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EUROpean clinical validation of a new ex vivo eXpanded stem cell theraPy for cArdiac regeNeration after acute myocarDial infarction: EUROXPAND

Periodic Reporting for period 2 - EuroXpand (EUROpean clinical validation of a new ex vivo eXpanded stem cell theraPy for cArdiac regeNeration after acute myocarDial infarction: EUROXPAND)

Reporting period: 2019-10-01 to 2020-06-30

- Heart Failure (HF) after Acute Myocardial Infarction (AMI) remains the first cause of death in developed countries, above cancer, with life expectancy less than 5 years. Furthermore, it is one of the few cardiovascular conditions whose prevalence continues to rise, due to improved survival following AMI, coupled with detrimental lifestyle behaviour, and ageing population. With an overall cost of 108 billion dollars (83 billion euros) per year worldwide, heart failure represents a global public-health issue.

- There is an urgent medical need to prevent delayed-onset HF after AMI. Despite progress in percutaneous coronary intervention, bypass surgery and drug therapy, current treatments fail to limit heart remodelling after AMI. None of them compensate the irreversible loss of cardiomyocytes, and the limited ability of the heart muscle to regenerate. Since the early 2000s, regenerative medicine offers hopeful perspectives to prevent heart failure, but no cell therapy has succeeded yet to translate into clinical therapies.
The need for improved post-AMI therapies has led to the development of cell-based regenerative therapy. Since human embryonic stem cells raises ethical issues, and allogeneic stem cells may present safety problems, most of cell therapies developed, and clinically evaluated, to improve cardiac regeneration are based on autologous adult stem cells. Each cell types presents limitations and advantages.

- Develop cell technologies in medical application; Improve health outcomes Confirm the safety and efficiency of the first stem cell therapy that regenerate heart muscle, after a severe myocardial infarction
Develop personalizing medicine, cell therapy based on patients own cells (autologous graft) to prevent safety problems (like transplant rejection)
Reduce health inequalities Build clear guidelines integrating CellProthera cell therapy into the myocardial infarction care pathway to prevent HF
Promote active and healthy ageing by preventing HF, Improve Patients life expectancy, and quality of life, in a world where HF incidence is increasing with ageing population
Contribute to the sustainability and equity of European health and care systems Decrease health costs related to HF in the order of 50% to 75%, by reducing HF-related drug therapies, surgical treatments and hospitalizations

3 CTC were selected at the moment with StemXpand® delivery: EFS-ABG at Nantes (FR), Newcastle Bio-engineering CTC (EN) and EFS-ABG at Besancon (FR). As mentioned before, CTCs at Nantes and Newcastle were trained to processes and to manufacture grafts with StemXpand®, according to all standard operating procedures developed by CellProthera, and process validation.

It is important to note that the process validation is a part of Good Manufacturing Practice (GMP) and consists of Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). IQ, OQ, QP protocols allow to establish that StemXpand® installed in CTCs will offer a high degree of quality assurance, so that, in the end, manufacturing processes will consistently produce cell grafts that meet predetermined quality requirements. IQ will analyse if StemXpand® is installed and configured in accordance with CellProthera specifications. The main purpose of OQ is to identify and inspect features of the equipment that can influence final product quality, like temperature, CO2, pressure, humidity… PQ will check if StemXpand® works reproducibly within a specified working range.

On another hand, the CTC validation consists on the validation of the aseptic production process, and the assessment of graft manufacturing global process with healthy donors, to fulfil GMP. Media fill tests are critical microbiological tests carried out to simulate the normal manufacturing conditions by replacing cell graft with culture media alone. Tests are performed at each step of graft manufacturing and packaging. Media fill tests developed in this task will be used as a risk management plan to ensure final product safety, during the phase III trial.
The validation of the graft manufacturing global process will be achieved by evaluating identity, purity and microbiological state of 3-manufactured grafts from healthy donors treated with G-CSF. To validate the process, obtained results must be conform to the previously established specification.
• Application route: Two routes of cell delivery have been mainly used in cell therapy: intracoronary arteries or intra-myocardial. Intra-myocardial delivery with several injections could be a risk factor for triggering ventricular arrhythmias. On the other hand, intra-coronary cell administration might reduce the risk for arrhythmias but may foster cell loss and decrease LVEF improvement. Indeed, experimental studies have shown that cell retention within the few hours following intra-coronary delivery was consistently lower than following intra-myocardial delivery, even when taking in account mechanical leakage and washout favoured by beating heart.
For CellProthera, intra-myocardial cell delivery is the best route of injection to achieve an optimal cell therapy efficacy on cardiac function. To prevent ventricular arrhythmia and increase CD34+ cells homing in the heart, CellProthera has developed an injection process into the infarcted zone, which reduce arrhythmia risks, and can be performed on an outpatient basis.

• Timing of cell delivery: A huge dilemma remains regarding the best time for stem cell delivery to patients. Many trials suggest that the optimal efficacy of cell therapy is observed if administered early after AMI (between 8 days and 2 months after AMI). However, it might be dangerous to perform direct cell injection into the ischemic lesion before the end of the second week, the injured myocardium being too crumbly within the immediate post-AMI period to be safely injected. On the opposite, if the treatment is administered a long time after AMI, diminution of chemokines secretions and scar formation associated with fibrosis occurrence will progressively reduce the benefit of cell therapy. This lack of efficacy was observed during the Proof of Concept trial performed by Pr. Hénon. One patient treated 8 years after AMI with CellProthera therapy saw no improvement of heart function, and died 5 years after its inclusion in the trial.
Since, the development of scar/fibrosis formation is relatively slow and takes several months to be fully achieved, the optimal timing of cell delivery is comprised between 2 weeks and 6 months after AMI.

• In terms of manufacturing, the Cellprothera project is also innovative because of the chosen model: the CD34+ grafts are not manufactured by CellProthera, but by a large network of GMP Cell Therapy Centers, in a standardised way. This will allow to disseminate much more efficiently the therapeutic offer, and to share investment risks and benefits between the Company and CTCs. This particular model is needed to anticipate the growing demand. We estimate to treat over 150 000 patients by 2026, in targeted regions (Europe, North America, and South East Asia, see section Impact). To meet this demand, over such large territories, logistics (blood samples and graft shipping within 37h) will be a critical parameter. Having a large network of CTCs equipped with CellProthera’s technology, at the centre of a local network of nearby hospitals, is the key to solve this issue economically.
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