PK/PD of EA-230 During Endotoxemia

Endotoxemia, Systemic Inflammatory Response

EA-230, Inflammatory response, Kidney Injury, Endotoxemia

EA-230 is a newly developed synthetic compound with anti-inflammatory properties. Pre-clinical data indicate that EA-230 may be a valuable treatment for systemic inflammation resulting from a variety of causes such as surgery, trauma, infection, irradiation and others. Although previous studies in healthy volunteers have shown an excellent safety profile, the safety and tolerability of higher doses administered per continuous infusion need to be investigated. Also, the dose-effect relation on systemic inflammation needs to be further elucidated before a phase II trial in patients can be commenced.

Although the immune system is essential to survival, a variety of diseases originate from inappropriate activation of the immune response. Besides a range of auto-inflammatory disease like rheumatoid arthritis, inappropriate or undesirable activation of the immune system can occur during infectious diseases like sepsis, after major surgery like cardiac artery bypass grafting, after radiation therapy in the treatment of cancer, or after organ transplantation. For auto-inflammatory diseases, in the last decades therapies have come available that specifically target parts of the immune system. The development of 'biologicals', recombinant antibodies that specifically block one antigen or receptor, has had an enormous impact on the treatment of chronic autoimmune diseases. However, these treatments have been shown not to be effective in other types of (acute) systemic inflammation, like sepsis. Of the many downstream consequences of exaggerated inflammatory response, organ injury and failure is the most serious, most often involving the kidneys. This also holds true for cardiac surgery with cardiopulmonary bypass, in which various factors, including the inflammatory cascade, cause a temporarily decline or even permanent loss of renal function. As kidney failure is an independent prognostic factor for mortality in critically ill patients, treatments aimed at preventing acute kidney injury are warranted. EA-230 is a novel pharmacological compound being developed for the treatment of systemic inflammatory states like sepsis, and for the treatment of inflammation associated organ dysfunction like acute kidney injury (AKI). It's a linear tetrapeptide derived from the human chorionic gonadotropin hormone (hCG). It has shown anti-inflammatory properties and protects against organ failure in several pre-clinical models of sepsis or systemic inflammation which will be described in more detail below. Most notably, EA-230 has shown marked protective effects in the kidney during abdominal sepsis in animals. 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, especially in the kidney. Having performed extensive research into the pharmacology, pharmacokinetics and toxicology of EA-230, a first in human study was previously conducted with escalating single doses of EA-230, which showed that EA-230 was well tolerated up to i.v. doses of 30 mg/kg three times a day (daily dose of 90 mg/kg) for three days, and did not result in adverse events that were related to the study treatment. In a human model of systemic inflammation elicited by the administration of a low dose of endotoxin, EA-230 showed to attenuate the innate immune response at a single i.v. dose of 10 mg/kg, even though EA-230 was administered 30 minutes after endotoxin administration. A full dose- and concentration-response profile was not collected in that study. In addition, until now, only bolus administrations of EA-230 were tested, whereas in view of the short terminal half life of less than 15 minutes, a continuous administration of EA-230 over a longer time interval may be more effective. For that reason, an additional phase I study in healthy volunteers is required to complete the profile of EA-230 response in inflammation before a dose or dose range can be chosen for a first 'prove-of-concept' study in patients. The safety profile of EA-230 has to be extended beyond the daily dose of 90 mg/kg addressed to date; the dose- and concentration response information collected during escalation will provide the dose for proof-of-concept testing in patients.

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