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The aim was to show whether S1P\n 1<\/jats:sub>\n activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Type\u20102 diabetes patients, enriched for endothelial dysfunction (flow\u2010mediated dilation, FMD <7%;\n n<\/jats:italic>\n = 54), were randomized, in 2 sequential cohorts, to 28\u2010day once\u2010daily 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\u2010week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The maximum FMD change from baseline\n vs<\/jats:italic>\n placebo for all treatments was reached on day 35; mean differences\n vs<\/jats:italic>\n placebo were 0.60% (95% confidence interval [CI] \u22120.34 to 1.53%;\n P =<\/jats:italic>\n .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%;\n P =<\/jats:italic>\n .026) for 5 mg SAR247799 and 0.88% (95% CI \u22120.15 to 1.91%;\n P =<\/jats:italic>\n .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal\u2010to\u2010no lymphocyte reduction and small\u2010to\u2010moderate heart rate decrease.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n These data provide the first human evidence suggesting endothelial\u2010protective properties of S1P\n 1<\/jats:sub>\n activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub\u2010lymphocyte\u2010reducing doses (\u22645 mg), is warranted in vascular diseases associated with endothelial dysfunction.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bcp.14632","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T16:45:07Z","timestamp":1604076307000},"page":"2303-2320","source":"Crossref","is-referenced-by-count":13,"title":["Endothelial\u2010protective effects of a G\u2010protein\u2010biased sphingosine\u20101 phosphate receptor\u20101 agonist, SAR247799, in type\u20102 diabetes rats and a randomized placebo\u2010controlled patient trial"],"prefix":"10.1111","volume":"87","author":[{"given":"Luc","family":"Bergougnan","sequence":"first","affiliation":[{"name":"Sanofi R&D 1 Avenue Pierre Brossolette Chilly Mazarin France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grit","family":"Andersen","sequence":"additional","affiliation":[{"name":"Profil Neuss 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