THU0190 THE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF BMS-986166, A NOVEL, SELECTIVE, PARTIAL AGONIST OF THE SPHINGOSINE-1-PHOSPHATE (S1P) SUBTYPE 1 RECEPTOR IN HEALTHY PARTICIPANTS
Authors: Shalabh Singhal, Ihab Girgis, Jenny Xie, Santanu Dutta, Diane Shevell, John Throup
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> S1P mediates a number of immune processes including the egress of lymphocytes from lymphoid organs via stimulation of the S1P subtype 1 receptor (S1P1R). S1P1R inhibition has the potential to suppress abnormal immune responses and modulate autoimmune inflammatory diseases.<sup>1</sup> BMS-986166, a novel, selective partial agonist of S1P1R, which is phosphorylated in vivo to its pharmacologically active form, BMT-121795, may have utility for the treatment of autoimmune and/or inflammatory diseases. <h3>Objectives</h3> To investigate safety, pharmacokinetics (PK), and pharmacodynamics (PD) of BMS-986166 in single- and multiple-ascending dose (SAD/MAD) placebo (PBO)-controlled studies in healthy participants. <h3>Methods</h3> SAD study (NCT02790125): BMS-986166 was administered as a single dose of 0.75, 2.0, or 5.0 mg (n=10/group; 4:1 ratio of BMS-986166:PBO); a series of upwardly titrated single daily doses of 0.25, 0.5, 0.75, 1.0, then 1.5 mg over 14 days (n=16; 3:1 ratio); or as a single 2.0-mg dose in participants who were fed, fasted, or administered famotidine prior to dosing (n=8/group). MAD study (NCT03038711): BMS-986166 was administered as once-daily doses of 0.25 (n=12; 2:1 ratio), and 0.75 or 1.5 mg (n=10/dose; 4:1 ratio), for 28 days. Safety, PK, and PD (absolute lymphocyte count [ALC]) were assessed. Cardiac safety was assessed by continuous cardiac monitoring and at intervals by 12-lead electrocardiogram. <h3>Results</h3> 70 (60 BMS-986166, 10 PBO; mean [standard deviation (SD)] age: 32.8 [8.5] years) and 32 (24 BMS-986166, 8 PBO; mean [SD] age: 35.8 [8.6] years) participants were randomised to dosing in the SAD and MAD studies, respectively. Participants were predominantly male. Mean (SD) body mass index was 26.8 (2.9) and 27.2 (2.5) kg/m<sup>2</sup>, respectively. Multiple oral doses of BMS-986166 up to 1.5 mg daily for 28 days were generally well tolerated, and all treatment-related adverse events were mild (Grade 1). In the MAD (Figure 1) and SAD studies, a clinically insignificant, dose-related decrease in mean hourly heart rate (HR) was observed following administration of BMS-986166 compared with PBO, based on a time-matched analysis of nominal hourly HR data from continuous cardiac monitoring over 72 hours post dose. Compared with participants receiving PBO, a mean decrease from baseline in hourly HR was apparent for participants in the 2 higher dose panels (2.0 mg, 5.0 mg) in the SAD study. In the SAD study, the largest decreases in PBO-corrected, time-matched, nadir hourly HR were –0.29, –6.38, and –8.37 bpm for the 0.75, 2.0, and 5.0 mg dose panels, respectively. Similarly, in the MAD study, these numbers were –0.83, –3.46, and –5.54 bpm at the 0.25, 0.75, and 1.5 mg dose levels, respectively. Increases in systemic plasma exposure (maximum concentration and area under the curve from time 0–24 hours) of BMS-986166 and its active metabolite BMT-121795 were approximately proportional to dose increases over the range of 0.75–5 mg with single doses, and of 0.25–1.5 mg on Days 1, 14, and 28 with multiple doses. Decreases in percent change from baseline in ALC with multiple doses of BMS-986166 vs PBO were dose-related over the 28-day treatment period. Between Day 0 and 35, median (range) nadir in lymphocyte reductions were 53.7% (31.7–55.9%), 75.9% (63.3–85.8%), and 81.9% (37.9–92.2%) at 0.25, 0.75, and 1.5 mg BMS-986166 dose levels, respectively. Recovery of ALC levels began 14, 14–21, and 7 days after the last dose of 0.25, 0.75, and 1.5 mg, respectively, on Day 28. <h3>Conclusion</h3> In healthy participants, multiple daily doses of BMS-986166 in the range of 0.25–1.5 mg were well tolerated, with no clinically relevant lowering of HR. PK were linear and decreases in ALC were dose related. <h3>Reference</h3> [1] Urbano M, et al. Bioorg Med Chem Lett2013;23:6377–89 <h3>Acknowledgement</h3> Professional medical writing: Lola Parfitt, MRes (Caudex); funding: Bristol-Myers Squibb <h3>Disclosure of Interests</h3> Shalabh Singhal Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Ihab Girgis Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Jenny Xie Employee of: Bristol-Myers Squibb, Santanu Dutta Employee of: Bristol-Myers Squibb, Diane Shevell Shareholder of: Merck, Employee of: Bristol-Myers Squibb, John Throup Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb