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

Aims: SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P₁ ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P₁ -desensitizing molecules developed for multiple sclerosis, can activate S1P₁ 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 S1P₁ activation (heart rate reduction) and S1P₁ 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 S1P₁ activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P₁ activation without tachyphylaxis. Sub-lymphocyte-reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P₁ and exhibit endothelial-protective properties, had minimal-to-no heart rate reduction and displayed no marked safety findings.

Conclusion: SAR247799 is suitable for exploring the biological role of endothelial S1P₁ activation without causing receptor desensitization.