Stem cells haven’t exactly panned out as hoped when it comes to approved therapeutics. There are only a couple that have received a nod from the FDA in very specific indications. But the ongoing COVID-19 pandemic could push stem cells back into the limelight and more firmly establish them as therapeutically relevant.

There are at least a few dozen trials looking at various types of stem cells to treat different aspects of COVID-19 in patients in different states of disease severity. Cleveland-based Athersys Inc. has started a large, pivotal clinical study to enroll up to 400 COVID-19 patients to treat those with moderate to severe acute respiratory distress syndrome (ARDS) with its Multistem candidate, which is available frozen, off-the-shelf and derived from the bone marrow of adult donors.

Building on ARDS data

A small phase I/II study of Multistem to treat ARDS in non-COVID patients previously reported positive results, shortening the average time on a ventilator and in an intensive care unit (ICU).

“Although underpowered, there was a signal there that the cell-based therapy may be beneficial. In the randomized, placebo-controlled, blinded portion of the study, the cell-based therapy was associated with a decrease in ICU days and ventilator day and decreased mortality,” Frank Jacono, who is an associate professor of medicine and a pulmonary and critical care medicine physician at University Hospitals Cleveland and the Cleveland VA Medical Center, told BioWorld of the phase I/II results. “If anything, that signal was strongest in the sickest of the patients. Basically, that is the foundation for the evaluation of COVID-19 moderate to severe ARDS.”

Jacono participated as a site investigator in the phase I/II trial and is the site principal investigator for the newly started phase II/III study of Multistem to treat COVID-19 induced, moderate to severe ARDS.

Multistem has been investigated in various neurological, inflammatory and immune, as well as cardiovascular and other critical care indications, but it has not gained FDA approval. The most advanced indication for the stem cell candidate is to treat patients after an ischemic stroke; it is in a phase III clinical trial in that indication.

In May 2019, Athersys received fast track designation from the FDA for the Multistem for the treatment of ARDS. There are no FDA-approved drugs to treat this indication.

The phase I/II study, known as MUST-ARDS, started with the examination of two doses, first 300 million cells in three patients and then 900 million cells in three patients. The subsequent randomized, double-blinded, placebo-controlled 30-patient trial randomized patients 2:1 to intravenous administration of 900 million Multistem cells vs. placebo.

The study was primarily a safety study – and not powered for efficacy results. However, it did find lower mortality, particularly for more severe ARDS patients; improved quality of life; fewer days on a ventilator (12.9 vs. 9.2 with placebo); and more intensive-care free days (10.3 vs. 8.1 with placebo). Among a prospectively defined group of severe ARDS patients in that study, average ventilator-free days were 14.6 vs. 8 in the placebo subgroup and mean ICU-free days were 11.4 vs. 5.9 days with placebo. These were all assessed after 28 days.

Multiple mechanisms

Multistem vial. Credit: Athersys Inc.

The mechanisms of action for Multistem is not pathogen-specific, of course, so it would potentially work to help the immune system function more effectively to reduce the severe lung inflammation that leads to ARDS. This would include SARS-COV-2, as well as any secondary bacterial pneumonia infection in the same patient.

Multistem is thought to express factors that work to reduce inflammation, protect damaged or injured tissue and enhance the formation of new blood vessels after injury. They are believed to have a drug-like profile in regulating the immune system and promoting system repair. The candidate is expected to decrease the activation of the peripheral immune system, thereby reducing tissue damage and scarring and accelerating repair processes.

“The product is frozen, so it could eventually be deployed widely in lots of different hospital settings because of the company's formulation,” said Jacono. “Sometimes, when people hear stem cells, they think about stem cells going in and repopulating and growing into new cells that would then replace the old cells in the patient. That's not what's hypothesized here.”

“The stem cells will enter the circulation and go to the lungs. It's hoped that they would express factors to help restore and re-regulate the immune response in the lungs – transitioning back from a damaging type of response to a more beneficial response and then leave the body,” he continued. “But they don't persist in the body, they don't set up and grow new cells, they don't replace cells; they just act to sort of modulate the immune response while they're there.”

The recently started phase II/III trial will again start with a dose-ranging precursor. The study’s large enrollment size could mean that it could take a couple of years to get to the results. The inherently unpredictable nature of the ebb and flow of the number of COVID-19 infections, as well as the concurrently shifting availability of other treatments and testing of other candidates, make it difficult to assess how motivated patients and their families will be to enroll in the phase II/III trial.

Known as MACOVIA, the primary efficacy endpoint is the number of ventilator-free days through day 28 vs. placebo. Secondary endpoints include 60-day all-cause mortality, time in the intensive care unit, pulmonary function, tolerability and quality of life among survivors after one year.

Other recent small clinical trials provide some reason to hope for some success with stem cells in COVID-19 treatment. These include a 12-patient study of another allogeneic stem cell therapy, remestemcel-L from Mesoblast Ltd., recently reported positive data treating ventilator-dependent COVID-19 patients with moderate to severe ARDS. A phase II/III study is already ongoing. A seven-patient evaluation of compassionate use of an allogeneic, mesenchymal-like cell therapy from Pluristem Therapeutics Inc. in COVID-19 patients also showed promise.

The expectation for Multistem is that, regardless of the path of the pandemic, the pivotal trial will provide further insight into the usefulness of the candidate in treating moderate to severe ARDS from any cause, which had been the focus previously.

“We want to study this carefully and scientifically,” summed up Jacono. “But at the end, we'll be confident as a result whether or not this is beneficial for patients and should be considered more routinely as part of therapy.”