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J Clin Pharmacol. 2012 Jul;52(7):996-1006. doi: 10.1177/0091270011408728. Epub 2011 May 12.

Pharmacological modulation of peripheral T and B lymphocytes by a selective sphingosine 1-phosphate receptor-1 modulator.

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Daiichi Sankyo Pharma Development, Edison, NJ 08837, USA.


CS-0777 is a selective sphingosine 1-phosphate receptor-1 (S1P(1)) modulator under development for treatment of autoimmune conditions. A randomized, double-blind, placebo-controlled study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CS-0777 in escalating dose cohorts of healthy male participants (0.1, 0.3, 1.0, and 2.5 mg; 6 active, 2 placebo per cohort). Primary pharmacodynamic parameters were absolute lymphocyte counts and lymphocyte subsets (CD4 and CD8 T and B cells). CS-0777 resulted in a pronounced, dose-dependent decrease in absolute lymphocyte counts (mean percent decrease from baseline at 24 hours postdose: 7%, 26%, 52%, 79%, and 85%, for placebo and 0.1, 0.3, 1.0, and 2.5 mg, respectively). Dose-related decreases of similar magnitude were observed for T and B cell subsets. Mean total white blood cell and neutrophil counts remained within normal ranges for all dose levels. CS-0777 was well tolerated, and there were no serious or severe adverse events. Mild, asymptomatic bradycardia and transaminase elevations (<3-fold upper limit of normal), similar to findings for other S1P receptor modulators, were observed at the highest dose level (2.5 mg). Therefore, CS-0777 shows potent activity in humans and may hold potential for treatment of autoimmune conditions such as multiple sclerosis.

[Indexed for MEDLINE]

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