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

Abstract

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 (flowmediated 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. The authors confirm that the Principal Investigators for the clinical study were Grit Anderson and Leona Plum-Mörschel and that they had direct clinical responsibility for patients at the Neuss and Mainz sites, respectively. In addition, Grit Andersen was coordinating principal investigator.

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

“…Indeed, we showed in the present study in Ob-ZSF1 rats, that SAR247799, through its mechanism of action on endothelial function, reduced VLF bands of systolic blood pressure variability, an index of endothelial nitric oxide pathway activation (23). Similarly, our previous work shows that SAR247799 improves coronary microvascular reserve in a pig model of ischemic injury (15) and endothelial and renal function in diabetic rats (16). Furthermore, SAR247799 improves flow-mediated dilation in type-2 diabetes patients (16).…”

“…Effects of SAR247799 on physiological parameters SAR247799 was incorporated in the chow at the dose of 250 mg/kg as a previous study from our laboratory demonstrated the effect of this dose in endothelial protection in another rat model of metabolic dysfunction (16). In this study, the plasma concentration of SAR247799 after weeks of treatment was 7-fold higher in young compared to the old ZSF1 rats.…”

“…SAR247799 thus exhibits endothelial-protective properties without reducing lymphocytes (15). SAR247799 improves the coronary microvascular hyperemic response in pigs, improves endothelial barrier integrity in a rat model of renal ischemia/reperfusion injury (15) and restores renal function and endothelial parameters in a rat model of type-2 diabetes (16). Moreover, SAR247799 demonstrates good safety and tolerability in healthy subjects (17) and improves endothelial function, as assessed by flow-mediated dilation in type-2 diabetic patients (16).…”

“…Despite efforts to explore the effects of some endothelial-based therapies in the components of HFpEF, there is no confirmation at present that restoring endothelial function would provide clinical improvements in the progression of the components of HFpEF. We therefore set out to test whether 4-week oral treatment with the S1P 1 agonist, SAR247799, a molecule that we have previously shown has endothelial protective effects in animals and humans (14)(15)(16)(17) improves cardiac structural and functional parameters in a rat model of LVH and diastolic function. We used the diabetic Zucker fatty spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat, carrying two separate leptin receptor mutations (fa and facp), which has been described as a genetically-hypertensive, obese and diabetic model of HFpEF (18,19).…”

S1P Stimulates Erythropoietin Production in Mouse Renal Interstitial Fibroblasts by S1P1 and S1P3 Receptor Activation and HIF-2α Stabilization

“…This compound is a G protein-biased selective S1P 1 agonist that activates the G i/0 pathway more potently than the β-arrestin recruitment and S1P 1 internalization [87]. Therefore, the compound will activate S1P 1 without receptor desensitization and lymphocyte depletion [87,88]. Regarding renal Epo production, it would be very interesting to see whether this compound can stimulate Epo production in a more long-term situation.…”