive—are not easily transferrable to gene and cell therapies, as the cells are unlikely to survive these methods. “Anything that would disrupt a contaminating virus would also likely inactivate and damage gene therapies whose effectiveness depends on virus activity,” Drs Glover and Gantier said.
Expansion of Cross-Industry Partnerships
Distributed or decentralized manufacturing is another option to expand capacity into producing more gene therapies. Industry stakeholders are spending billions of dollars to this effect: in 2018, Novartis acquired AveXis for $8.7 billion, and the company recently made a $115 million investment into a manufacturing plant in North Carolina that would give them the opportunity to manufacture multiple gene therapies simultaneously, according to a press release from the North Carolina Chamber of Commerce.
More mergers and acquisitions in the field have followed. In March of 2019, Thermo Fisher Scientific announced their acquisition of gene therapy contract manufacturing firm Brammer Bio for $1.7 billion. Catalent Inc spent $1.2 billion to acquire manufacturer Paragon Bioservices Inc in April of 2019, and Astellas announced an acquisition of Audentes Therapeutics for $3 billion in December of 2019.
Industry stakeholders are also joining in partnerships with other industry organizations and government entities. The National Institutes of Health and Bill & Melinda Gates Foundation recently announced they would invest $200 million into developing affordable genebased cures for sickle cell disease and HIV globally. These collaborations appear to be producing results: the Centre for Process Innovation announced their CRD IUK project—a collaboration of Cobra Biologics and GE Healthcare Life Sciences—had made headway in developing a purification process for adeno-associated viruses.
“Any additional investment in innovative approaches to develop cell and gene therapies will help to move the field forward,” Mr Isgur said. “If the team is successful at producing affordable gene therapies at scale, it could provide tools and lessons for the entire field.”
While these acquisitions hold the promise of greater manufacturing potential, it is unknown how the FDA would respond to significant changes in the manufacturing processes of gene and cell therapies, Dr Spjut explained.
“As the biologic approval process with the FDA includes looking at the manufacturing process and the ability to create a consistent product, changing that process will involve additional FDA scrutiny and approval,” he said. “As some of these potentially optimized processes have not been reviewed by the FDA at all yet, no one is quite sure what sorts of testing or documentation will be required in the end.”
Off-the-Shelf Gene Therapy
Some stakeholders have proposed allogenic gene therapy products as a way to overcome the lag time in autologous gene therapies between cell collection and delivering the therapy back to the patient, as well as the significant costs of manufacturing one-off treatments.
In the case of CAR T-cell therapy, an allogenic therapy could be made in large batches and significantly improve manufacturing efficiency. “They could also improve the speed at which the treatment gets to the patient and provide greater opportunities for scale up, depending upon the size of the indication,” Mr Isgur said.
The concept of allogenic gene and cell therapies is still in its infancy, and there are questions about whether the treatment would be as effective as autologous therapies or if there would be unintended side effects. Graft vs host disease is a concern with patients who receive allogenic CAR T-cell therapy, Mr Isgur noted.
“Another challenge has been getting these cells to continue to expand and persist in the patient following initial treatment,” he said. “While autologous CAR T and viral vector gene therapies can be dosed just once to achieve long-term, durable responses, allogeneic CAR Ts haven’t shown as durable of a response in clinical trials and may require re-dosing.”
It is also unlikely there would be a single therapy that is effective for all patients. Rather, several human leukocyte antigen (HLA) therapies would likely be produced and matched against a patient’s immunological profile, according to Drs Glover and Gantier. “If many hundreds of allogeneic, HLA-matched therapies are required, then the economic benefits of these over autologous approaches may not be as large as some would hope,” they said.
Lowering Indirect Costs of Therapy
Another area of potential cost savings is in reducing the indirect costs associated with a patient receiving gene or cell therapy. “I think that most manufacturers recognize that health plans will not only be sensitive to the drug cost for gene therapies, but also the ancillary services needed for a successful round of treatment,” said Dr Spjut.
Patients who undergo ex vivo gene therapies such as CAR T-cell therapy are usually expected to stay within a 2-hour drive of the large academic centers where treatments are offered, and are hospitalized for cell collection and reinfusion, which results in significant clinical and administrative costs, especially if a patient develops complications from therapy. In vivo gene and cell therapies can be done in an outpatient setting, but still require trained staff and prolonged wait times between initiation of treatment and reinfusion.
“Companies are working with regulators and clinicians to improve the safety and monitoring of cell and gene therapies and improve the ability to predict possible toxicity early on, potentially reducing the need for patients to remain in the hospital for lengthy periods,” Mr Isgur said. Some companies providing gene therapies are also beginning to offer compensation for patients and their families who need to stay near the treatment facility in the weeks after treatment, he added.
In a white paper describing the costs of gene therapy, CVS Health sees the role of specialty pharmacy expanding as more stakeholders are looking to lower costs of gene therapies to make them affordable for payers and patients. Specialty pharmacies, they argue, can negotiate costs of gene therapies directly with the manufacturer, and patients can avoid the markup some hospitals and physicians would place on the drug.
“One of the biggest roles I think we will see specialty pharmacy fill is the central point of checking to make sure the pieces line up,” Dr Spjut said. “It is a unique position to be interacting with the patient, the provider, the facility, and the distribution channel and I think this placement will help specialty pharmacy offer value in the gene therapy process.”
Future of Gene Therapy
Ultimately, the question of whether improving the manufacturing process of gene and cell therapies will lead to significant cost savings is an open one, Dr Spjut said. “One thing that has seemed clear in the pharmaceutical industry as of late is that the manufacturing costs of most drugs on the market today play a small, or no, role in the market price of the drug,” he said. “Even if manufacturing costs for gene therapies is reduced, I am not sure if the savings will be reflected in the drug price or the company’s bottom line—or possibly a combination of the two.)”
“The addition of these tools to the gene and cell therapy toolbox will create further productivity challenges, as manufacturing systems are currently not well set up for these types of highly personalized therapies,” Drs Glover and Gantier said. “But the benefits they could bring to patients will be unprecedented, so it is a challenge that we as an industry need to be ready to tackle head on.”
In January of 2020, the FDA released a long-awaited draft guidance for interpreting the “sameness” of gene therapy products under its orphan drug regulation. The draft guidance states similar gene therapy drugs will be considered candidates if they express different transgenes, use vectors from a different viral class, or are clinically superior to a previously approved drug with the same use or indication. If a product is granted an orphan drug designation, it receives 7 years of exclusivity as an orphan drug, tax credits for qualified clinical testing, and waiver of FDA fees for marketing applications.
Because the FDA “opened the door” to a number of different scenarios where they could define sameness, Mr Isgur said, “it’s too early to know whether or how the agency’s implementation of this definition will impact companies seeking orphan designation for gene therapies in the future.”