Cell and gene therapies can treat disease in a more targeted, effective way than traditional drugs ever could. The difficulty is that the cost and complexity of making such products are also much, much higher.
Interest in cell and gene therapies is undeniable. In January, US FDA Commissioner Scott Gottlieb outlined policies designed to accommodate an anticipated surge in cell and gene therapy submissions.
Gottlieb highlighted manufacture as a challenge facing developers and said the agency will issue guidance to promote a better understanding of critical quality attributes and other factors related to product manufacturing.
Complexity
Manufacturing a cell or gene therapy is difficult and costly. Primarily this is because no two products are made the same way and few production processes or technologies have been standardised.
In addition, as Eric Althoff from Swiss pharmaceutical firm Novartis points out, making a patient-specific product like a CAR-T therapy is very different from producing a volume drug. “While manufacturing any medicine is a complex process, traditional therapies are manufactured through a linear process, from mass production to packaging and delivery to patients.
“Manufacturing of CAR-T cell therapies is a highly sophisticated, circular process that is individualised for each patient, beginning with the patient’s cells and ending with infusion in that same patient.”
Althoff cites Novartis’ Kymriah (tisagenlecleucel), a blood cancer cell therapy approved in Europe and the US last year, as an example of the differing manufacturing costs.
“A traditional biopharmaceutical batch can supply thousands of patients and can be manufactured on a very large scale. Even if it’s costly to produce a biopharmaceutical, that cost can be spread across many patients. In the case of a personalised therapy like CAR-T, the cost of the raw materials, the components and the labour that goes into manufacturing, testing and logistics are all for just one patient.”
High production costs and high prices
The high cost of making cell and gene therapies is reflected in the prices charged for such products, said Anthony Davies, CEO of specialist support organisation Dark Horse Consulting.
“Cell and gene therapies are currently expensive to manufacture. We do not believe that recently marketed products, with US prices ranging from $373,000 for Yescarta to $850,000 for Luxturna, include unusually high margins for their companies, but rather reflect high Cost of Goods Sold (COGS).
“It’s worth noting that most are regarded as single treatments, with no repeat dosing, and that some are potentially curative of diseases with no current Standard of Care. But, obviously, these prices will have to decrease if such therapies are approved for any large indications. For this to occur, the COGS must decrease if historical pharmaceutical margins are to be retained.”
This view is shared by Andrew Sinclair, managing director of consulting organisation BioPharm Services, who said cell therapies in particular are costly because of the processes used to manufacture them.
“We estimate the cost [of making a CAR-T cell therapy for a single patient] to be in the region of $100,000-150,000, of which the gene vector costs about 30%, although this is product specific. For a typical biopharmaceutical product, the manufacturing costs represent about 5-20% of the selling price and herein lies the issue for these new therapies.”
Also, as Sinclair points out, strategies like process scale-up that have been used to reduce the cost of making a monoclonal antibody to $50-200 per dose cannot really be applied to patient-specific therapies.
“For cell therapies, the issue is that manufacture is geared to one person, so one batch equals one dose. For traditional biopharmaceutical products one batch equals many doses, therefore there is an economy of scale that is not seen with personalised medicines.
“This is in contrast with the typical biopharmaceutical product which achieves its cost reductions by scaling-up to larger batch sizes and greater process efficiency leading to increased doses per batch,” he said.
Optimisation
As economies of scale are not an option, cell and gene therapy developers’ cost reduction efforts have instead focused on optimisation, both the processes themselves and the technologies involved.
Minh Hong, head of commercial development for cell therapies at Swiss contract manufacturer Lonza, said: “There is so much variability between cell and gene therapies and each process at the moment, but obviously the goal
is to industrialise these therapies as we have for proteins.
“It’s clear the costs are high because of the lack of platforms and scalable processes, but as the industry matures, we will undoubtedly see COGS fall.”
Lonza has worked with 150 cell and gene therapy developers and each project has required a different approach, Hong added.
“Every process is different and therefore no two products are alike. Process development is critical at this stage because everything is bespoke,” he said. “The other issue is that we are dealing with living material and all the challenges that brings for characterisation and stability.”
In the future the plan is to standardise such projects, according to Hong.
“Moving forward, we’re looking to develop enabling technologies, including platform processes for cell and gene therapies, just like we have done for mammalian manufacturing over the last few decades. Thankfully, a lot of the knowledge gained in cell line development and scale-up of mammalian cells may be transferrable to cell and gene technologies.”
One example is Lonza’s use of 2000L suspension cultures for viral vector manufacturing instead of traditional 2D methods, which the firm says has significantly improved efficiency.
Another example is Lonza’s gene therapy- focused partnership with scientists at the Massachusetts Eye and Ear research hospital in the US. The aim, Hong said, is to improve how the Adeno-associated virus (AAV) vectors used to deliver gene therapies are made.
“We’re working with the Vandenberghe Lab at Massachusetts Eye and Ear to offer a synthetic AAV platform based on Anc80,” he said. “This library of vectors means that labs and companies can find the virus with the best stability in their target tissue.”
The partnership also fits with Lonza’s efforts to help customers to make good technology choices early in the process, according to Hong.
“Companies have a dizzying choice of relatively immature technologies for cell and gene manufacturing, so taking a bet on any particular one may seem difficult. As we see standardisation and rationalisation of the tools and processes, the cream will rise to the top and early adoption will become easier.”
Analytics and automation
Elsewhere, cost reduction efforts are focused on gaining better process understanding said Anthony Davies from Dark Horse Consulting.
“For all products, robust and predictive analytics, deployed in a strong Quality-by-Design framework, or equivalent, will underpin more efficient and dependable manufacturing.
He added, “Especially for autologous products, automation is a critical path to reducing costs, as a major contributor is highly skilled human capital. But this is hard to achieve until the product and processes are well understood.”
“And even for allogeneic cell therapies and gene therapies, raw materials and analytical testing costs will also need to be reduced” Davies said.
This observation fits with what Novartis is seeing according to Eric Althoff, who said, “Significant progress is being made to reduce the costs of the unique raw materials used in the CAR-T manufacturing process.”
Logistics
Although transportation is not part of the manufacturing process per se, it is connected and it is definitely part of the reason cell and gene therapy production is expensive.
Moving such products is costly because the storage requirements for each product are unique, according to Minh Hong from Lonza.
“We freeze some cell therapies, while others need to be fresh, which poses logistical issues, and this is one of the reasons we made sure we set up a manufacturing network with key hubs in the US, Europe and Asia. This means we are never more than a few hours flight time away from the major treatment centres.”
As a result, Lonza’s efforts to reduce cell and gene therapy production costs involve logistics, said Hong.
“We are seeing some changes in the relationship between pharma/biotech companies and hospitals – as this relationship needs to be more seamless between the two. From a manufacturing perspective, we are also looking at how we can optimise the journey from apheresis to reinjection, and we could see some new concepts in this space.”
Novartis has also adopted a more patient- and physician-centric approach to logistics and, although the main aim is to improve convenience, the personalised nature of the products means transportation decisions feed back into the production process, Althoff said.
“The manufacturing process for Kymriah uses cryopreserved leukapheresis, which enables patients to be apheresed early in their course of therapy, giving physicians the flexibility to schedule apheresis at a time that is in the best interests of their patients, including times far in advance of manufacturing.
“It also gives Novartis flexibility on when to start manufacturing Kymriah for the patient, and allows for manufacturing and treatment of patients from around the world,” he added.