Randomized Double Blind Placebo-controlled Phase II Study on the Effects of EA-230 on the Systemic Inflammatory Response Following On-pump Cardiac Surgery

Systemic inflammation is a condition in which the innate immune system is activated due to a variety of causes such as sepsis, trauma, and major surgical interventions. The clinical condition in which the body responds to such stimuli by the release of circulating inflammatory mediators is well known as the systemic inflammatory response syndrome (SIRS) and is defined by tachypnoea, tachycardia, leucocytosis or leucopenia and hyper- or hypothermia.

Although this activation of the immune system is essential for survival, the often subsequent overwhelming pro-inflammatory response may be detrimental. Of the many downstream consequences of this exaggerated inflammatory response, organ injury and failure is the most serious, most often involving the kidneys. Multiple organ failure (MOF) is associated with high morbidity and mortality, whereas failure of kidneys is an independent prognostic factor for mortality in critically ill patients.

This exaggerated systemic pro-inflammation also occurs during major surgical procedures, especially in cardiac surgery procedures. Multiple stimuli during these procedures, such as sternotomy, extra-corporal cardio-pulmonary bypass (ECC) and aortal cross-clamping, account for substantial systemic inflammatory activation. The extent of inflammation following this procedures is directly associated with patient outcome, as high post-operative levels of IL-6 have been proven to correlate with adverse outcome and mortality. Also at organ level, the incidence of inflammation associated development of acute kidney injury (AKI) following cardiac surgery is high and correlates with adverse outcome and mortality.

To date, no immunomodulatory treatments, aimed at dampening the (acute) systemic inflammatory reaction following cardiac surgery with cardio-pulmonary bypass, have shown to improve essential outcome. Current strategies consist of prevention and supportive treatment; new strategies aiming at attenuating this exaggerated pro-inflammatory response are therefore warranted.

EA-230 is a novel pharmacological compound, developed for the treatment of systemic inflammation and associated organ dysfunction. It is a linear tetrapeptide derived from the human chorionic gonadotropin hormone (hCG). It has shown anti-inflammatory properties and protects against organ failure and associated mortality in several pre-clinical models of sepsis or systemic inflammation. As EA-230 attenuates the pro-inflammatory response in neutrophils and monocytes ex vivo, and neutrophil influx in tissues during systemic inflammation in vivo is abrogated, it is thought that EA-230 acts by protecting the host against the detrimental effects of neutrophils during acute systemic inflammatory diseases, thereby preventing organ damage.