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Aims  SAR247799 is a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 (S1P 1 ) agonist designed to activate endothelial S1P 1  and provide endothelial‐protective properties, while limiting S1P 1  desensitization and consequent lymphocyte‐count reduction associated with higher doses. The aim was to show whether S1P 1  activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation.    Methods  Type‐2 diabetes patients, enriched for endothelial dysfunction (flow‐mediated dilation, FMD <7%;  n  = 54), were randomized, in 2 sequential cohorts, to 28‐day once‐daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5‐week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing.    Results  The maximum FMD change from baseline  vs  placebo for all treatments was reached on day 35; mean differences  vs  placebo were 0.60% (95% confidence interval [CI] −0.34 to 1.53%;  P =  .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%;  P =  .026) for 5 mg SAR247799 and 0.88% (95% CI −0.15 to 1.91%;  P =  .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal‐to‐no lymphocyte reduction and small‐to‐moderate heart rate decrease.    Conclusion  These data provide the first human evidence suggesting endothelial‐protective properties of S1P 1  activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub‐lymphocyte‐reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.

british journal of clinical pharmacology

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