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• W3026145530 abstract "SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. A dose-response study in diabetic rats with 5-week SAR247799 treatment demonstrated, at sub-lymphocyte-reducing doses, renal function and endothelial biomarker improvements and was used to select doses for human investigation. Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD<7%) (n=54), were randomized, in two 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. The maximum FMD change from baseline versus placebo for all treatments was reached on day 35; mean differences versus placebo were 0.60% (95% CI -0.34%-1.53%; p=0.203) for 1 mg SAR247799, 1.07% (95% CI 0.13%-2.01%; p=0.026) for 5 mg SAR247799 and 0.88% (95% CI -0.15%-1.91%; p=0.093) 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. These data provide the first human evidence for endothelial-protective properties of S1P1 activation, with SAR247799 being at least as effective as the clinical benchmark, sildenafil." @default.
• W3026145530 created "2020-05-29" @default.
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• W3026145530 date "2020-05-20" @default.
• W3026145530 modified "2023-10-01" @default.
• W3026145530 title "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." @default.
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• W3026145530 doi "https://doi.org/10.1101/2020.05.15.20103101" @default.
• W3026145530 hasPublicationYear "2020" @default.
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