Twenty-First Century Cell Therapy

In August, The Medicine Maker’s advanced medicines supplement illustrated the explosive growth of the cell therapy industry (1). Over the last decade, the industry has moved from great expectations to clinical realities, with a growing number of ongoing clinical trials in multiple indications. Clinical trials are now primarily sponsored and driven by industry, rather than academia – an exciting feature of the maturing field. There is also growing acceptance that allogeneic products will not completely replace autologous transplantation approaches – there will be a need for both systems. As more autologous therapies come to market, the industry is also getting to grips with the supply chain and business model challenges.

Initially, approved cell therapy products tended to be focused on regenerative medicine and tissue engineering, but now the field has shifted to immunotherapy. Novartis’ CAR-T therapy, Kymriah, will hit the market soon, after being approved by the FDA at the end of August. It will be manufactured for each individual patient using their own cells and cryopreserved to allow for treatment flexibility. Other companies are also hoping for CAR-T approvals; for example, Kite Pharma won the 2017 “Clinical Trial Result of the Year” for its Pivotal CAR-T Trial in Patients with Aggressive Non-Hodgkin Lymphoma at the Clinical and Research Excellence Awards. It’s safe to say that immunotherapy and cell therapies are in the spotlight.

Although cell therapy knowledge and expertise has increased significantly over the last decade, manufacture still remains a challenge. First of all, it has taken time for the regulatory environment to develop, with trailblazers like Dendreon and TiGenix helping to forge the way forward. Novartis – the first of big pharma to launch a cell therapy product – will also be a key company to watch.

In terms of development and manufacturing technologies, there are a number of fundamental gaps, such as lack of processes for efficiently differentiating stem cells – not only adult mesenchymal stem cells, but also now embryonic stem cells and pancreatic stellate cells – into functional, therapeutically-relevant cell types. Similarly, there remains a pressing need for technology that can promote integration of stem cell products into three-dimensional structural matrices in the body. Looking at the manufacture of cell therapies more generally, there is a great need for more automated and closed systems (especially as human error or contamination can be fatal) – and great opportunities for equipment manufacturers to step up and cement an early place in the market.

But perhaps one of the most significant challenges in the maturing cell therapy field is getting the balance right: on one hand you need to get to the clinic as quickly as possible, on the other hand, you need to take the time to develop a robust, efficient and commercially sustainable manufacturing process – and with a third hand, you need to ensure you have reasonable cost of goods (COGs). Many companies talk about COGs, but examples of true process optimization are rare. Going to the commercial stage with an inefficient process can result in manufacturing unit costs that exceed the realistic price of the final therapy – potentially killing the business.

Cell mates

Given the challenges, many cell therapy medicine makers consider outsourcing – and increasing numbers of service providers are emerging. Partnerships between a CDMO and pharma companies lead to a virtuous circle: by gathering expertise from multiple client projects, CDMOs become increasingly skilled – subsequently becoming better versed at helping the industry overcome the manufacturing challenges of cell therapies.

One of the key benefits of outsourcing to a CDMO is improved cost control. The alternative (in-house manufacturing) requires enormous upfront investment, which can have a devastating impact on a company’s cash situation. For example, the debt taken on by Provenge to build an in-house production facility severely hampered subsequent product commercialization efforts. Part of the problem associated with in-house manufacturing by the innovator company is that decisions regarding systems and processes must be made at an early stage – that is, without knowledge either of future needs or of the capabilities that will be required to meet those needs. Consequently, companies may find that their facilities and staff remain unutilized for long periods, such as between clinical study phases, or that their facilities and processes are not flexible enough to meet the needs of an evolving pipeline. A CDMO can also help with local manufacturing, as many large CDMOs have a global network. Given the logistics and shelf life constraints of most cell therapy products, the ability to manufacture as close to the point of care as possible can be crucial.

Although partnering with a CDMO can be an effective and less risky approach than going it alone, some companies are wary because of the perceived lack of control. In addition, finding the right CDMO is often trickier than you imagine, particularly with more and more springing up. Take your time to find the right partner, don’t underestimate the technology transfer phase (crucial if you want to ensure the process is fully controlled), and be wary of any company that sees quality as a burden. It takes time to get cell therapies right, and companies should never compromise the quality and safety of products, no matter the pressure on cost or timing.

It is important to remember that using a CDMO does not mean you have to outsource the entire manufacturing process. Some companies prefer to seek support for specific aspects, such as product characterization or the development of quality control assays that don’t use up vast quantities of product.

Future sales, future cells

COGs and reimbursement levels are key to the commercial viability of the product, and all cell therapy companies should pay close attention to these areas at an early stage. No matter how good a product is, it stands that if it is unaffordable, it will not sell. Unfortunately, prediction of price levels, which are necessary to assess whether manufacturing costs are acceptable, remains difficult given that so few cell therapies have reached the market.

Existing points of reference for cartilage products show a price of around US $20,000-30,000, while intravenously administered cell therapy products are commonly in the $100,000-200,000 range. The $665,000 price tag achieved by GlaxoSmithKline for Strimvelis, their ex-vivo stem cell gene therapy developed to treat patients suffering from a rare disease called ADA-SCID (severe combined immunodeficiency due to adenosine deaminase deficiency) cannot be seen as a benchmark given the very limited size of the market. For therapies that extend life rather than offering a cure, it is not uncommon to see chemotherapies priced at $17,000, or kinase inhibitors priced at $95,000; very often, such therapies only prolong patient life by a year or two. For therapies that can potentially save lives, reimbursement of at least $150,000 would seem reasonable. Novartis’ Kymriah will hit the US market at $475,000 – less than some analysts expected.

Reimbursement levels tend to be calculated based on health economics and, increasingly, we are seeing conditional approval and pricing – at least in Europe, Japan or South Korea, where reimbursement depends on the observed level of benefits. Products that offer only a subtle improvement versus existing therapies are problematic with this model, but cell therapy products, where the benefits are usually anticipated to be significant, are a somewhat safer bet. Even so, market success is not assured; for example, Novartis’ Entresto, once expected to be a blockbuster, had a slow start because of barriers to patient access and an underfunded launch. Marketing is likely to be particularly critical for revolutionary treatments – administering cell therapies is very different from traditional drugs, and effective promotion will be crucial to generate adoption by physicians and patients.

With the industry getting to grips with cell therapy manufacture, CDMOs taking the strain, and more clarity over pricing and reimbursement emerging, I anticipate a bright future for the cell therapy market. But companies – and investors – need to do the right thing if they want the right results. It is essential for companies to enter the development process with a deep knowledge of the cell product and its mode(s) of action. Analytical processes should be available from the start, and all data from early bench work and onwards should be stored and curated. Even so, additional development will be required at the Phase III and commercialization stages. Finally, I urge companies not to neglect the process optimization required to control COGs.

I am now more excited than ever before about the cell therapy industry. I feel like I am helping to write one of the most exciting pages in the pharma history book. And there are even more exciting opportunities to come; for example, development of combination therapies comprising cell products and conventional biologics. I firmly believe that the dream of curing cancer has never been so close to reality.

Denis Bedoret is Managing Director at Masthercell, Belgium.

The Medicine Maker’s special report “Advancing Medicine” features insight and opinions on the rapid rise of advanced medicines and the challenges surrounding their manufacture. Topics include tackling the rise of unapproved cell therapies in the US, how to cope with the complexities of the supply chain for advanced medicines, a technical roundtable discussing the field’s success stories and needs for the future, and a one-on-one interview with Steve Oh from the Bioprocessing Technology Institute at the Agency for Science, Technology and Research (A*STAR).

Read the Advanced Medicines Supplement at: https://themedicinemaker.com/issues/0717/advancing-medicine/