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.
P Gergely  1 ,  B Nuesslein-Hildesheim ,  D Guerini ,  V Brinkmann ,  M Traebert ,  C Bruns ,  S Pan ,  N S Gray ,  K Hinterding ,  N G Cooke ,  A Groenewegen ,  A Vitaliti ,  T Sing ,  O Luttringer ,  J Yang ,  A Gardin ,  N Wang ,  W J Crumb Jr ,  M Saltzman ,  M Rosenberg ,  E Wallström
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Basel, Switzerland Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
PMID: 22646698 DOI: 10.1111/j.1476-5381.2012.02061.x
Abstract

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.

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