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


METHODS
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.


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.


CONCLUSIONS
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.
Novartis Institutes for BioMedical Research, Basel, Switzerland Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
P
P
Gergely
B
B
Nuesslein-Hildesheim
D
D
Guerini
V
V
Brinkmann
M
M
Traebert
C
C
Bruns
S
S
Pan
N S
NS
Gray
K
K
Hinterding
N G
NG
Cooke
A
A
Groenewegen
A
A
Vitaliti
T
T
Sing
O
O
Luttringer
J
J
Yang
A
A
Gardin
N
N
Wang
W J
WJ
Crumb
M
M
Saltzman
M
M
Rosenberg
E
E
Wallström
D000293:Adolescent; D000328:Adult; D000818:Animals; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use; D001593:Benzyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004311:Double-Blind Method; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D013045:Species Specificity; D055815:Young Adult
D001384:Azetidines; D001593:Benzyl Compounds; D007155:Immunologic Factors; D049349:Receptors, Lysosphingolipid; C578989:siponimod