Amiselimod, a novel sphingosine 1‐phosphate receptor‐1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk

Abstract

Background and PurposeWe conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT‐1303), a second‐generation sphingosine 1‐phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators.Experimental ApproachThe selectivity of the active metabolite amiselimod phosphate (amiselimod‐P) for human S1P receptors and activation of G‐protein‐coupled inwardly rectifying K+ (GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determined in rats, and cardiovascular telemetry was assessed in monkeys. We also examined the pharmacokinetics, pharmacodynamics and safety of amiselimod in healthy humans.Key ResultsAmiselimod‐P showed potent selectivity for S1P1 and high selectivity for S1P5 receptors, with minimal agonist activity for S1P4 and no distinct agonist activity for S1P2 or S1P3 receptors and approximately five‐fold weaker GIRK activation than fingolimod‐P. After oral administration of amiselimod or fingolimod at 1 mg·kg−1, the concentration of amiselimod‐P in rat heart tissue was lower than that of fingolimod‐P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters. In healthy human subjects, peripheral blood lymphocyte counts gradually reduced over the 21 day dosing period, with similar lymphocyte count profiles with the highest doses by day 21, and no clinically significant bradycardia observed on day 1 or during the study.Conclusions and ImplicationsAmiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.

Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties

“…It is thus conceivable that the interplay of several S1P receptor subtypes and distinct signaling pathways influence physiological airway responses. In support of this hypothesis, we show that the nonselective, Ca 2+ signaling S1P 1‐5 receptor agonist pFTY720 induces pronounced bronchoconstriction ex vivo and in vivo, as reported previously, and in addition we now show that the selective, Ca 2+ signaling S1P 1 receptor agonist p‐amiselimod also leads to bronchoconstriction.…”

“…However, whereas S1P and pFTY720 preserved a similar or higher potency for inducing Ca 2+ signaling in HUVEC compared to ( 35 S)‐GTPγS binding, cenerimod was much less potent (approximately 500‐fold) in Ca 2+ signaling than in ( 35 S)‐GTPγS assays. Interestingly, p‐amiselimod, the active metabolite of amiselimod, and siponimod, two other recently described selective S1P 1 receptor agonists in clinical development, were also devoid of such a pronounced pathway bias (Table ), suggesting that cenerimod is indeed different. The Ca 2+ signaling responses in HUVEC were pertussis toxin sensitive and fully blocked by the selective S1P 1 receptor antagonist TASP0277308 (Figure ).…”

“…Similar results were seen in isolated rat bronchus (data not shown). Interestingly, the active metabolite of amiselimod (p‐amiselimod), which is a potent and selective S1P 1 receptor agonist with Ca 2+ signaling activity, also induced effective rat trachea constriction at 1 μmol·L ‐1 and 10 μmol·L ‐1 (Figure ). To extend these studies, we performed concentration response experiments in human bronchi.…”

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

“…In addition, amiselimod‐P has shown a significantly attenuated potential to activate the GIRK channel in human atrial myocytes compared with fingolimod‐P in an in vitro GIRK channel assay . The favourable cardiac safety profile of amiselimod has also been demonstrated in human subjects: In a phase I multiple ascending dose study in healthy subjects, no clinically significant negative chronotropic/dromotropic effects were observed at doses up to 0.75 mg . In the phase II study, which enrolled more than 400 patients with RRMS, amiselimod up to 0.4 mg has shown a benign safety profile in addition to its superior efficacy to the placebo control .…”

A review of bioanalytical quantitative methods for selected sphingosine 1‐phosphate receptor modulators

“…Separation was achieved using C 18 column using an isocratic flow for nonclinical samples and gradient flow for clinical sample bioanalysis. Amiselimod ( m/z 378 → 175) and amiselimod phosphate ( m/z 456 → 79) were detected in multiple reaction monitoring (MRM) mode with positive ion (Sugahara et al, ).…”