Safety, tolerability, and immunomodulatory effects of EA-230 in humans

Introduction The systemic inflammatory response syndrome (SIRS) can lead to pronounced tissue damage and is a frequent cause of multi‐organ failure and mortality in Intensive Care units1. SIRS can be elicited by a variety of insults, such as sepsis, trauma, and major surgery, and no specific therapy is currently in routine use. EA‐230 is a newly developed synthetic linear tetrapeptide derived from the β‐human chorionic gonadotropin hormone (β‐hCG), which has shown promising anti‐inflammatory and tissue‐protective effects in animal studies2,3. Objectives To investigate the tolerability, safety and immunomodulatory effects of EA‐230 in humans. Methods We conducted a double blind, placebo controlled, doseescalating randomized clinical trial in 60 healthy volunteers. The study was carried out in two phases. In the first phase (n = 24), safety and tolerability was established for escalating doses of EA‐230 (30, 90, and 180 mg/kg). In the second phase (n = 36), the same doses were used to assess the effects of EA‐230 on systemic inflammation during experimental human endotoxemia. At t = 0 hours, 2 ng/kg E. Coli endotoxin was administered i.v. followed by a 2‐hour continuous i.v. infusion of EA‐230 or placebo. Levels of circulating cytokines and adhesion molecules as well as body temperature and flu‐like symptoms were assessed. Furthermore, effects on renal function were investigated using plasma clearance of iohexol. Results EA‐230 was well tolerated and showed an excellent safety profile. Treatment with the highest dose of EA‐230, but not with lower doses, resulted in a significant attenuation of the endotoxininduced increase in plasma levels of IL‐6, IL‐8, IL‐1RA, MCP‐1, MIP‐1α, and MIP‐1β (IL‐6, IL‐8, and MCP‐1 shown in Fig. 50a, b, and c), and the adhesion molecule VCAM‐1 (Fig. 50d). Furthermore, the highest dose of EA‐230 reduced fever and flu‐like symptoms (Fig. 51). Endotoxemia resulted in a marked increase in GFR, but no differences between groups were observed. Conclusion Administration of EA‐230 is safe and results in attenuation of the systemic inflammatory response in humans. These promising results pave the way for a phase IIb clinical trial to assess the anti‐inflammatory and tissue‐protective effects of EA‐230 in patients.