A randomized double‐blind, placebo‐controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA‐230 during experimental human endotoxaemia

Abstract

Aims EA‐230 is a human chorionic gonadotropin hormone‐derived linear tetrapeptide, developed for the treatment of systemic inflammation‐related disorders. EA‐230 has shown promising immunomodulatory and tissue‐protective effects in animals and an excellent safety profile in human phase I studies that we performed. The present phase IIa study follows‐up on these results by investigating the safety, efficacy and pharmacokinetics of EA‐230 under systemic inflammatory conditions induced by experimental human endotoxaemia. Methods In this randomized, double blind, placebo‐controlled phase IIa study, systemic inflammation was induced by intravenous administration of Escherichia coli‐derived lipopolysaccharide (LPS). At t = 0 hours, 36 healthy male volunteers received 2 ng/kg LPS, followed by a 2‐hour continuous infusion of EA‐230 (15, 45 and 90 mg/kg/h, n = 8 per group) or placebo (n = 12). Results EA‐230 was well tolerated and showed a favourable safety profile. Treatment with the highest dose of EA‐230 resulted in a significant attenuation of the LPS‐induced increase in plasma levels of inflammatory mediators interleukin (IL)‐6, IL‐8, IL‐1 receptor antagonist, monocyte chemoattractant protein‐1, macrophage inflammatory proteins‐1α and ‐1β, and vascular cell adhesion protein‐1 (% reduction of 48, 28, 33, 28, 14, 16 and 19 respectively, p < .01), and reduced fever (peak decrease from 1.8 ± 0.1°C to 1.3 ± 0.2°C, P < .05) and symptom scores (peak decrease from 7.4 ± 1.0 to 4.0 ± 1.2 points, P < .05). EA‐230 exhibited a very short elimination half‐life and a large volume of distribution in the highest dosage group (geometric mean and 95% confidence interval: 0.17 [0.12–0.24] hours and 2.2 [1.3–3.8] L/kg, respectively). Conclusion Administration of EA‐230 is safe and results in attenuation of the systemic inflammatory response in humans.

Pharmacokinetics, safety and tolerability of the novel β‐hCG derived immunomodulatory compound, EA‐230

“…The total of 80 volunteers in the three phase I studies with EA-230 would generally be regarded as sufficient. Based on these results, a phase IIa study in volunteers exposed to endotoxin has been conducted to investigate the immunomodulating properties of EA-230 (described elsewhere in this issue 33 ) and a clinical trial in cardiac surgery patients has been initiated. 34 In conclusion, these dose-escalating phase I studies with different administration strategies, describe a PK profile of EA-230 with a large volume of distribution and a short half-life, and demonstrate that i.v.…”

The Human Chorionic Gonadotropin Derivate EA-230 Modulates the Immune Response and Exerts Renal Protective Properties: Therapeutic Potential in Humans

“…In a slightly different setup, the effect of continuous administration of EA-230 on LPS-induced systemic inflammation was investigated in 36 healthy volunteers. 38 Briefly, in this study EA-230 was administered continuously considering its short half-life. Subjects were randomly assigned to one of three dosage groups: 15, 45, or 90 mg/kg/h.…”

An Update on Antimicrobial Peptides (AMPs) and Their Delivery Strategies for Wound Infections

“…A D2A21 AMP encapsulated into Ag nanocomposite exhibited significantly increased antibacterial potency compared to native AMP and AgNPs (MIC: 1 to 3 μg/mL versus 4–6 μg/mL) against P. aeruginosa , S. aureus , and E. coli via membrane damage [ 60 ]. An Andersonin-Y1 peptide has been conjugated to AgNPs through a peptide containing a cysteine linker either at the N- or at the C-terminal.…”