A Phase 1 First‐in‐Human Single‐Ascending‐Dose Trial With ESB1609, a Selective Agonist to the Sphingosine‐1‐Phosphate Receptor 5

Abstract

ESB1609 is a small‐molecule sphingosine‐1‐phosphate‐5 receptor–selective agonist designed to restore lipid homeostasis by promoting cytosolic egress of sphingosine‐1‐phosphate to reduce abnormal levels of ceramide and cholesterol in disease. A phase 1 study was conducted in healthy volunteers to determine the safety, tolerability, and pharmacokinetics of ESB1609. Following single oral doses, ESB1609 demonstrated linear pharmacokinetics in plasma and cerebrospinal fluid (CSF) for formulations containing sodium laurel sulfate. Plasma and CSF median time to maximum drug concentration (tmax) were reached by 4–5 hours and 6–10 hours, respectively. The delay in achieving tmax in CSF relative to plasma, likely due to the high protein binding of ESB1609, was also observed in 2 rat studies. Continuous CSF collection via indwelling catheters confirmed that a highly protein‐bound compound is measurable and established the kinetics of ESB1609 in human CSF. Mean plasma terminal elimination half‐lives ranged from 20.2 to 26.8 hours. The effect of either a high‐fat or standard meal increased maximum plasma concentration and area under the concentration‐time curve from time 0 to infinity compared to the fasted state by 2.42–4.34‐fold higher, but tmax and half‐life remained the same irrespective of fed state. ESB1609 crosses the blood‐brain barrier with CSF:plasma ratios ranging between 0.04% and 0.07% across dose levels. ESB1609 demonstrated a favorable safety and tolerability profile at exposures expected to be efficacious.