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

Article Details

Citation

Tran JQ, Hartung JP, Peach RJ, Boehm MF, Rosen H, Smith H, Brooks JL, Timony GA, Olson AD, Gujrathi S, Frohna PA

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

J Clin Pharmacol. 2017 Aug;57(8):988-996. doi: 10.1002/jcph.887. Epub 2017 Apr 11.

PubMed ID
28398597 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
OzanimodSphingosine 1-phosphate receptor 1ProteinHumans
Yes
Agonist
Details
OzanimodSphingosine 1-phosphate receptor 5ProteinHumans
Yes
Agonist
Details