Dose-dependent Reduction of Lymphocyte Count and Heart Rate After Multiple Administration of LC51-0255, a Novel Sphingosine-1-phosphate Receptor 1 Modulator, in Healthy Subjects

Sphingosine-1-phosphate receptor mediates the egress of lymphocytes from lymphoid organs, and its inhibition results in a decreased number of circulating lymphocytes. The aim of the current study was to investigate the safety and pharmacodynamic and pharmacokinetic characteristics of a novel sphingosine-1-phosphate receptor modulator, LC51-0255. A phase 1 randomized, double-blind, placebo-controlled, multiple dosing, dose-escalation study was conducted on healthy Korean male subjects. After single and daily administration of LC51-0255 for 21 days, a dose-dependent decrease in lymphocyte count and heart rate was observed through 0.25-2 mg dose range of LC51-0255. The mean elimination half-life of LC51-0255 was 76-95 h. LC51-0255 was accumulated with a mean accumulation ratio of 5.17-6.64. During the study, LC51-0255 was generally well tolerated. The most common treatment-emergent adverse event was bradycardia. No clinically significant event of arrhythmia, including AV block, was observed. No clinically significant difference in blood pressure was observed between the dose groups. In other safety assessments, no clinically significant abnormalities were observed, except for bradycardia. Daily administration of LC51-0255 in the range of 0.25-2 mg resulted in a dose-dependent reduction of lymphocyte counts and heart rate. LC51-0255 is generally safe and well tolerated in healthy volunteers.