title: Pharmacological modulation of peripheral T and B lymphocytes by a selective sphingosine 1-phosphate receptor-1 modulator.
abstract: 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.
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ 08837, USA. jmoberly@dsi.com
authors.forename: James B
authors.initials: JB
authors.lastname: Moberly
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Hamim
authors.initials: H
authors.lastname: Zahir
authors.forename: Ching
authors.initials: C
authors.lastname: Hsu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Noveck
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Truitt
mesh_terms: D000328:Adult; D000605:Amino Alcohols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
chemical_list: D000605:Amino Alcohols; C569297:CS 0777; D011758:Pyrroles; D049349:Receptors, Lysosphingolipid