title: 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 S1P1Rand S1P5Rreceptors 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.
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Jonathan Q
authors.initials: JQ
authors.lastname: Tran
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Hartung
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Peach
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Boehm
authors.affiliation: Scripps Research Institute, San Diego, CA, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Smith
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Brooks
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Timony
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Allan D
authors.initials: AD
authors.lastname: Olson
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Gujrathi
authors.affiliation: Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, CA, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Frohna
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D005215:Fasting / Q000378:metabolism; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D055815:Young Adult
chemical_list: D007189:Indans; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; C000607776:ozanimod
keywords: first-in-human study; ozanimod; pharmacodynamics; pharmacokinetics; safety; sphingosine-1-phosphate receptor