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 (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 cardiac S1P(1) activation without tachyphylaxis. Sub‐lymphocyte‐reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P(1) 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 S1P(1) activation without causing receptor desensitization.