Some thoughts to consider...Stem cell therapy is one of several...

Some thoughts to consider...

Stem cell therapy is one of several biological interventions which has shown promise in treating acute respiratory distress syndrome (ARDS).

COVID-19 is an acute respiratory distress syndrome caused by the SARS-CoV-2 coronavirus. Influenza viruses can also cause ARDS.

The hypothesis driving the use of stem cells to treat ARDS and COVID-19 is that stem cells can counteract the hyper-inflammatory response in the lungs that is typical of ARDS.

Athersys' Phase I/II ARDS Trial (2016-2018)

In May 2019, US company Athersys released one year follow up data of a Phase II randomised, double-blind, placebo-controlled trial of its Multistem cell therapy in 30 patients with ARDS. Twenty patients were in the treatment arm and 10 patients were in the placebo group. [NCT02611609]

Multistem is an off-the-shelf (allogeneic) stem cell product that is derived from multipotent adult progenitor cells, sourced from bone marrow.

The exploratory study showed that Multistem was well tolerated through a 4-hour infusion, no adverse events of special interest occurred and no SAEs were recorded over the 12 month follow-up.

Multistem achieved a median of 18.5 ventilator-free days com-pared to 6.5 for the placebo group, a median 12.5 ICU-free days compared to 4.5 for the placebo, and a mortality rate of 25% at day 28, compared to 40% in the placebo group. The results were even more positive for patients with severe ARDS (eight patients in each sub-group), with Multistem achieving a median of 18.5 ventilator free days compared to 3.5 days in the placebo group.

Athersys also reported that 45% of Multistem treated patients were taken off ventilator support by day 7 compared to 20% for placebo, and that after one year, 80% of surviving patients were caring for themselves independently compared to 40% from the placebo group. Athersys recently commenced a 400 patient randomised, double-blind, placebo-controlled trial in COVID-19 patients, with the primary endpoint being ventilator-free days during the 28 day clinical assessment.

2,500 Patients in 39 Stem Cell Trials

According to the leading clinical trials database, Clinicaltrial.gov, Athersys' 400 patient trial is the largest of an estimated 39 COVID-19 stem cell therapy trials planned or underway, which are enroll-ing 2,461 patients. Of these trials, 21 are underway, and are enroll-ing 1,625 patients.

The next largest trial is that sponsored by ASX-listed Mesoblast and Icahn School of Medicine at Mount Sinai, which is aiming to recruit 300 patients, for a 12-month study.

The median number of patients to be enrolled is these 39 trials is 40.

29 trials have declared primary completion dates by the end of 2020.

75% of these studies are randomised.

36 trials are evaluating mesenchymal stem cell (MSCs) therapies, in which the cells are sourced from adipose (fat) tissue, dental pulp, umbilical cord, olfactory mucosa and bone marrow.

One therapy is derived from human embryonic stem cells (CAStem). ASX-listed Cynata is planning a Phase II trial of its Cymerus MSCs which are derived from induced pluripotent stem cells (iPSCs) and Athersys' Multistem (multipotent adult progenitor cells) are sourced from bone marrow.

Of special interest is that two trials [NCT04276987 and NCT04366063], will involve extracellular vesicles (Exosomes) de-rived from MSCs, with one of these interventions being delivered by a nebuliser (aerosolised and then inhaled).

Exosomes are 'cargo carriers' which contain the cytokines and growth factors and other signalling molecules which deliver anti-inflammatory effects at the site of inflammation.

Another trial [NCT04299152] is aiming to prime immune cells through apheresis and exposure to cord blood stem cells and then return the cells to circulation.

This is an interesting although commercially unscalable approach, in contrast to those therapies which take advantage of frozen, donor cells (allogeneic or off-the-shelf approaches) as developed, for example by Athersys, Mesoblast, Hope Biosciences, Pluristem and Cynata.

Patient Recruitment

One the challenges facing groups seeking to evaluate therapies to treat COVID-19 is access to patients.

An analysis of Clinicaltrials.gov (and including Cynata’s planned trial) shows that 704 trials are underway or planned for therapies (radiation, drugs and biologicals), combination products, devices and procedures directed to COVID-19, aiming to recruit 392,904 patients. These figures exclude vaccines.

These 39 trials, if they could all be completed, have the potential to increase understanding of the effects of different doses and dosing frequencies of stem cell therapies applied to treating ARDS, as well as potentially bring forward insights into exosome approaches, a technology being investigated and developed by ASX-listed Exopharm.

Exopharm's focus is on scalable exosome manufacture but the company also plans to enter the clinic with an allogeneic platelet derived product, Plexaris