ARDS is an inflammatory process leading to build-up of fluid in the lungs and respiratory failure. It can occur due to infection, trauma and inhalation of noxious substances. ARDS often affects previously healthy individuals. It accounts for approximately 10% of all ICU admissions and almost 25% of patients requiring mechanical ventilation. Survivors of ARDS are often left with severe long term illness and disability. ARDS is a frequent complication of patients with COVID-19.
Cynata collaborated with a world leading, multi-centre research team, Critical Care Research Group (CCRG), to investigate its Cymerus™ MSCs as a treatment for ARDS, in combination with extracorporeal membrane oxygenation (ECMO). The study was funded by the Queensland State Government, the National Health and Medical Research Council (NHMRC), the Intensive Care Society UK, and the Prince Charles Hospital Foundation. ECMO circulates blood through an artificial lung, oxygenating the blood before putting it back into the bloodstream of a patient. ECMO has emerged as a valuable treatment adjunct to support the vital organs in patients with severe ARDS, which can provide short-to-medium term mechanical pulmonary support. However, ECMO is not in itself a treatment for ARDS, and the mortality among patients supported by it remains high.
MSC therapy could be used as a possible treatment for ARDS due to the ability of MSCs to reduce inflammation, enhance clearance of pathogens and stimulate tissue repair.
The study sought to determine if Cymerus MSC treatment improves oxygenation in sheep with ARDS supported by ECMO, and to evaluate the effects on lung mechanics, blood flow, inflammation and lung injury, as well as safety. Cymerus MSC treatment was shown to exert a number of important beneficial effects in this study:
• The severity of lung injury was significantly reduced, as shown by histological lung injury score;
• Inflammation was significantly reduced, as shown by levels of the inflammatory cytokine IL-8 in the lungs at 3, 13 and 23 hours after treatment ;
• There was a reduction in the depth and severity of circulatory shock, as shown by a highly significant increase in arterial blood pressure after 4 hours, and a significant reduction in the requirement for noradrenaline (a drug used to maintain blood pressure) over the entire study period. Circulatory shock is a life-threatening condition that often occurs in patients with ARDS, which can result in low blood pressure, increased heart rate, and impaired function of multiple organs.
The pre-clinical study results, which have been published in American Journal of Respiratory and Critical Care Medicine (AJRCCM), provide a sound basis for progressing to a clinical study. In May 2020 Cynata received ethics committee approval to undertake a clinical trial to investigate the early efficacy of Cynata’s proprietary Cymerus MSCs in adults admitted to intensive care with COVID-19. Twelve patients will be randomised to receive Cymerus MSC infusions, in addition to standard of care, while 12 patients will be randomised to the control group and will receive current standard of care. The primary efficacy endpoint will be improvement in PaO2/FiO2 ratio (a measure of hypoxemia, a low level of oxygen in the blood caused by compromised lung function) by Day 7. Safety and tolerability up to Day 28 will also be a primary endpoint.
The trial opened for patient enrollment at study centers in Australia in August 2020. With relatively low numbers of COVID-19 patients in Australia, Cynata successfully sought to expand the recruitment criteria to include patients in intensive care with respiratory failure arising from causes beyond COVID-19. The trial enrolled the first patient in May 2021, with completion dependent upon recruitment rate and originally expected by the end of 2021. However, the changing nature of the COVID-19 pandemic together with continuous pressure on healthcare systems, created significant delays in recruitment as hospitals experienced staffing shortages and prioritised conventional standards of care over clinical trials. In addition, the introduction of new antiviral drugs and rapid uptake of COVID vaccines meant fewer patients migrating to ICU, further reducing the pool of eligible patients. Given the uncertainty surrounding timely patient recruitment, continuation was considered to be imprudent, particularly in light of the other promising indications within Cynata's portfolio. The trial was therefore concluded in August 2022.