Study to Assess the Pharmacodynamic Effects of Repeated Oral Doses of SAR247799 on Endothelial Function in Male and Female Patients With Type 2 Diabetes Mellitus

Primary Objective:
To assess the pharmacodynamic effects of SAR247799 on macrovascular endothelial function of the brachial artery using flow-mediated dilation (FMD) in patients with type 2 diabetes mellitus (T2DM).
Secondary Objective:
To assess the pharmacodynamic effects of SAR247799 on microvascular endothelial function using laser Doppler perfusion monitoring in patients with T2DM.
To assess the safety profile of SAR247799 in patients with T2DM.
To assess the plasma pharmacokinetic profile of SAR247799 in patients with T2DM.

开始日期2018-03-07

申办/合作机构

Sanofi

100 项与 SAR-247799 相关的临床结果

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100 项与 SAR-247799 相关的转化医学

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100 项与 SAR-247799 相关的专利（医药）

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项与 SAR-247799 相关的文献（医药）

2021-05-01·British Journal of Clinical Pharmacology2区 · 医学

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

2区 · 医学

Article

作者: Benain, Xavier ; Tardat, Agnes ; Andersen, Grit ; Plum‐Mörschel, Leona ; Boiron, Rania ; Evaristi, Maria Francesca ; Muslin, Anthony J. ; Sansone, Roberto ; Janiak, Philip ; Parkar, Ashfaq A. ; Poirier, Bruno ; Ermer, Marcel ; Herbrand, Theresa ; Deutsch, Paul ; Vitse, Olivier ; Radzik, David ; Hurbin, Fabrice ; Arrubla, Jorge ; Kirkesseli, Stephane ; Heiss, Christian ; Coester, Hans Veit ; Bergougnan, Luc ; Hovsepian, Lionel

AimsSAR247799 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. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation.MethodsType‐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.ResultsThe 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.ConclusionThese data provide the first human evidence suggesting endothelial‐protective properties of S1P1 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.

2021-02-01·British Journal of Clinical Pharmacology2区 · 医学

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

2区 · 医学

Article

作者: Radzik, David ; Muslin, Anthony J. ; Hovsepian, Lionel ; Gaudin, Christophe ; Scemama, Michel ; Armani, Sara ; Poitiers, Franck ; Hurbin, Fabrice ; Vitse, Olivier ; Tardat, Agnes ; Kirkesseli, Stephane ; Golor, Georg ; Parkar, Ashfaq A. ; Bergougnan, Luc ; Deutsch, Paul

AimsSAR247799 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).MethodsSAR247799 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.ResultsSAR247799 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.ConclusionSAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.

2020-10-01·FEBS Open Bio4区 · 生物学

A label‐free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P₁ agonists

4区 · 生物学

ArticleOA

作者: Parkar, Ashfaq A. ; Beauverger, Philippe ; Boutarfa‐Madec, Asma ; Janiak, Philip ; Grailhe, Patrick

Sphingosine‐1 phosphate receptor‐1 (S1P1) activation maintains endothelial barrier integrity, whereas S1P1 desensitization induces peripheral blood lymphopenia. The latter is exploited in the approval and/or late‐stage development of receptor‐desensitizing agents targeting the S1P1 receptor in multiple sclerosis, such as siponimod, ozanimod, and ponesimod. SAR247799 is a recently described G protein‐biased S1P1 agonist that activates S1P1 without desensitization and thus has endothelial‐protective properties in patients without reducing lymphocytes. As SAR247799 demonstrated endothelial‐protective effects at sub‐lymphocyte‐reducing doses, the possibility exists that other S1P1 modulators could also exhibit endothelial‐protective properties at lower doses. To explore this possibility, we sought to quantitatively compare the biased properties of SAR247799 with the most advanced clinical molecules targeting S1P1. In this study, we define the β‐arrestin pathway component of the impedance profile following S1P1 activation in a human umbilical vein endothelial cell line (HUVEC) and report quantitative indices of the S1P1 activation‐to‐desensitization ratio of various clinical molecules. In a label‐free impedance assay assessing endothelial barrier integrity and disruption, the mean estimates (95% confidence interval) of the activation‐to‐desensitization ratios of SAR247799, ponesimod, ozanimod, and siponimod were 114 (91.1–143), 7.66 (3.41–17.2), 6.35 (3.21–12.5), and 0.170 (0.0523–0.555), respectively. Thus, we show that SAR247799 is the most G protein‐biased S1P1 agonist currently characterized. This rank order of bias among the most clinically advanced S1P1 modulators provides a new perspective on the relative potential of these clinical molecules for improving endothelial function in patients in relation to their lymphocyte‐reducing (desensitization) properties.

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