In August 2017, Novartis received FDA approval for its chimeric antigen receptor T (CAR-T) cell therapy, Kymriah, for the treatment of children and young adults with B-cell acute lymphoblastic leukaemia (ALL)
Research scientists have worked on using a human’s own immune system to fight cancer for many years. Through this extensive research, CAR-T therapy, which achieves exactly this, was pioneered. This treatment is entirely unique to the individual compared with typical small molecule and biologic products, and because of this a fundamental shift in how manufacturing, logistics, and administration takes place will have to occur.
As this therapy is currently at the beginning of commercialisation, it seemed pertinent to ask what regulations could be put in place to ensure that it’s standardised both in the US and internationally. Martin Lamb, VP at TrakCel, a provider of integrated software that facilitates the tracking of cell and gene therapy programmes, comments: “As this therapy is produced from a patient’s own cells and these differ between individuals, the starting material will always be inconsistent. As such, I do not think there is going to be a standardised therapy. Regulations aim to ensure that other factors, which can always be controlled, are appropriately managed. Advanced therapies are rapidly evolving and regulators are working hard to ensure that legislation keeps up with this pace of change. Regulations governing the use of cell therapies are currently under review in the US, and the EMA has published a number of draft guidance documents in recent years ahead of implementing GMP guidelines for advanced therapies.”
To prevent counterfeit therapies from reaching the market, Lamb says: “Kymriah is a personalised therapy — it cannot be bought off-the-shelf as it is manufactured specifically for each patient using their own cells. The same unique identifiers required by regulations to ensure that the right product is dosed to the right patient can be used to guarantee that each product is genuine.”
“Also, as each product is tracked throughout the supply chain and therapy owners know where each product is at all times, it would be impossible for a counterfeit product to enter the supply chain. In the same way that standard commercial therapies are serialised to eliminate counterfeits, this approach is already a ubiquitous part of autologous cell therapy production.”
CAR-T treatment requires hospitalisation; aggressive therapies with potentially severe side-effects mean that recipients require close monitoring after treatment. This typically requires a hospital with experience of identifying and managing potential side-effects, which, in turn, will limit their initial use to specific centres of excellence. As a result, some patients may not easily access these new medicines — at least initially. As technology used across the supply chain improves and more centres gain experience with or are trained to manage cell therapies, Lamb expects this accessibility to improve.
When considering scaling-up the manufacturing process, Lamb comments that autologous therapies are as personalised as it gets, with each batch representing only one patient’s treatment. Mass production is therefore impossible to achieve. However, within this personalised manufacturing process, there are steps that can be taken to reduce cost-of-goods. “The implementation of existing IT solutions into manufacturing can support planning and minimise over/under ordering of materials (MRP/ERP systems),” comments Lamb.
He adds: “Reducing paperwork, such as the batch records associated with manufacturing can help to improve review and release timelines. Electronic batch records can also make autologous therapy administration more manageable.”
“The production of a batch of autologous therapy involves multiple partners. Close co-ordination of the activities of these providers can help to minimise product wastage and improving asset utilisation can help to reduce cost-of-goods. Track and trace technologies such as TrakCel include scheduling functionality to support this. Additionally, the implementation of cryogenic freezing can help to introduce some flexibility into the process, supporting scheduling and improved implementation, although care must be taken to ensure this process does not impact product integrity.” The quality of a cell therapy product is determined by controllable (adherence to protocols, environmental controls) and uncontrollable factors (quality of the patient’s cells used to produce the therapy). Minimising the risk associated with a therapy’s integrity through controllable factors (handling, environmental conditions, freezing or thawing cryopreserved products) can reduce the risk of rejected materials and have a favourable impact on cost-of-goods. Plus, the implementation of prescriptive workflows can minimise the risk of mishandling. Tracking the product’s handling and environmental exposure outside of the manufacturing facility can also help reduce these risks.
Automated and closed systems can reduce the reliance on expensive manufacturing resources such as expert operators and cleanrooms. These technologies already exist as off-the-shelf systems — such as Miltenyi’s Prodigy system — or can be custom designed and built by companies such as Invetech. Integration of this equipment into systems such as TrakCel allows data to be captured throughout the manufacturing process. Capturing data across the supply chain and making this available to the QA team in real-time can reduce the time needed to release products for infusion to patients. Again, this is a potential application for track and trace technology platforms.
The location of facilities and their proximity to potential patients should also be considered when planning a manufacturing strategy. Setting up a centralised manufacturing site (one site produces the therapy for patients around the world) can be cost- and time-effective, but can introduce additional risks such as longer cycle times from starting material collection to infusion and product loss owing to excursions during long-distance transits.
Other potential risks include regulatory differences between regions. For example, if product is manufactured in the US for use in Europe, how will import and qualified person (QP) release of the product be managed? How scalable will this be if there are thousands of potential batches? The use of in-house versus outsourced resource must also be considered. For example, the use of outsourced resource can help companies to increase the scale of their manufacturing quickly and without the need to invest in infrastructure, in addition to giving them access to expertise and equipment they may lack in-house. Vendors can also allow companies to quickly widen their global footprint, overcoming some of the geographic challenges.
Lamb believes the commercialisation of Kymriah is a milestone for the cell and gene therapy sector. He comments: “There are a growing number of companies developing autologous cell therapies based on T-Cells. Novartis’s success is very exciting news for the industry and everybody is monitoring the progress of their therapy.”
Competition in this market will increase as multiple companies gain approval for therapies and begin manufacturing. To be effective — with minimal side-effects — a T-cell therapy ideally requires an antigen target that’s abundant on cancer cells, but not found on any other cells. This is a very rare set of attributes, making it difficult for biotech companies to diversify directly into solid cancers.
“If successful, Kymriah could make life easier for other CAR-Ts reaching the market in the future. As a provider of supporting technology, TrakCel is especially interested to see how payment models evolve for this type of therapy — as the next logical functionality for the company to develop will be outcomes monitoring and reimbursement support. Before it can develop this functionality, it would be useful to have a real-world example to base our system on. The company expects that this will differ between countries and regions and has already engaged a partner company to develop a full end-to-end service offering for the industry.”
Owing to the lifelong value of CAR-T therapies, Lamb is optimistic that Kymriah offers a good investment for Novartis. When the reimbursement of new medicines being declined is reported in the media, it is often a case of the benefit not justifying the cost, says Lamb. However, he adds: “CAR-Ts are potentially transformative, curative therapies and I truly hope that HTAs around the world take this into consideration and work closely with industry to devise innovative reimbursement models that improve patient access to these therapies.”
Looking to the future, Lamb hypothesises that Novartis will expand its manufacturing footprint to support approval of its product in new regions and countries. He said: “Although Novartis has developed a product that can be cryostored and shipped, which in theory should support a centralised manufacturing model globally, challenges such as QP release in Europe may drive them to look for a manufacturing option within the EU, either internally or through a third party.”
“And whereas Novartis has taken a brave step with their ‘success or your money back’ approach to reimbursement, I suspect alternative models will need to be developed as they enter negotiations with individual payers both in the US and as they rollout the therapy to new countries.”
In the future, CAR-Ts will face numerous challenges. Acceptance of the price tag is likely to be a considerable challenge, encouraging buyers to look beyond the initial cost and appreciate the potential full life value. However, Lamb believes that “as more data and particularly longer-term data become available to support the therapies as curative, I think this will diminish.”
The complexity of scaling-up manufacturing and the requirement of highly skilled operators may limit their expansion, although the future automation of systems, with accelerating technological advancements, may reduce this problem. Despite encouraging treatment rates, Kymriah does have the potential to cause severe or life-threatening side-effects such as cytokine release syndrome (CRS) or neurological toxicities. Owing to the risk of these side-effects, Kymriah is therefore only available through a restricted programme under the Kymriah Risk Evaluation and Mitigation Strategy (REMS).
This programme — approved by the FDA — acts to inform and educate healthcare professionals about the risks associated with this treatment. Hospitals requiring experience in identifying and managing CRS will limit the growth of these therapies to treatment centres with appropriately trained staff and intensive care units. Although, next-generation CAR-Ts with multiple antigen targets, new antigen targets and on/off switches may help to prevent this limitation in the long-term and make the therapies more widely available. The lack of data on the long-term effects of CAR-Ts may also slow their growth.
Considering other radical treatments, Lamb believes that the approval of Kymriah could serve as a driver for the cell therapy industry. He said: “A large number of developers of cell-based therapies are already developing treatments for conditions other than cancer. For example, Bluebird Bio is developing treatments for rare diseases such as beta-thalassemia and sickle cell; Orchard Therapeutics is, like GSK, developing a therapy for ADA-SCID; CRISPR therapeutics are also focused on rare diseases. While oncology is undoubtedly the major target for developers of cell and gene therapies, the potential of these treatments in other conditions is already being actively explored.”
The FDA-approved Luxturna gene therapy from Spark Therapeutics was recently in the news and with a price tag of $850,000 is one of the most expensive medicines ever sold. “The approval marks another first in the field of gene therapy — both in how the therapy works and in expanding the use of gene therapy beyond the treatment of cancer to the treatment of vision loss — and this milestone reinforces the potential of this breakthrough approach in treating a wide-range of challenging diseases,” said Dr Scott Gottlieb, FDA Commissioner.
“Kymriah has demonstrated that gene-editing therapies can be brought to the market. This is already encouraging investors — spurred on not only by the approval, but also by recent acquisition activity in the market. More investors will make more money available to developers, which, in turn, will drive more research. If Kymriah is successful commercially, the effect will be even greater,” Lamb concludes.