• P Gergely, 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, M Saltzman, M Rosenberg, and E Wallström.
• Novartis Institutes for BioMedical Research, Basel, Switzerland Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
• Br. J. Pharmacol. 2012 Nov 1; 167 (5): 1035-47.

Background And PurposeBAF312 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 ApproachBAF312 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 ResultsBAF312 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 ImplicationsThis 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.© 2012 Novartis Institutes for Biomedical Research. British Journal of Pharmacology © 2012 The British Pharmacological Society.

40 keywords...

hide…