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

Figures

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  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

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  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

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  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

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  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)

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  FIGURE 5. Model for achieving separated pharmacological profiles at S1P1 suitable for endothelial protection