Results From the First‐in‐Human Study With Ozanimod, a Novel, Selective Sphingosine‐1‐Phosphate Receptor Modulator

Abstract

The sphingosine‐1‐phosphate 1 receptor (S1P1R) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune‐mediated, inflammatory diseases. This first‐in‐human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose‐escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose‐limiting toxicities. The most common ozanimod‐related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady‐state volume of distribution (73–101 L/kg), moderate oral clearance (204–227 L/h), and an elimination half‐life of approximately 17 to 21 hours. Ozanimod produced a robust dose‐dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose‐dependent negative chronotropic effect was observed following the first dose, with the dose‐escalation regimen attenuating the first‐dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once‐daily regimens under clinical investigation.

Cardiac Safety of Ozanimod, a Novel Sphingosine‐1‐Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study

“…Receptor desensitization, internalization, and degradation of the cardiac S1P 1R have been proposed to explain the time‐related attenuation of heart‐rate effects . In a previous phase 1 single‐ascending‐dose and multiple‐ascending‐dose study with ozanimod, a mild dose‐dependent, first‐dose reduction in HR was observed, which was attenuated with an increasing dose‐escalation regimen . No further reduction in HR was observed when the ozanimod dose was escalated up from 1 mg to 2 mg in this study, confirming the effectiveness of the dose‐escalation regimen employed in this TQT study.…”

“…Following oral administration, the median time to maximum concentration (T max ) was approximately 8.0 hours. Ozanimod exhibited linear PK, with a dose‐proportional increase in exposure and low to moderate intersubject variability; a high steady‐state volume of distribution; a moderate apparent oral clearance; and an elimination half‐life of 17 to 21 hours . Ozanimod is eliminated primarily via biotransformation followed by biliary excretion .…”

“…Ozanimod pharmacokinetics (PK) was characterized in healthy volunteers for single oral doses up to 3 mg and multiple oral doses up to 2 mg QD . Following oral administration, the median time to maximum concentration (T max ) was approximately 8.0 hours.…”

Effects of High‐ and Low‐Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine‐1‐Phosphate Receptor Modulator

“…The safety, pharmacokinetics (PK), and pharmacodynamics of ozanimod hydrochloride (HCl) in single oral doses (up to 3 mg) and multiple oral doses (up to 2 mg once daily) were characterized in a phase 1 study of healthy volunteers . Following oral administration under fasting conditions, the median time to maximum concentration (T max ) was approximately 8 hours .…”

“…The safety, pharmacokinetics (PK), and pharmacodynamics of ozanimod hydrochloride (HCl) in single oral doses (up to 3 mg) and multiple oral doses (up to 2 mg once daily) were characterized in a phase 1 study of healthy volunteers . Following oral administration under fasting conditions, the median time to maximum concentration (T max ) was approximately 8 hours . Ozanimod exhibited linear PK, with dose‐proportional increases in exposure and low to moderate intersubject variability (% coefficient of variation, 17%–32%), high apparent volume of distribution (81.9 L/kg), moderate apparent oral clearance (233 L/h), and elimination half‐life of approximately 17 hours .…”