The Safety, Tolerability, and Effects on the Systemic Inflammatory Response and Renal Function of the Human Chorionic Gonadotropin Hormone-Derivative EA-230 Following On-Pump Cardiac Surgery (The EASI Study): Protocol for a Randomized, Double-Blind, Placebo-Controlled Phase 2 Study

Aarnoutse

et al. 2019

Brit J Clinical Pharma

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Aims EA‐230 is a newly developed synthetic linear tetrapeptide (AQGV) derived from the chorionic gonadotropin hormone (β‐hCG). We investigated the pharmacokinetics, safety and tolerability of EA‐230 in healthy subjects using different administration strategies. Methods Double‐blind, randomized, placebo‐controlled, dose‐escalating phase I studies in healthy subjects using intravenous administration were conducted. In the single dosage study, 32 subjects were assigned to four single dosage groups (1, 3, 10 or 30 mg/kg). In the multiple dosage study, 24 subjects were assigned to three dosage groups (10, 20 or 30 mg/kg, thrice daily for 3 days). In the continuous dosage study, 24 subjects were assigned to three dosage groups (15, 30, or 90 mg/kg/hour for 2 hours). Pharmacokinetics, safety and tolerability assessments were performed up to 14 days. Results The highest dosage of EA‐230 (continuous infusion of 90 mg/kg/hour for 2 hours) showed more than proportional increases in exposure (Cmax136%; AUC0‐last137%), a large volume of distribution (geometric mean and 95% CI: 13 [3–58] L/kg), a high clearance rate (26 [15–43] L/h/kg), and a short half‐life (0.35 [0.13–1.0] minutes). EA‐230 was well tolerated and no safety concerns were observed. Conclusion These dose‐escalating phase I studies with different administration strategies reveal a pharmacokinetic profile of EA‐230 with a large volume of distribution and a short half‐life. Furthermore, EA‐230 was well tolerated and no safety issues emerged. These results have enabled further clinical development in a phase IIa trial assessing the pharmacodynamics of this compound during systemic inflammation described elsewhere in this issue.

Section: Discussionmentioning

confidence: 73%

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

Aarnoutse

et al. 2019

Brit J Clinical Pharma

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“…These inflammation‐related effects on pharmacokinetic characteristics of EA‐230 need to be further elucidated. The favourable safety profile of EA‐230 and promising immunomodulatory results pave the way for a phase IIb clinical trial to assess the anti‐inflammatory and tissue‐protective effects of EA‐230 in patients …”

Section: Discussionmentioning

confidence: 99%

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

Leijte

et al. 2019

Brit J Clinical Pharma

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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.

“…The next step in the clinical development of EA-230 is represented by a currently ongoing patient trial, of which the design is described in detail elsewhere. 39 Briefly, this Figure 2. Area under the time-concentration curve of both phase 2a experimental human endotoxemia studies.…”

Section: Phase 2b Studymentioning

confidence: 99%

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

Beunders

et al. 2019

Seminars in Nephrology

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The extent of the systemic inflammatory response following infectious or noninfectious insults is related to impaired patient outcome. Pregnancy is associated with immunotolerance and an increased glomerular filtration rate. EA-230 is a newly developed synthetic linear tetrapeptide derived from the "pregnancy hormone" human chorionic gonadotropin. In this review, we describe the immunomodulatory and renoprotective properties of EA-230 in preclinical animal models, phase 1 studies in humans and phase 2a studies performed during human experimental endotoxemia. In addition, details pertaining to the design of a recently completed phase 2b study in 180 patients who underwent cardiac surgery to investigate the safety and immunomodulatory and renoprotective properties of EA-230 are discussed.