CellProthera | Post-AMI

Therapy

Personalized regenerative medicine for cardiovascular disease

Epidemiology of AMI and unmet medical need

What is a heart attack?

A myocardial infarction, also known as a “heart attack”, is the destruction of a more or less extensive area of the heart muscle. It is mostly the consequence of the obstruction of a coronary artery when cholesterol (fat) accumulates in the form of atheromatous plaques on its walls.

A myocardial infarction occurs when a plaque breaks off, moves and is trapped in a coronary artery. A blood clot forms around the plaque and interrupts the blood supply, depriving the heart of oxygen.

In France

An average 80,000 people have a heart attack every year in France.
Approximately 12,000 people die each year as a result of a myocardial infarction:

One person in 10 dies within an hour,
Then the mortality rate is 15% in the first year and continues to fall as therapeutic progress, the speed and quality of intervention by rescue teams(provided they are called quickly) are more efficient and interventional cardiology units availability is increased.

Unmet medical needs: Post-AMI heart failure
Regenerative Medicine is a new model for transforming medicine to provide a solution. Today despite availability of small molecules to treat symptoms of heart failure there is still huge unmet medical needs.

Blocked artery causes Acute Myocardial Infarction (AMI) and damages to the heart muscle (loss of muscle cells).

Loss of cells reduces heart contractility and leads to heart failure

Therapy value proposition

Post AMI Cell Therapy- 4 Critical Success Factors

Successful cell therapy in acute ischemic heart diseases likely depends on direct injection into or at the border of the ischemic lesion of the largest number possible of CD34+stem cells via an appropriate catheter, between 15 days and two months after severe AMI. These four points: CD34+ stem cells; high cell doses; intramyocardial injection route; and acute or subacute myocardial ischemia indication, appear as to be the key factors that allow avoiding secondary heart failure, which is very difficult to effectively treat and is associated with a short/ middle term bad prognosis (Fig. 2). Until now, none of the reported clinical trials have associated all of these key factors.

This is the objective of the on-going EXCELLENT trial (EUDRACT 2014–001476-63) using autologous PB-CD34+ cells, expanded via the automated StemXpand® device and StemPack® production kits we have developed, and injected trans-endocardially via the Helix™ catheter at the end of the fourth week post-AMI.

CellProthera is the only company able to bring all 4 factors together.

Literature

1 Key Success Factors for Regenerative Medicine in Acquired Heart Diseases, Ph. Hénon, Stem Cell Rev Rep. 2020; 16(3): 441-458, 2020
2 Quyyumi, A. A., et al. (2017). PreSERVE AMI. Circulation Research, 120, 324-331.ging studies: 24, 35, 37
3 Mitsutake, Y., et al. (2017). Improvement of local ceel delivery using helix transendocardial delivery catheter in a porcine heart. International Heart Journal, 58, 1-645
4 Schächinger, V., et al. (2006). REPAIR-AMI. The New England Journal of Medicine, 355, 1210-1221

Proof of concept demonstrates potential of CD34+ cell therapy

We have shown that there is long term benefit after intracardiac delivery of autologous CD34+ cells in both young and old patients with acute myocardial infarct (Pasquet et al. 2009 ). This was an open label clinical trial in which some of the patients were scheduled to receive a heart transplant after acute myocardial infarct. But after the transplantation of CD34+ cells, the improvement was such that they no longer needed the heart transplant and are still alive and well 12 years later. Left ventricular ejection fraction values increased with time, associated with PetScan demonstration of myocardial structure regeneration and revascularization and New York Heart Association grade improvement.

For a normal subject LVEF is over 70%. The patients included in the study had a LVEF lower than 35%, clearly indicating the presence of a severe heart failure.
By using Adult Stemcell obtained from a patient’s own body, this therapeutic approach avoids all challenges currently faced by other types of cell-based clinical therapies including tissue rejection, immunosuppressive treatments and instances of the cells differentiating into cells other than cardiomyocytes and vessels at the contact of the myocardial ischemic zone.
This one-shot treatment can be considered as an innovative solution revolution for the management of patients suffering severe AMI compared to existing treatments.

6 months after stem cells grafting

Mycocardial regeneration

Such imaging technique using labeled products like glucose and ammonium allow the quantification of functional recovery (regeneration of myocardial tissue) and also the revascularization of myocardium after cell graft.

The necrotic area after AMI does not fix glucose or ammonium and therefore is not any longer visualized providing a lacuna image on the PET Scan. When the myocardium has initiated its regeneration it become again visualized by fixing labeled ammonium and glucose.
From a clinical standpoint, the myocardial regeneration translated into a progressive improvement of the infarcted zone contractility leading to a parallel improvement of the global cardiac function as illustrated by a reduction of the observed cardiac dilatation and a concomitant significant increase in the left ventricular ejection fraction (LVEF). The LVEF corresponds to the ratio between the systolic ejection volume (ventricular volume when emptied after myocardium contraction) and the diastolic volume (full volume). This a key measure to assess the cardiac muscle function.
The measurements of the LVEF after cell graft revealed a progressive and prolonged significant improvement up to +43 points (an 160% increase) compared to the pretreatment assessments
Most of the treated patients with cell graft experience a nearly normal life, some of them with a follow-up period exceeding 13 years.
All three patients initially awaiting a heart transplant are since then leading a normal life with the additional benefit of no immunosuppressive treatment as the cell graft was prepared from their own cells (autologous stem cells).

On-going clinical trial phase I / IIb

A multicentric controlled phase I / IIb study evaluating the safety and the efficacy of in vitro expanded peripheral blood CD34+ stem cells output by the StemXpand® device Automated Process, and injected in patients with an acute myocardial infarction and a Left Ventricle Ejection Fraction (LVEF) remaining below 50% versus standard of care.

EXCELLENT – Expanded Cell Endocardiac Transplantation – multicentric placebo-controlled phase 2 clinical trial to evaluate the safety and efficacy of autologous CD34+ stem cells in patients with an acute myocardial infarction (EXCELLENT study, ClinicalTrials.gov Identifier: NCT02669810).
Based on 44 patients, the clinical trial is currently ongoing in both France and UK for patients who have suffered from an acute myocardial infarct and have a low left ventricular ejection fraction LVEF

In this study we expand peripheral blood CD34+ stem cells with our proprietary StemXpand® Automated Process (Saucourt et al. 2019 ). We obtain similar numbers of CD34+ cells from both old and young donors and the expanded cells (ProtheraCytes®) have the same properties as native CD34+ cells. They also :

regenerate the injured heart after myocardial infarction,
improve ventricular contractility and relaxation, left ventricular ejection fraction, cardiac output, and stroke volume in animal models
reduce the ischemic surface area and increase ventricle wall thickness (Saucourt et al. 2019).

Patients pathway

When a patient with an acute myocardial infarction is admitted to a cardiology emergency, he or she is managed by the medical team. If the patient meets the criteria for inclusion in the clinical trial, the investigating doctor will determine whether he or she is suitable to participate in the study by checking, among other things, the patient’s medical history, current state of health, etc. He or she will then present the consent form to the patient for reading, understanding and acceptance.

If the patient agrees to participate, he/she signs the consent form and participates in the randomisation:

either in the STANDARD TREATMENT ARM, the patient receives the standard care commonly performed to treat the condition and the 1, 3 and 6 month follow-up programme applies.
or in the Verum arm in which he will receive the study treatment by injection of an autologous graft, and the following steps will apply.

1. Myocardial infarction
A heart attack or Myocardial infarction occurs when a blood clot blocks the coronary artery. The heart muscle becomes ‘‘starved” of oxygen. A severe heart attack leads to heart failure: a chronic disease that weakens heart function and reduces life expectancy (survival rate of 50% at 5 years)

2. Blood mobilization
The first step of the therapy is to collect a blood sample of enriched stem cells. This mobilization phase consists of one administration visit per day for a total of five days using a ‘‘stem cell booster
drug”.

3. Blood Collection
Once the blood has been enriched with stem cells, a blood collection is performed

4. Cell Expansion
The blood collected is processed in a cell therapy centre. The purpose is to obtain a high concentration of purified stem cells called Protheracytes®.

5. Stem Cell Injection
The Protheracytes® are then injected into your heart through the femoral artery by the cardiologist.

Follow-up of the injected patient
A visit at 3 and 6 months is planned for each patient in the clinical trial. This visit takes place in the hospital where the patient was treated.

Potential benefits
The injection of an autologous CD34+ stem cell graft may allow for the improvement of cardiac ventricular function, functionality and viability of cardiac tissue and therefore improve life expectancy and quality of life.

This treatment is a one-time procedure, is autologous (from the patient himself) and does not induce rejection. It contributes to the improvement of the therapeutic possibilities of acute myocardial infarction.