The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate

Br J Pharmacol. 2012 Nov;167(5):1035-47. doi: 10.1111/j.1476-5381.2012.02061.x.


Background and purpose: BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P(1) and S1P(5 ) receptors. S1P(1) receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data.

Experimental approach: BAF312 was tested in a rat experimental autoimmune encephalomyelitis (EAE) model. Electrophysiological recordings of G-protein-coupled inwardly rectifying potassium (GIRK) channels were carried out in human atrial myocytes. A Phase I multiple-dose trial studied the pharmacokinetics, pharmacodynamics and safety of BAF312 in 48 healthy subjects.

Key results: BAF312 effectively suppressed EAE in rats by internalizing S1P(1) receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4(+) T cells, T(naïve) , T(central memory) and B cells within 4-6 h. Cell counts returned to normal ranges within a week after stopping treatment, in line with the elimination half-life of BAF312. Despite sparing S1P(3) receptors (associated with bradycardia in mice), BAF312 induced rapid, transient (day 1 only) bradycardia in humans. BAF312-mediated activation of GIRK channels in human atrial myocytes can fully explain the bradycardia.

Conclusion and implications: This study illustrates species-specific differences in S1P receptor specificity for first-dose cardiac effects. Based on its profound but rapidly reversible inhibition of lymphocyte trafficking, BAF312 may have potential as a treatment for immune-mediated diseases.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Azetidines / pharmacology
  • Azetidines / therapeutic use
  • Benzyl Compounds / pharmacology
  • Benzyl Compounds / therapeutic use
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Double-Blind Method
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology
  • Female
  • Heart Rate / drug effects*
  • Humans
  • Immunologic Factors / pharmacology*
  • Immunologic Factors / therapeutic use
  • Lymphocyte Count
  • Lymphocytes / drug effects*
  • Lymphocytes / physiology
  • Male
  • Middle Aged
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology
  • Rats
  • Receptors, Lysosphingolipid / physiology*
  • Species Specificity
  • Young Adult


  • Azetidines
  • Benzyl Compounds
  • Immunologic Factors
  • Receptors, Lysosphingolipid
  • siponimod