title: Effects of multiple-dose ponesimod, a selective S1P1receptor modulator, on lymphocyte subsets in healthy humans.
abstract: This study investigated the effects of ponesimod, a selective S1P1receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days) or placebo (ratio 3:1). The overall change from baseline in lymphocyte count was -1,292±340×106cells/L and 275±486×106cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naïve CD4+T cells (CD45RA+CCR7+) from baseline was observed only after ponesimod treatment (-113±98×106cells/L, placebo: 0±18×106cells/L). The number of T-cytotoxic (CD3+CD8+) and T-helper (CD3+CD4+) cells was significantly altered following ponesimod treatment compared with placebo. Furthermore, ponesimod treatment resulted in marked decreases in CD4+T-central memory (CD45RA-CCR7+) cells (-437±164×106cells/L) and CD4+T-effector memory (CD45RA-CCR7-) cells (-131±57×106cells/L). In addition, ponesimod treatment led to a decrease of -228±90×106cells/L of gut-homing T cells (CLA-integrin β7+). In contrast, when compared with placebo, CD8+T-effector memory and natural killer (NK) cells were not significantly reduced following multiple-dose administration of ponesimod. In summary, ponesimod treatment led to a marked reduction in overall T and B cells. Further investigations revealed that the number of CD4+cells was dramatically reduced, whereas CD8+and NK cells were less affected, allowing the body to preserve critical viral-clearing functions.
authors.affiliation: Department of Biomedical Sciences, University of Westminster, London, UK.
authors.forename: Stipo
authors.initials: S
authors.lastname: Jurcevic
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Pierre-Eric
authors.initials: PE
authors.lastname: Juif
authors.affiliation: Division of Transplantation Immunology & Mucosal Biology, King's College London, London, UK.
authors.forename: Colleen
authors.initials: C
authors.lastname: Hamid
authors.affiliation: Division of Transplantation Immunology & Mucosal Biology, King's College London, London, UK.
authors.forename: Roseanna
authors.initials: R
authors.lastname: Greenlaw
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Daniele
authors.initials: D
authors.lastname: D'Ambrosio
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000284:Administration, Oral; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D064368:Healthy Volunteers; D006801:Humans; D016131:Lymphocyte Subsets / Q000187:drug effects* / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C550169:ponesimod
keywords: CD45RA/CCR7; S1P1 receptor; lymphocyte subsets; multiple dose; ponesimod