Progress in Stem Cell Therapy for Transplant, Stroke and ARDS Patients

Researchers from the University of Newcastle recently published results that demonstrated an improvement in the function of suboptimal donor kidneys following delivery of MultiStem® – an adult stem cell product candidate being developed by Athersys – in combination with an organ-preservation method. The findings suggest that the quality of transplant organs could ultimately be improved, helping patients to receive more efficient donor organs.

Technology Networks spoke with Gil Van Bokkelen, CEO of Athersys, to learn more about MultiStem and the main mechanisms of action the cells have on the body. Gil also discussed some of the additional indications that the cells are being investigated as potential therapies for, including ischemic stroke and acute respiratory distress syndrome (ARDS).

Anna MacDonald (AM): What is MultiStem and how are the MultiStem cell banks created?

Gil Van Bokkelen (GVB): MultiStem is an investigational cell therapy consisting of a special class of stem cells called Multipotent Adult Progenitor Cells, or MAPC®. They are obtained from healthy adult bone marrow and can be administered by intravenous administration, without tissue matching or immune suppression. These cells are distinct from mesenchymal stem cells (MSCs) and other cell types, and preclinical and clinical results suggest they can promote healing and tissue repair in multiple ways. These cells may be expanded outside the human body using our proprietary manufacturing processes.

We begin with a healthy, consenting adult donor, who undergoes a full medical review and subsequently provides a tissue donation. While our research has shown that we can isolate the cells that comprise MultiStem from a variety of tissue sources, starting with a bone marrow aspirate is the easiest, most consistent, and most practical way to do it. We isolate cells from the bone marrow and expand them to a certain amount to create a Master Cell Bank (MCB), consisting of standard units of MAPC to be used for subsequent cell bank production and product manufacturing. The MCB is thoroughly assessed and characterized using a variety of tests, and once it is qualified, it is ready for use. We use MCB cells to create a Working Cell Bank (WCB). Once the WCB is qualified, we use WCB cells to perform manufacturing runs, i.e., create an inventory of doses, using our proprietary process.

We are focused on bioreactor manufacturing, which allows for three-dimensional cell culturing as opposed to traditional two-dimensional cell factories, to harness the scalability aspect of the technology. This will enable us to meet the demands (and corresponding opportunity) for indications like stroke, and other critical care areas where our therapeutic platform is relevant. Bioreactors allow for increased cell production and are more cost-effective per expansion batch. Having a streamlined biomanufacturing process will be essential for large scale commercialization of cell and gene therapies, enabling these technologies to enter mainstream of medicine. At Athersys we are always working to improve the process and improve cell counts while decreasing costs.

AM: What makes these cells special and well suited for cellular therapy?

GVB: MultiStem offers many advantages over MSCs and other cell types. The first is the scalability, which is extremely important for the commercialization as I mentioned above. Unlike some stem cell types that senesce over time and are hard to grow over multiple passages in the lab, MultiStem are genetically unmodified marrow stromal cells with robust growth properties and a demonstrated capacity to yield millions of doses from a single healthy, consenting adult donor source.

The second advantage of these unique cells is they can be administered without tissue matching or immune suppression, similar to Type O blood. The cells have potent immunomodulatory and immunoregulatory properties that make this possible, and we have data from multiple clinical and preclinical studies that illustrate the tolerability and consistency of this approach. In addition, the cells that comprise MultiStem are not genetically modified, nor do they need to be differentiated prior to use as a therapeutic.

Third, the cells are extremely easy to store, prepare and administer. We spent years optimizing a fast and efficient system because we knew it would be advantageous to have a simple method for hospital pharmacy staff. MultiStem cell therapy is an “off-the-shelf” product candidate, and the cells are stored frozen in a vial. To prepare the cells, the frozen suspension of cells in the vial is thawed, the liquid cell suspension is removed from the vial using a sterile syringe and the cells are then added to an IV bag. The cells can be prepared for the patient typically within 30 minutes or less and are then administered intravenously.

We have also been developing a proprietary technology called SIFU™ (Secure Integrated Freezer Unit) which allows for even faster and simpler product storage and preparation, while also enabling fully secure track and trace inventory control. The SIFU works without the need for liquid nitrogen, and with its small footprint, it will fit easily in most pharmacies. The freezer unit robotically retrieves a dose of MultiStem, thaws the vial, and dispenses it to the authorized hospital staff when it is ready. The cells are then transferred to the IV bag and delivered to the patient.

Fourth, in contrast to single modality therapies (e.g., traditional pharmaceuticals or conventional protein or peptide biologics), MultiStem consists of living cells that have been shown to dynamically respond to signals of tissue damage and injury in multiple ways, such as downregulating the inflammatory cascade, stimulating immunomodulatory repair mechanisms, stimulating neurogenic or neurotrophic mechanisms or cardiogenic/cytoprotective pathways where such responses are biologically relevant, and promoting angiogenesis/vasculogenesis in regions of ischemic damage and injury.

Fifth, MultiStem has demonstrated a consistent tolerability profile across numerous therapeutic areas. MultiStem has been delivered to many patients in both completed and ongoing clinical studies and the product has been well-tolerated.

AM: What are the main mechanisms of action that MultiStem cells have on the body?

GVB: In contrast to traditional pharmaceuticals or biologics, which typically act through a single mechanism of action, we have shown that MultiStem exerts a therapeutic benefit through multiple mechanisms of action. We and numerous collaborators have shown that the cells have the remarkable capacity to home to sites of tissue damage, inflammation, and injury, as well as to key organ systems that play a fundamental role in the body’s response to injury. The cells that comprise the MultiStem product downregulate the hyperinflammatory cascade that occurs after a stroke or trauma, or the cytokine storm that is causing pulmonary dysfunction in patients with ARDS. In addition, they upregulate key healing mechanisms and pathways that help the body, and the patient, recover. This reduces inflammation resulting in less secondary tissue damage and scarring, and allows for accelerated repair processes to begin, potentially improving recovery and outcomes for the patients.

The cells can express a range of therapeutically relevant proteins and other factors that have the potential to deliver therapeutic benefits, such as reducing inflammation, protecting damaged or injured tissue, and enhancing the formation of new blood vessels in regions of ischemic injury. These cells exhibit a “drug-like” profile, in that they act primarily through the production of factors that regulate the immune system, and the cells are subsequently cleared from the body over time – much like a traditional drug or biologic treatment. However, it’s important to recognize that unlike traditional pharmaceuticals or biologics, MultiStem is a living biologic that dynamically responds to the needs of the body and conveys benefit through multiple distinct mechanisms of action.

AM: A recent study by researchers at Newcastle University showed that MultiStem combined with Normothermic Machine Perfusion improved the function of marginal kidneys. Can you tell us more about the study, the effects the cells had on the kidneys, and the implications of the findings?

GVB: We are very excited about these encouraging results from this study, which give hope for the advancement of techniques for improving the quality of transplant organs for patients on a waiting list.

The UK kidney transplant waiting list stands at over 5,000 patients. Kidney transplantation is the best treatment for patients with kidney failure, however, on average, patients wait three years for an organ to become available. Often, kidney organs for donation are classified as “marginal”, meaning they are of suboptimal quality and will not last a lifetime in the patient.

To help these patients in need, there have been research efforts to improve the quality and health of kidneys after they have experienced irreversible loss of function due to a variety of factors.

This was a randomized controlled study where kidneys underwent a procedure called Normothermic Machine Perfusion (NMP), a recently established method for organ preservation. In addition to NMP, some of the kidneys were treated with MultiStem cells and some were given control.

Dr Emily Thompson, who led these research efforts, discovered that the kidneys treated with MultiStem demonstrated several responses associated with better function caused by the release of anti-inflammatory molecules, improving blood flow to damaged cells and increasing urine production.

These results suggest that we may be able to pre-treat kidneys ex vivo, as opposed to treating the patient before or after transplantation. This was the first successful delivery of cellular therapy to a human kidney during NMP, and we are very proud of the hard work by Dr Thompson and colleagues. This is promising for the future of organ transplants, as the data suggests we may ultimately be able to improve the quality of transplant organs, reduce waiting times, and improve the health outcomes for patients.

AM: MultiStem is also part of clinical trials for a range of other diseases, including stroke and ARDS. Can you tell us more about the progress of these trials and the findings so far?

GVB: Absolutely. We are currently running a Phase 3 clinical trial for the treatment of ischemic stroke (MASTERS-2 study), recently initiated a Phase 2/3 pivotal trial for the treatment of COVID-19 induced ARDS (MACoVIA study), and we have FDA authorization to start a Phase 2 clinical trial for the treatment of trauma (MATRICS-1), which we expect to launch this summer. In addition to these three trials, our partner in Japan, HEALIOS K.K. is also conducting a clinical trial using MultiStem cell therapy for the treatment of ischemic stroke (the TREASURE study) and an ARDS clinical trial (the ONE-BRIDGE study). Both of their studies are expected to finish enrollment this year.

Ischemic stroke is the leading cause of disability in the world. Athersys is developing MultiStem for the treatment of ischemic stroke, which may be administered to a patient up to 36 hours after the stroke, based on prior clinical results. This could dramatically extend the time window for therapy, potentially enabling up to 90-95% of stroke patients to be eligible to receive the therapy.

The MASTERS-2 Study, our trial for the treatment of ischemic stroke is being conducted primarily in North America and Europe. This pivotal, 300-patient clinical trial is being run under a Special Protocol Assessment, or SPA, by the FDA for the design and planned analysis. In addition, the program has received multiple regulatory designations meant to expedite approval, including Fast Track designation and Regenerative Medicine Advanced Therapy, or RMAT, from the FDA. The European Medicines Device Agency, or EMA, granted the program a Final Scientific Advice positive opinion establishing alignment between European and the United States regulators about the potential for approval based on the success of the planned MASTERS-2 study, which further expedites development. We expect to complete enrollment of the MASTERS-2 study sometime next year.

ARDS is a serious immunological and inflammatory condition characterized by widespread inflammation in the lungs. ARDS can be triggered by pneumonia, sepsis, or trauma and represents a major cause of morbidity and mortality in the critical care setting. It has significant implications, as it may result in a prolonged intensive care unit (ICU) and hospital stays and may also require convalescence in the hospital and rehabilitation. ARDS is the leading cause of death among COVID-19 patients that become seriously or critically ill.

In 2019 we announced positive results for an exploratory Phase 1/2 clinical study evaluating MultiStem cell therapy for the treatment of ARDS. Patients in the double-blind, randomized, placebo-controlled exploratory study were evaluated through 28 days for the primary clinical assessment and were further assessed through a one-year follow-up period. Topline clinical trial results showed meaningful improvements in mortality, ventilator-free days, and ICU-free days among MultiStem treated patients in comparison with patients receiving placebo. Additional data was presented at the 2019 American Thoracic Society International Conference in May 2019, which was highlighted as a key presentation. This program has been granted Fast Track designation by the FDA because of this promising data.

In April 2020 we initiated the MACOVIA study to evaluate MultiStem cell therapy for the treatment of COVID-19 induced ARDS patients. This trial is a multicenter study with an open-label, single active treatment arm for cohort 1 followed by a double-blind, randomized, placebo-controlled Phase 2/3 portion. The primary objectives of the MACOVIA study are to evaluate the safety and efficacy of MultiStem as a therapy for subjects with moderate to severe ARDS due to COVID-19.

The primary efficacy endpoint will be an evaluation of ventilator-free days through day 28 as compared to placebo, a well-established endpoint for ARDS trials that evaluate an intervention’s combined impact on survival and liberation from invasive mechanical ventilation. The secondary objectives of this study include evaluation of pulmonary function, all-cause mortality, time in intensive care, hospitalization, tolerability, and quality of life (QoL) among survivors, and a biomarker analysis will also be performed.

The study is designed to enroll approximately 400 subjects and will be conducted at leading pulmonary critical care centers throughout the United States.

AM: What future directions do you envisage for MultiStem?

GVB: We believe our technology has broad potential applications in critical care medicine, including complications from trauma, transplantation support, and other areas. We and our collaborators around the world are doing a lot of preclinical and clinical research to explore the ways that MultiStem may help in a variety of indications, including neurological, cardiovascular disease, and inflammatory/immune disorders. This research has shown great promise.

We believe MultiStem may also help with certain chronic conditions, but we are primarily focused on acute critical care indications where research suggests that MultiStem may be administered to reduce the hyperinflammatory cascade and the corresponding damage it creates, reduce cell death, and promote better recovery by creating an environment that is more conducive to repair and healing. These are also clinical indications where the current standard of care is limited or inadequate for many patients, and represent major areas of clinical need, as well as substantial commercial opportunities.



Gil Van Bokkelen was speaking to Anna MacDonald, Science Writer for Technology Networks.