Having raised the bar in immunotherapy, chimeric antigen receptor (CAR) T-cell therapy is now one of the most promising and sought-after cancer treatments. However, in an exclusively autologous format, CAR-T is currently burdened with high costs and challenges in scaling up to meet the demand.
Companies such as Gilead/Kite Pharma are racing to develop allogeneic or ‘off-the-shelf’ variations, yet there are concerns for safety and efficacy which are yet to be solved. What can be done to make CAR-T therapies more affordable in the meantime? And how far off are we to a universally accessible CAR-T therapy? We put the question to three industry experts:
- Xiuyan Wang, Assistant Director, Memorial Sloan Kettering Cancer Center
- Benoit Bossuge, Strategic Project and Account Manager, Novartis Technical Operations
- Philippe Parone, Director, Industrialization, Celyad
What are the most effective ways to reduce the cost of goods for CAR-T therapies?
Xiuyan Wang: I think automation, better CAR design hence lower required cell dose, decrease paperwork hence less QA staff, simpler manufacturing flow/platform, etc. will all reduce the cost of goods.
Benoit Bossuge: Closed Systems and standardized platforms along with automation are the future. A great deal of innovation is taking place to reduce costs and complexity, and improve processes in manufacturing of CGTs. Improving manufacturing efficiency through automation is one of the big challenges that will need to be addressed to see a reduction in CoGs. Rise of smart technologies amongst which the development of smart packaging as a supply chain solution (i.e use of Blockchain technology) will also play a key role in CoGs reduction.
Benoit Bossuge is speaking about viral vector supply and demand for gene therapies on 5 December at the Cell Therapy Manufacturing & Gene Therapy Congress in Amsterdam.
Philippe Parone: The manufacturing of CAR-T cell therapies is a complex process with a high cost of goods (COGS), which is likely to be a challenge for the long-term sustainability of commercialized CAR-T products. Nevertheless, there are several approaches that can be used to tackle COGS, including labor and raw material costs. One such approach is automation of the manufacturing process and analytical methods. Automation not only reduces labor costs but also manufacturing deviations and batch failure, both of which can drive COGS. Process automation also enables scale out, which maximizes use of raw materials and facilities. Of course, the most efficient way to reduce COGS for CAR-T therapies is to transition to allogeneic products, providing these have comparable efficacy and safety. Manufacturing of allogeneic products benefits from multiple factors that contribute to lowering COGS, including a simpler supply chain, economies of scale on raw materials and reduced QC costs for release.
An approach to optimize COGS for allogeneic products is to increase batch size without substantially changing labor and material costs. This will decrease patient dose costs proportionally to the increase in batch size. Optimizing manufacturing yield can be done using in-line monitoring sensors to adjust culture conditions in real time to achieve maximal expansion. Enhancing gas exchange during culture is another approach for maximizing growth.
These are only a few approaches that can be tested to tackle COGS for CAR-T cell therapies, but each comes with a development cost and it is a balancing act to find the right timing to test and implement these cost saving measures.
How do you see the accessibility for CAR-T therapies changing in 2020?
Xiuyan Wang: I think more CAR-T cell products will be approved which will increase the accessibility of this therapy. However, if the cost of CAR-T therapies remains as high as today, it will still be a major barrier for the broader application of this therapy.
Xiuyan Wang will be speaking about the development of CAR T cell manufacturing on 5 December at the Cell Therapy Manufacturing & Gene Therapy Congress in Amsterdam.
Philippe Parone: The high price tag and limited reimbursement for CAR-T therapies are hurdles to patient accessibility. Nevertheless, there is a continual drive to increase patient access to these life-saving therapies and certain events that took place in 2019 should expand that access in 2020. For example, August 2019 saw the Centers for Medicare and Medicaid Services in the United States raise reimbursements for CAR T-cell therapies, thus lowering financial threshold for access to these treatments. The same effect is likely to result from the decision by Novartis to provide Kymriah at a discounted price in Japan following its approval in May. Facilitating reimbursement may also result from innovative payment models, such as the payment for outcomes recently proposed by Gilead which ties the therapy’s clinical success to its payment.
Accessibility of CAR-T therapy to patients is also limited by the complex nature of the treatment and the side effects it is associated with. Thus, access to CAR-T cells is highly regulated, being available only at certified centers and the patient referral system is particularly complex. To offset this complexity and favor patient access, Gilead is encouraging identification of Yescarta-eligible patients by informing physicians and helping them with patient referrals. From a safety perspective, the unified grading system for toxicities associated with CAR-T therapies released by the American Society for Transplantation and Cellular Therapy at the beginning of the year should streamline the treatment of CAR-T related toxicities across sites. This together with new approaches for the treatment of CAR-T related toxicities currently being tested (e.g. early intervention using a combination of Siltuximab and Anakinra) should contribute to enhancing the safety of CAR-T treatments thus increasing accessibility to patients.
In conclusion, there are multiple barriers to accessing CAR-T therapies but recent decisions with regards to cost of treatment, reimbursement and management of side effects are likely to favor patient accessibility in 2020.
Philippe Parone will be presenting ‘CYAD-101: A Non-Gene Edited Allogeneic Approach’ on 3 December at the Cell Therapy Manufacturing & Gene Therapy Congress in Amsterdam.