Yescarta to Europe: Steps learned and production 97% on-spec
When Novartis’ Kymriah (tisagenlecleucel) and Gilead’s Yescarta (axicabtagene ciloleucel) chimeric antigen receptor (CAR)-T treatments were approved much of the focus was on the magnitude of the clinical success seen by the treatments.
Both treatments were able to send a high proportion of patients with certain leukaemia’s into complete remission when other treatment options had failed, and hailed the advent of a new kind of cell therapy.
With this new technology also came a new challenge – how to manufacture the treatment consistently at a commercial scale.
Novartis has admitted that it has had issues manufacturing the treatment to specifications, which it is now moving to rectify by further investing in its process.
After buying into the space through its acquisition of Kite, Gilead has not had any such issues and when BioPharma-Reporter (BPR) spoke to Dominique Tonelli (DT), Kite’s head of medical affairs in Europe, she expressed confidence in its process.
In terms of hitting its product specification, Tonelli told us that the company is producing 97% of treatments to specification. As a result, the company is now focusing on increasing its capacity with a facility in the Netherlands to be able to produce the treatment in Europe, for European patients.
BPR: How is the roll-out of Yescarta to patients developing in Europe and what lessons have been learned along the way?
DT: I would start by saying bringing Yescarta to European patients has been a journey. Beyond the science of the product, in terms of efficacy and safety, it is really a new type of drug: for Gilead, for regional authorities, for the national authorities, and for the hospital organisation directors – it's new to all of us.
What does it mean that it is something new? This is something that you hear quite often, anytime something new comes to the market. I have worked in the pharma industry for something like 25 years, always on the medical side, whether in clinical or medical affairs, and I’ve worked on a number of products, such as Taxotere (docetaxel), Taxol (paclitaxel) Sprycel (dasatinib), or Yervoy (ipilimumab). I’ve brought many new and fantastic products that changed the paradigm of treatment of cancer; however, it was always a pill or an IV drug that pharmacists, doctors and nurses would administer to patients. With these treatments, you would never wonder what it meant to produce these drugs. This is one of the main differences with cell therapy. In addition, at the hospital unit, multiple stakeholders need to be involved beyond the haematologists, the nurses, the cell therapy unit and the pharmacist; it is a teamwork effort, involving neurologists and intensive care unit specialists, which is key for patient care.
BPR: What does that mean for bringing the treatment to hospitals and patients?
DT: After the approval of Yescarta in Europe, in August 2018, we have started to open qualified centres across different countries. The reason we have used qualified centres is because to manufacture the product requires a cell journey and a patient journey, where different departments and individuals are involved – from hospitals and from the pharma company. As such, we need to look at the different processes already in place in hospitals and see whether these match our requirements that we have submitted and received approval for from the EMA.
Now, France, Germany, UK, Italy, and Spain have at least one hospital ready for treatment with Yescarta, which is a great achievement in just a few months and we have already started to treat patients. In the US, they have treated over 1,000 patients – the level of knowledge in Europe is not yet the same, but is improving quickly.
BPR: As of now, the therapy needs to be sent across to the US to complete the manufacture. How much time does this add to the process? How is Gilead working to negate this step?
DT: There is a plant currently being built in the Netherlands, the building exists already, which just needs to be furnished and to be approved by the European Medicines Agency – we plan to have it live in 2020. This will reduce the amount of time greatly, as the treatment currently has to travel to Los Angeles, US, from Europe, and then back to Europe. I believe this will reduce the time needed to produce the product by a minimum of three days, if not four. Currently, the average time from apheresis to the delivery of Yescarta at the site is 26 to 29 days.
This is important and, beyond that, in Europe, we will become independent. In the US, the capacity for treatment is very high but they also manufacture drugs that we have in development, of which there are a number. So, having a similar capacity in Europe for Yescarta and for the other drugs under development will be fantastic.
BPR: Speaking to people in the industry on cell and gene therapy manufacture, they will often say that the process is a learning experience that can constantly be improved on. How far do you agree with this, in relation to Yescarta’s process?
DT: There is something about this product that is very different to most, we are working with a live product through the use of human cells. What you have to do as a manufacturer is implement a process where 100% of the time, 100% of the cells react in a way that you would expect – that is where we’re learning.
Regarding Yescarta’s manufacturing, the steps are learned and we’re done. Our manufacturing success, where our treatments are produced on-specification, is at 97%. One of the outcomes is that we can ask the hospitals to do apheresis and we don’t need to ask them any more questions because we know that we will be able to produce a treatment for most of the patients.
BPR: Could you speak on why Gilead decided to discontinue investigational CAR-T treatment, KITE-585, for multiple myeloma?
DT: Multiple myeloma is a very interesting disease, scientifically; at the moment, you can never be cured of the disease. I think it is very important to bring CAR-T to this disease, to potentially cure a certain proportion of patients with one injection.
I cannot comment on the data [for KITE-585] but what I know is that our objectives, in terms of efficacy, are very high and, as such, we are looking at the best drugs for further development. In short, the treatment didn’t manage strong enough results and so it was discontinued. We have other drugs in development for multiple myeloma, including one in Phase I, that are showing more potential than this particular candidate – so far, what we have seen is promising. In my view, the ultimate expectation in this area should be to cure the disease in a good proportion of patients.
Dominique Tonelli is the head of Medical Affairs Europe, Oncology and Cell Therapy at Kite, a Gilead company. Tonelli has over 27 years of experience in clinical oncology and immunology therapeutics across the fields of clinical research, drug development and medical affairs.
