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

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.

Trial registration: ClinicalTrials.gov NCT03462017.

Keywords: SAR247799; diabetes; endothelium; flow-mediated dilation; sphingosine-1 phosphate receptor-1.

Conflict of interest statement

At the time of conduct of the studies, L.B., M.F.E., B.P., A.T., O.V., F.H., R.B., X.B., D.R., P.J., A.J.M., L.H., S.K., P.D. and A.A.P. were employees of Sanofi; G.A., L.P., M.E., T.H., J.A. and H.C. were employees of Profil Institute; R.S. and C.H. received personal fees from Profil Institute. Authors affiliated with Sanofi may have equity interest in Sanofi. A.A.P., B.P. and P.J. are inventors of US patent number 9 782 411. C.H. received grants from Deutsche Forschungsgemeinschaft, Mitsubishi Cleansui, Wild Blueberry Association of North America, University of Surrey, Philips, National Processed Raspberry Council, Cranberry Institute and Rheacell, and personal fees from Bayer and Novo Nordisk, all outside of the submitted work.

© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

FIGURE 1

Effects of SAR247799 on lymphocytes, heart rate and renal parameters in diabetic rats. Zucker diabetic fatty (ZDF) rats treated for 5 weeks with chow formulated with control (0), low (L; 0.002% w/w), intermediate (I; 0.007% w/w) or high (H; 0.0245% w/w) doses of SAR247799. Age‐matched lean rats treated with control chow (0) for comparison. n = 8, 12, 14, 12 rats in lean, ZDF 0, ZDF L, ZDF I, ZDF H groups, respectively. Bars are mean ± standard error of the mean when Shapiro–Wilks test did not reject normality hypothesis (A, B) and median ± interquartile range otherwise (C–G). #P < .05, ##P < .01, ###P < .001 for lean vs ZDF control group; A and B by Student t test; E, F, G by Wilcoxon test; C and D baseline comparisons of lean vs the 4 ZDF groups by Kruskal–Wallis followed by Wilcoxon posthoc test; C and D treatment comparisons of lean vs ZDF control group by Wilcoxon test. * P < .05, ** P < .01, *** P < .001 for treated groups vs ZDF control group; A and B by 1‐way ANOVA followed by Dunnett's test; E, F, G and C & D (treatment) by Kruskal–Wallis test followed by Wilcoxon posthoc test

FIGURE 2

Effects of SAR247799 on plasma biomarkers in diabetic rats. Zucker diabetic fatty (ZDF) rats following 5‐week treatment with chow formulated with control (0), low (L; 0.002% w/w), intermediate (I; 0.007% w/w), or high (H; 0.0245% w/w) doses of SAR247799. Age‐matched lean rats treated with control chow (0) for comparison. n = 8, 12, 14, 12 rats in lean, ZDF 0, ZDF L, ZDF I, ZDF H groups, respectively. Bars represent mean ± standard error of the mean when Shapiro–Wilks test did not reject normality hypothesis (C) and median ± interquartile range otherwise (A, B, D, E, F, G). ##P < .01, ###P < .001 for lean vs ZDF control group; Student t‐test for C, or Wilcoxon test for A, B, D, E, F, G. * P < .05, ** P < .01, for treated groups vs ZDF control group; Kruskal–Wallis test followed by Wilcoxon posthoc test for A, B, D, E, F, G

FIGURE 3

Design and patient (pt) progress through randomized, double‐blinded clinical trial to evaluate SAR247799 on flow‐mediated dilation in type‐2 diabetes patients. (A) Study design. (B) Flow chart of patient progress through trial. of the 122 patients not meeting inclusion criteria, 14 were because flow‐mediated dilation (FMD) was >7%. # 1 patient excluded for unusable FMD data and 1 patient withdrawn. DSM, dose selection meeting; PK, pharmacokinetics; B, baseline; EOS, end of study; BAD, brachial artery diameter; HR, heart rate; BP, blood pressure; PK, pharmacokinetics

FIGURE 4

Effect of SAR247799 (1 and 5 mg), sildenafil (50 mg), or placebo on heart rate (A) and lymphocytes (B) in type‐2 diabetes patients. Heart rate and lymphocytes expressed on each day (D1–D28) at time points associated with maximal pharmacodynamic effects (4 and 6.5 h, respectively). Mean ± standard error of the mean; P values shown when < .05 (repeated‐measure model as described under Methods)

FIGURE 5

Effect of SAR247799 (1 and 5 mg), sildenafil (50 mg), or placebo on % flow‐mediated dilation (FMD) in type‐2 diabetes patients. FMD data expressed as change from baseline (A), or change from baseline, placebo corrected (B). Bars are mean ± standard error of the mean. Variation in the placebo groups in B (placebo‐corrected FMD change) illustrated by retaining error bars with mean zero (first group at each time point). Precise P‐values for difference vs placebo shown when P < .05; repeated‐measure model as described under Methods. Number of patients with FMD data in each histogram was as follows for placebo/1 mg SAR247799/5 mg SAR247799/50 mg sildenafil, respectively; 12/15/15/10 (D14, D21, D28 and D42) and 12/15/13/10 (D35)