Impact of Etrasimod on Blood Pressure and Hypertension: Data From the Etrasimod Ulcerative Colitis Clinical Program

Introduction: Increased blood pressure (BP) and hypertension are known adverse effects of sphingosine 1-phosphate (S1P)1,4,5 receptor modulators. Etrasimod is an investigational, oral, once-daily, selective S1P1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Methods: We assessed the impact of etrasimod on BP and hypertension development among patients (pts) in the etrasimod UC clinical program. Pivotal (placebo [PBO]-controlled phase [p]3 [NCT03945188; NCT03996369] studies) and All UC (PBO-controlled plus open-label extension [OLE]; p2 [NCT02447302], p3, and OLE [NCT03950232 and NCT04176588, data snapshot January 31, 2022; NCT02536404] studies) cohort data were analyzed. BP was assessed at each visit and at 2 and 4 weeks (wks) post-treatment cessation. Proportions and exposure-adjusted incidence rates (EAIRs; pts with AEs divided by the total pt-years [PY] at risk for AEs, per 1 PY) of treatment-emergent hypertension (Medical Dictionary for Regulatory Activities preferred term [PT]) AEs among pts receiving etrasimod (2 mg once daily; both cohorts) or PBO (Pivotal UC cohort) were assessed. Characteristics of pts with hypertension AEs that met sponsor-designated events of interest (SDEI) criteria (related to hypertension associated with sustained increases in BP [systolic/diastolic: ≥ 160/100 mmHg], or requiring new or increased antihypertensive therapy) were analyzed descriptively. Results: In the Pivotal and All UC cohorts, 11/527 (2.1%; EAIR, 0.04; PBO: 2/260 [0.8%; EAIR, 0.02]) and 20/942 (2.1%; EAIR, 0.03) etrasimod-treated pts had PT hypertension, respectively; none led to study treatment discontinuation. In the All UC cohort, 19/942 (2.0%; EAIR, 0.02) etrasimod-treated pts had hypertension-related SDEIs. Of these events, 6 were in pts with hypertension history; none were serious or led to treatment discontinuation; 6 resolved (5 with intervention), 8 were resolving/unknown outcome and 3 were unresolved. Etrasimod-treated pts had minimal changes in BP over time (All UC cohort, mean change in systolic/diastolic BP at Wk52: 2.9/1.2 mmHg, respectively; Table 1). In the All UC cohort, at Wk104, no etrasimod-treated pts had a systolic/diastolic BP > 160/100 mmHg, respectively. Conclusion: Hypertension events were infrequent among etrasimod-treated pts. No clinically meaningful changes in BP with etrasimod 2 mg over time or following treatment discontinuation were observed up to 2 years. Data interpretations are limited by small pt numbers. Table 1. - Change from Baseline in BP Over Time Among Pts in the Etrasimod UC Clinical Program (Pivotal and All UC Cohorts) Time point Pivotal UC cohort Time point All UC cohort Systolic BP, mmHg Diastolic BP, mmHg Systolic BP, mmHg Diastolic BP, mmHg Etrasimod2 mg QD (N=527) PBO (N=260) Etrasimod2 mg QD (N=527) PBO (N=260) Etrasimod 2 mg QD (N=942) Baseline [a], mean (SD) [etrasimod, n=527; PBO, n=260] 120.7 (12.50) 121.3 (13.08) 75.8 (8.53) 77.2 (9.56) Baseline [a], mean (SD) [n=942] 119.6 (12.89) 75.6 (8.57) Change at Wk12, mean (SD) [etrasimod, n=474; PBO, n=231] 2.0 (11.17) -1.4 (10.68) 1.6 (8.08) -0.4 (8.07) Change at Wk12, mean (SD) [n=821] 2.1 (10.78) 1.7 (8.01) Change at Wk52, mean (SD) [etrasimod, n=162; PBO, n=44] 2.2 (11.08) 1.3 (9.16) 0.4 (8.47) -0.8 (8.52) Change at Wk52, mean (SD) [n=246] 2.9 (10.39) 1.2 (8.36) Change at Wk78/ Wk104 [b], mean (SD) [N/A] - - - - Change at Wk78/ Wk104, mean (SD) [Wk78, n=147; Wk104, n=29] 1.9 (10.65)/-0.7 (13.54) 1.1 (8.05)/0.8 (7.40) Change at 2-/4-wk follow-up visit [c], mean (SD) [2 wk: etrasimod, n=39; PBO, n=6; 4 wk: etrasimod, n=36; PBO, n=10] 0.2 (10.66)/-0.4 (11.47) 6.7 (10.61)/8.1 (8.18) 1.6 (7.99)/0.2 (10.40) 3.2 (3.71)/3.0 (7.12) Change at 2-/4-wk follow-up visit [c], mean (SD) [2-wk; n=203; 4-wk, n=105] 2.6 (13.73)/1.9 (12.43) 1.3 (8.74)/1.4 (9.18) Pivotal UC cohort comprised pts from the PBO-controlled p3 ELEVATE UC 52 (NCT03945188) and p3 ELEVATE UC 12 (NCT03996369) studies. All UC cohort comprised pts from the p2 OASIS (NCT02447302), p2 OASIS OLE (NCT02536404 [completed November 01, 2018]), p3 ELEVATE UC 52 (NCT03945188), p3 ELEVATE UC 12 (NCT03996369), and p3 ELEVATE UC OLE (NCT03950232 [data snapshot January 31, 2022]) studies, and the open-label phase of the p3 study NCT04176588 (data snapshot January 31, 2022). [a] Baseline is defined, by study treatment group received, as the last non-missing measurement taken on or prior to the study treatment group start date; [b] Wk78 and 104 data are not provided for the Pivotal UC cohort as only data up to Wk52 of ELEVATE UC 52 are included for pts in this cohort; [c] Pts who did not participate in the OLE study had 2-wk and 4-wk follow-up visits after their last treatment administration. BP, blood pressure; N, total number of patients; n, number of patients with evaluable data at a visit; N/A, not applicable; OLE, open-label extension; p, phase; PBO, placebo; pts, patients; QD, once daily; SD, standard deviation; UC, ulcerative colitis; wk, week.