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

Abstract

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.

Keywords: SAR247799; endothelium; pharmacodynamics; pharmacokinetics; sphingosine 1-phosphate.

FIGURE 1

Study dosing scheme. Each cohort in the single ascending dose (SAD) part was composed of 6 subjects on SAR247799 and 2 subjects on placebo. The fed part had 6 subjects in a cross‐over design for the fed and fasted arms. Each cohort in the multiple‐dosing part had 9 subjects on SAR247799 (except n = 10 for the 2.5 mg dose) and 3 subjects on placebo. Each cohort had a 7 day follow‐up period

FIGURE 2

Lymphocyte changes vs baseline following single and 14‐day oral administration of SAR247799 to healthy subjects. A, Day 1 of single ascending dose (n = 6 per dose, 10 placebo). B, Day 1 of multiple‐dosing study (n = 9 at 0.5 mg and 1 mg, n = 10 at 2.5 mg, n = 9 at 5 mg, 10 mg and 15 mg, and n = 18 on placebo). C, Day 14 of multiple‐dosing study (n = 9 at 0.5 mg and 1 mg, n = 10 at 2.5 mg, n = 9 at 5 mg and 10 mg, n = 1 at 15 mg, and n = 16 on placebo). Arithmetic mean and standard deviation

FIGURE 3

Heart rate changes vs baseline following single and 14‐day oral administration of SAR247799 to healthy subjects. A, Day 1 of single‐ascending dose (n = 6 per dose, 10 placebo. B, Day 1 of multiple‐dosing study (n = 9 at 0.5 mg and 1 mg, n = 10 at 2.5 mg, n = 9 at 5, 10 and 15 mg, and n = 18 on placebo). C, Day 14 of multiple‐dosing study (n = 9 at 0.5 and 1 mg, n = 10 at 2.5 mg, n = 9 at 5 and 10 mg, n = 1 at 15 mg, and n = 16 on placebo). Arithmetic mean and standard deviation. Baseline was defined as the average of replicate values at day 1 predose assessments

FIGURE 4

Changes from baseline in lymphocytes at 6.5 hours and heart rate at 4 hours, corrected for mean of time‐matched placebo. Lymphocyte and heart rate changes in single‐dose A, D, or 14‐day repeated‐dose studies B, E, with mean and standard deviation. Scatter plots for change of lymphocytes C, and heart rate F, for all subjects on day 1 of single ascending dose and multiple ascending dose parts, with linear regression lines as shown. Single doses had 6 subjects (10‐mg dose included from fasted arm of food interaction part). Multiple doses had 9 subjects at each time‐point, except for 2.5 mg (n = 10 at days 1 and 14) and 15 mg (n = 1 at day 14). Placebo correction was vs the mean heart rate change at 4 hours, or lymphocyte change at 6.5 hours, in placebo subjects; n = 10 (single doses), n = 18 (day 1 of multiple‐dose study) or n = 16 (day 14 of multiple‐dose study)

FIGURE 5

Model for achieving separated pharmacological profiles at S1P₁ suitable for endothelial protection