By Marion Laguette and Marc-Olivier Bévierre, CEPTON Strategies
Several months after the FDA, the EMA has now approved Kymriah and Yescarta from Novartis and Kite/Gilead. There is no doubt that, from a medical perspective, these therapies are a revolution in cancer treatment. However, at such a cost per patient, what is their future on the European market?
Oncology represents more than 50% of the current R&D pipeline in cell and gene therapies with about 500 ongoing trials worldwide in 2017. By using genetic redirection of patient’s own immune system to kill its tumour cells, CAR-Ts appear as a revolutionary technology in cancer treatment.
CAR-Ts have been first developed for treating haematological malignancies, where tumour cells are easily accessible (compared to solid tumours). Clinical proof-of-concept with autologous CAR-Ts has been done on CD19 wearing tumour cancers. Autologous treatments are the most advanced: they are built from the patient’s own cells, contrary to allogeneic therapies that are built as off-the-shelf treatments from a unique healthy donor. Several autologous products are expected to reach the market soon. Allogeneic therapies still need to get their proof-of-concept done but will offer a much more cost-effective solution.
The arrival of autologous CAR-Ts for haematological malignancies on the European market
Since the approval of Novartis’ Kymriah and Kite’s Yescarta by the FDA in 2017 for the treatment of haematological malignancies, both companies have started to work out with the US Government possible ways to address the issues of payment of these treatments and creation of a suitable logistic chain for manufacturing and supplying these products.
Kymriah and Yescarta have received their European marketing authorization in August 2018. Several other CAR-T products will follow, developed, among others, by Celgene (that recently acquired Juno Therapeutics, and owns licence for BlueBird Bio products), Ziopharm, Celyad, and Janssen (that owns licence for commercialization of the Legend Biotech product in the US and Europe, the first CAR-Ts that have been under regulatory review in Asia). To ensure these revolutionary treatments are available to patients needing them, Europe must answer several strategic questions:
- How will the complex commercial scale manufacturing and delivery of these treatments be organised?
- How much are European National Health Systems be prepared to put on the table for CAR-T therapies? And what will they demand in return?
Autologous CAR-Ts will be produced via a centralized manufacturing model in the next few years
Logistics is critical for autologous CAR-T therapies because the patient is part of the manufacturing chain. Time between collection of T-cells and administration of CAR-T cells is critical and must be reduced as possible. Indeed, patients eligible to these CAR-T treatments have a short life expectancy (relapsed/refractory ALL or NHL for currently approved Kymriah and Yescarta). Their production and distribution require a complex organization between several players. Players include hospital teams (collection and administration), vector (mostly virus) providers and CAR-T manufacturers (transduction of T-cells).
Figure 1: Manufacturing process for autologous CAR-T cells
In the US, Kite and Novartis developed the same model for delivering their treatments: a multicentric collection and administration of products in a limited number of certified centers and transduction in a unique manufacturing site located in the US (Morris Plain for Novartis, and El Segundo for Kite Pharma) with virus produced externally. This model was developed for clinical stage production and need to be optimized for supplying a growing demand. 2 solutions are currently under investigation: either a Point-of-Care approach with a bedside production of CAR-Ts in dedicated centers or automation and optimization of the chain in a centralized plant.
With the current model, and for delivering their treatments in Europe, the two companies must adapt their logistic chain: manufacturing CAR-Ts on a different continent would be unsustainable at commercial scale considering costs and time constraints. A European manufacturing site would be sufficient to supply all European countries: an in-house plant or a CMO could do the job. Kite has made the choice to build a plant near Amsterdam airport (the Netherlands) to supply the European market, and Novartis announced the enlargement of its European plant in Stein to produce CAR-Ts, in addition to an agreement with the French CMO CellForCure.
European CMOs have a growing role to play in CAR-T development
CellForCure has already played a role as a CMO in the CAR-T field with the manufacturing of Cellectis allogeneic CAR-T cells for their trials (in addition to the Italian CMO MolMed). The role of such European CMOs will further increase with the growing demand for CAR-Ts. Expertise in autologous and allogeneic ex vivogene therapy is already present in Europe. For instance, PharmaCell already have experience with autologous and allogeneic ex vivogene therapy manufacturing for Orchard Therapeutics and Lion Biotech. Several promising CMOs are re-orienting to propose CAR-T lines and some CMOs have already bet on allogeneic CAR-Ts, the future step of CAR-Ts, such as MaSTherCell which signed agreements with Servier and CRISPR Therapeutics for production of their allogeneic CAR-Ts in development.
In addition to transduction and cell production expertise, virus suppliers emerge as key players due to a worldwide high demand and shortage in virus supply. Virus production does not require to be perfomed locally because virus can be frozen and shipped everywhere in the world. Novartis has for instance used virus produced by Oxford Biomedica (UK) for its US product. Here again, numerous European CMOs have developed expertise in virus manufacturing, such as YposKesi, MolMed, FinVector and Novasep and offer an alternative source of virus for CAR-T manufacturing.
CAR-Ts must be delivered in expert centers – an expertise measured with specific accreditation
Commercial scale production remains the first challenge for CAR-T supply, however CAR-Ts also require to be delivered in a highly controlled environment.
In the US, Novartis and Kite had selected a limited number of centers for delivering their treatments. They wanted to insure these centers were trained to manage side effects of CAR-Ts, that may be fatal for the patient (Cytokine Release Syndrome and Neurological Toxicities). In addition, because CAR-Ts are innovative life-time modifying treatments, rigorous collection of patient’s data must be performed for post-authorisation follow-up. This argument is also in favour of precisely selecting delivery centers.
One criterium in the US was the obtention of FACT accreditation (Foundation for the Accreditation of Cellular Therapy). By applying this selection process to Europe, the equivalent FACT-JACIE(Joint Accreditation Committee of ISCT-Europe and EBMT) accreditation appears as a first criterium of choice for hospital centers. The EMA CAR-T cells registries workshop organized in February 2018 between clinical, regulatory and development experts highlighted this as a fact of importance. Considering the selection, the number of hospitals providing autologous CAR-Ts will be restricted to a small proportion of expert centres, to where patients will have to travel to get treated.
Funding CAR-Ts: an exciting challenge for Europe
Besides high constraints in supply chain and delivery, CAR-Ts are also very expensive (~$400k public price per treatment in the US). Despite their therapeutic effect, it is unlikely that they will be used beyond specific very small population until prices decrease. Even in the US, where a pay-for-performance scheme seems to be adopted, the situation is not clear. There is still some conflict with official classification codes from the CMS (Centers for Medicare & Medicaid Services) that are not reflecting the total costs of the procedure that require ancillary cares and a question of who-is-going-to-pay.
The public prices in Europe are not known yet but cannot be dramatically different from the US prices. It should not be taken for granted, however, that European payors will accept the US prices. The future of CAR-Ts in Europe will strongly depend on what type of deals pharmaceutical companies will be able to negotiate with authorities. There is no doubt that a lot of creativity and long-term thinking will be needed if CAR-Ts are to be used on a significant scale in Europe.
The real change, and potential long-term solution, could be the development of allogeneic CAR-Ts, that should be available at a much lower price. This technology, if it proves effective in clinic, may actually be the real start for CAR-Ts.