First‐in‐human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of SAR247799, a selective G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist for endothelial protection

Abstract

SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P 1) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P 1-desensitizing molecules developed for multiple sclerosis, can activate S1P 1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization). Methods: SAR247799 was administered orally to healthy subjects in a double-blind, randomized, placebo-controlled study with single (2.5-37.5 mg) or 2-week once-daily (0.5-15 mg) doses. An open-label single dose pilot food-interaction arm with 10 mg SAR247799 in cross-over design was also performed. Results: SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose-dependent pharmacodynamics associated with S1P 1 activation (heart rate reduction) and S1P 1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose-proportional increases in exposure and was eliminated with an apparent terminal half-life of 31.2-33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7-23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P 1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating

A label‐free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P1 agonists

“…Furthermore, these preclinical findings showed translation to human studies, where SAR247799 showed improvement in endothelial function in type-2 diabetes patients, again at sub-lymphocyte-reducing doses [12]. SAR247799 displayed an attractive safety and tolerability profile in humans, and supratherapeutic doses were characterized by dose-dependent lymphocyte reduction, a biphasic effect consistent with that observed in preclinical studies [11,12,13].…”

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

“…Indeed, we showed in the present study in Ob-ZSF1 rats, that SAR247799, through its mechanism of action on endothelial function, reduced VLF bands of systolic blood pressure variability, an index of endothelial nitric oxide pathway activation (23). Similarly, our previous work shows that SAR247799 improves coronary microvascular reserve in a pig model of ischemic injury (15) and endothelial and renal function in diabetic rats (16). Furthermore, SAR247799 improves flow-mediated dilation in type-2 diabetes patients (16).…”

“…Effects of SAR247799 on physiological parameters SAR247799 was incorporated in the chow at the dose of 250 mg/kg as a previous study from our laboratory demonstrated the effect of this dose in endothelial protection in another rat model of metabolic dysfunction (16). In this study, the plasma concentration of SAR247799 after 4 weeks of treatment was 7-fold higher in young compared to the old ZSF1 rats.…”

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

“…However, in none of the treatment groups was blood pressure or BAD (prehyperaemia) altered compared to placebo; findings consistent with an absence of blood pressure effect with SAR247799 in healthy subjects. 52 Although S1P modulates blood pressure by acting on vascular smooth muscle (S1P 2/3 ) and endothelium (S1P 1/3 ), a lack of functional S1P 1 receptors on vascular smooth muscle, [81][82][83] lends further support that our FMD results with SAR247799 are unlikely to be influenced by a direct action on vascular smooth muscle.…”

“…50,51 In healthy subjects, SAR247799 has an attractive safety, tolerability and pharmacokinetics (PK) profile and the dose-response relationship for lymphocyte pharmacodynamics (PD) has been characterized. 52 Although preclinical studies with SAR247799 showed protective effects in the renal and coronary vasculature in a preventative setting using single doses administered prior to an insult of ischaemia/reperfusion-induced endothelial injury, the effect of chronic administration of SAR247799 on the endothelium is currently unknown. Furthermore, as previous molecules were S1P 1− desensitizing, the effect of S1P 1 activation on endothelial properties in patients has not yet been studied.…”