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

Published

Journal Article

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.

Full Text

Cited Authors

  • Moberly, JB; Rohatagi, S; Zahir, H; Hsu, C; Noveck, RJ; Truitt, KE

Published Date

  • July 2012

Published In

Volume / Issue

  • 52 / 7

Start / End Page

  • 996 - 1006

PubMed ID

  • 21566200

Pubmed Central ID

  • 21566200

Electronic International Standard Serial Number (EISSN)

  • 1552-4604

International Standard Serial Number (ISSN)

  • 0091-2700

Digital Object Identifier (DOI)

  • 10.1177/0091270011408728

Language

  • eng