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.

AIMS: 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. The aim was to show whether S1P1 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 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.

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 (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). 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 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. CONCLUSION: SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.

Modulation of vasoactivity and platelet aggregation by selective 5-HT receptor antagonism in humans.

BACKGROUND: Distinct serotonin [5-hydroxytryptamine (5-HT)] receptors are involved in platelet aggregation and vasoconstriction. Compounds that simultaneously and selectively inhibit the pertaining 5-HT receptors may therefore represent a therapeutic strategy for arterial thrombosis, observed frequently after atherosclerotic plaque rupture. The vasoactive and antiplatelet effects of the combined 5-HT1B and 5-HT2A receptor blocker SL65.0472-00 were investigated in humans to elucidate the functional involvement of these receptors. METHODS: Twenty-four volunteers, divided into 2 groups of 12, received an oral dose of 20 mg of SL65.0472-00 or placebo in a randomized, double-blind, crossover study. Pre dose and at 2, 4, and 6 hours after dosing, intra-arterial infusions of 5-HT1B agonist sumatriptan (n = 12) or 5-HT (n = 12) were administered. Forearm blood flow (FBF) was measured using plethysmography, and platelet aggregation was measured using whole blood aggregometry induced by a combination of a threshold collagen concentration and an excess of 5-HT. Treatments were compared using analysis of variance. RESULTS: After placebo treatment, infusion of 1 ng·kg·min 5-HT induced vasodilatation (FBF +80% change from baseline), whereas infusion of 30 and 80 ng·kg·min 5-HT resulted in vasoconstriction (FBF -25% and -50%). After SL65.0472-00 treatment, all 5-HT doses induced vasodilatation (FBF +25%-60%). Sumatriptan dose dependently decreased FBF (maximally -35%), but this effect was not altered by SL65.0472-00 treatment. 5-HT-induced platelet aggregation was effectively inhibited by 90% after SL65.0472-00 treatment for at least 6 hours. CONCLUSIONS: SL65.0472-00 has potent antagonistic effect on 5-HT-induced vasoconstriction and platelet aggregation but not on sumatriptan-induced vasoconstriction. This suggests that in humans, SL65.0472-00 is a 5-HT2A blocker without clear 5-HT1B antagonistic activity.