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

Abstract

BACKGROUND AND PURPOSEBAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P1 and S1P5 receptors. S1P1 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 S1P1 receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4+ T cells, Tnaïve, Tcentral 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 S1P3 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.

Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects

“…However, differences in specificity and pharmacokinetics, along with a paucity of available data, make it difficult to generalize cardiac effects across compounds in this class. Data on BAF312 preclinical models and healthy subjects have shown species-specific differences in S1P receptor specificity for first dose cardiac effects [9]. A previous study has demonstrated that initiation of BAF312 at a therapeutic dose of 10 mg resulted in clinically relevant bradycardia (as determined by measurement of mean HRmin) [7].…”

“…The study period was a maximum of 44 days for each subject, comprising a 21-day screening period, a 12-day treatment period (days [1][2][3][4][5][6][7][8][9][10][11][12] and an end of study assessment 10 days after the last treatment day (day 22). Sub-E. Legangneux et al…”

“…The concept of this dose titration, using the Fibonnaci ratio, is to induce the internalization (or down regulation) of S1P receptors at low doses that are known to have little or no cardiac effect. In addition, earlier data suggest that there may be a physiological compensatory mechanism that results in the correction of heart rate within 2 days of first dose administration of BAF312 at therapeutic dose [9]. It is considered that, if the dose titration regimen were to start at a pharmacologically, but not clinically active dose, this compensatory mechanism would also occur during the 10-day titration period.…”

Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials

“…7 However, clinical studies with S1P agonists with selectivity for S1P 1 over S1P 3 have suggested that in humans the heart rate reduction effects are controlled at least in part through agonism of S1P 1 . 8 Additionally, through the course of our own studies it was discovered that simply abolishing S1P 3 agonism was not sufficient to eliminate the acute and chronic pulmonary toxicity elicited in rodents by 1 or by selective S1P 1 full agonists, findings that led us to discontinue our efforts related to S1P 1 full agonists and seek alternative profiles that could overcome these liabilities. 9 In this letter we describe the identification of a differentiated S1P 1 receptor modulator, BMS-986104 (3d), which distinguishes itself from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.…”

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator

“…16−19 However, our recent report suggested species-dependent bradycardia and a dominant role of S1P 1 in mediating heart rate in humans, as the treatment with BAF312, a dual S1P 1,5 agonist sparing S1P 3 activity, caused GIRK channel activation in human atrial myocytes and bradycardia in healthy volunteers. 20 In the same report, we presented the in vitro profile of BAF312, including its effects on S1P 1 receptor internalization as well as its preclinical efficacy in a rat experimental autoimmune encephalomyelitis (EAE) model. Herein, we report our medicinal chemistry efforts that culminated in the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)-imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid 32 (BAF312, Siponimod), a potent S1P 3 -sparing S1P 1 agonist currently undergoing clinical trials in patients with multiple sclerosis.…”