Effects of multiple-dose ponesimod, a selective SIP1 receptor modulator, on lymphocyte subsets in healthy humans

Jurcevic, S., Juif, P.E., Hamid, C., Greenlaw, R., D'Ambrosio, D. and Dingemanse, J. 2016. Effects of multiple-dose ponesimod, a selective SIP1 receptor modulator, on lymphocyte subsets in healthy humans. Drug Design, Development and Therapy. 11, pp. 123-131. doi:10.2147/DDDT.S120399

TitleEffects of multiple-dose ponesimod, a selective SIP1 receptor modulator, on lymphocyte subsets in healthy humans
AuthorsJurcevic, S.
Juif, P.E.
Hamid, C.
Greenlaw, R.
D'Ambrosio, D.
Dingemanse, J.
Abstract

This study investigated the effects of ponesimod, a selective SIP1 receptor 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 +/- 340x10(6) cells/L and 275 +/- 486x10(6) cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naive CD4(+) T cells (CD45RA(+)CCR7(+)) from baseline was observed only after ponesimod treatment (-113 +/- 98x10(6) cells/L, placebo: 0 +/- 18x10(6) cells/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 +/- 164x10(6) cells/L) and CD4(+) T-effector memory (CD45RA(-)CCR7(-)) cells (-131 +/- 57x10(6) cells/L). In addition, ponesimod treatment led to a decrease of -228 +/- 90x10(6) cells/L of gut-homing T cells (CLA(-)integrin beta 7(+)). 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.

Keywordsponesimod; multiple dose; SIP1 receptor; lymphocyte subsets; CD45RA/CCR7
JournalDrug Design, Development and Therapy
Journal citation11, pp. 123-131
ISSN1177-8881
Year2016
PublisherDove Medical Press Ltd.
Publisher's version
Digital Object Identifier (DOI)doi:10.2147/DDDT.S120399
Publication dates
Published in print2017
Published online28 Dec 2016
Published28 Dec 2016
LicenseCC BY-NC 3.0

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