S1061 Efficacy and Safety of Etrasimod in Patients With and Without Concomitant Corticosteroid Treatment in the Phase 3 ELEVATE UC 52 and ELEVATE UC 12 Trials

Introduction: Etrasimod is an investigational, oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Methods: We report efficacy and safety of etrasimod in patients (pts) with/without concomitant corticosteroid (CS) use at baseline (BL) of the ELEVATE UC phase 3 trials. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), pts with moderately to severely active UC were randomized 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 used a treat-through design with a 12-week (wk) induction period followed by a 40-wk maintenance period. ELEVATE UC 12 had a 12-wk induction period. At entry, pts were permitted to receive oral concomitant CS (prednisone [≤ 20 mg/day], budesonide [≤ 9 mg/day], or equivalent]) if on a stable dose for ≥ 4 wks prior to screening endoscopy; from Wk 12 CS tapering was recommended. Primary and secondary efficacy endpoints (defined in Table 1) and safety were assessed by BL concomitant CS status. Results: In ELEVATE UC 52, 32.2% (93/289) and 29.2% (42/144) of etrasimod- and PBO-treated pts, respectively, were receiving CS at BL. In ELEVATE UC 12, 27.3% (65/238) and 29.3% (34/116) of etrasimod- and PBO-treated pts were receiving CS at BL. Among pts receiving CS at BL in ELEVATE UC 52, a higher proportion of etrasimod- vs PBO-treated pts achieved the endpoint of clinical remission (CR) at Wk 12 (P < 0.05) and Wk 52 (P < 0.001); this was also observed in pts not receiving CS at BL (P < 0.001 at Wks 12 and 52; Table 1). In ELEVATE UC 12, a higher observed proportion of etrasimod- vs PBO-treated pts receiving CS at BL achieved CR at Wk 12 (P > 0.05); a significant difference was observed in pts not receiving CS at BL (P < 0.01). In both studies, similar results were observed across all secondary endpoints, with greater differences between etrasimod and PBO seen in pts not receiving CS at BL (Table 1). Across both ELEVATE trials, there were fewer serious adverse events and serious infections in the etrasimod arm in pts with CS at BL, than in those without CS at BL. In the PBO arms, the opposite was true. Conclusion: Regardless of concomitant CS use at BL, etrasimod generally demonstrated efficacy at Wks 12 and 52, with greater treatment effect seen in pts without CS use at BL. No additional safety signal was apparent when etrasimod was initiated in combination with CS compared to without CS. Table 1. - Efficacy at Wk 12 and Wk 52 in Patients With and Without CS Use at Baseline in the ELEVATE UC 52 and UC 12 Phase 3 Trials ELEVATE UC 52Week 12 ELEVATE UC 52Week 52 ELEVATE UC 12Week 12 CS at BL no-CS at BL CS at BL no-CS at BL CS at BL no-CS at BL PBON=42 EtraN=93 PBON=102 EtraN=196 PBON=42 EtraN=93 PBON=102 EtraN=196 PBON=34 EtraN=65 PBON=82 EtraN=173 Clinical remission, [a] n (%) [b] 7 (16.7) 30 (32.3) 5 (4.9) 51 (26.0) 4 (9.5) 29 (31.2) 7 (6.9) 65 (33.2) 7 (20.6) 19 (29.2) 10 (12.2) 43 (24.9) Diff. % (95% CI), [c] 16.03 (1.08, 30.98) 22.70 (15.27, 30.13) 21.72 (8.82, 34.62) 26.72 (18.53, 34.92) 8.53 (-8.64, 25.71) 13.19 (3.78, 22.60) p [c] 0.036 < 0.001 < 0.001 < 0.001 0.330 0.006 Endoscopic improvement, [d] n (%), [b] 12 (28.6) 38 (40.9) 12 (11.8) 70 (35.7) 9 (21.4) 36 (38.7) 10 (9.8) 77 (39.3) 11 (32.4) 22 (33.8) 11 (13.4) 56 (32.4) Diff. % (95% CI) [c] 12.25 (-4.73, 29.23) 25.52 (16.25, 34.80) 17.15 (1.55, 32.74) 29.96 (21.04, 38.88) 1.40 (-17.69, 20.49) 19.43 (9.41, 29.46) p [c] 0.157 < 0.001 0.031 < 0.001 0.886 < 0.001 Symptomatic remission, [e] n (%) [b] 13 (31.0) 42 (45.2) 19 (18.6) 92 (46.9) 9 (21.4) 37 (39.8) 19 (18.6) 90 (45.9) 14 (41.2) 29 (44.6) 20 (24.4) 85 (49.1) Diff. % (95% CI) [c] 14.47 (-2.68, 31.62) 28.68 (18.22, 39.14) 18.01 (2.28, 33.74) 28.15 (17.92, 38.38) 3.23 (-16.61, 23.08) 25.58 (13.73, 37.42) p [c] 0.098 < 0.001 0.025 < 0.001 0.750 < 0.001 Endoscopic improvement, histological remission, [f] n (%) [b] 5 (11.9) 20 (21.5) 4 (3.9) 46 (23.5) 7 (16.7) 24 (25.8) 8 (7.8) 55 (28.1) 5 (14.7) 10 (15.4) 5 (6.1) 31 (17.9) Diff. % (95% CI) [c] 10.28 (-2.99, 23.55) 20.11 (12.77, 27.45) 8.15 (-6.32, 22.61) 21.10 (12.97, 29.23) 0.68 (-13.53, 14.89) 12.17 (4.48, 19.86) p [c] 0.129 < 0.001 0.270 < 0.001 0.926 0.002 Clinical response, [g] n (%) [b] 19 (45.2) 63 (67.7) 33 (32.4) 119 (60.7) 13 (31.0) 43 (46.2) 22 (21.6) 100 (51.0) 18 (52.9) 38 (58.5) 30 (36.6) 113 (65.3) Diff. % (95% CI) [c] 22.86 (5.21, 40.51) 28.56 (17.03, 40.10) 15.25 (-1.74, 32.23) 30.17 (19.62, 40.71) 5.32 (-15.06, 25.70) 29.85 (17.40, 42.29) p [c] 0.011 < 0.001 0.079 < 0.001 0.609 < 0.001 Data in bold indicate significant p values. All data shown refer to the full analysis set (MMS 4–9) with CS at baseline (CS at BL) or no CS at baseline (no-CS at BL).[a] Clinical remission, the primary efficacy endpoint, was defined as SFS=0 (or =1 with a ≥ 1-point decrease from baseline), RBS=0, and ES ≤ 1 (excluding friability).[b] Percentages are based on N, the number of patients in the subgroup in the analysis set by treatment, patients missing an assessment at the specified analysis visit are considered non-responders.[c] Difference is for etrasimod minus placebo and is based on estimated common risk difference using the Mantel-Haenszel weights; p value is 2-sided to test the hypothesis of the risk difference being 0.[d] Endoscopic improvement (key secondary efficacy endpoint) was defined as an ES ≤ 1 (excluding friability).[e] Symptomatic remission (key secondary efficacy endpoint) was defined as SFS=0 (or =1 with a ≥ 1-point decrease from baseline) and RBS=0.[f] Endoscopic improvement, histological remission (key secondary efficacy endpoint) was defined as ES ≤ 1 (excluding friability) with histologic remission measured by a Geboes Index score < 2.0.[g] Clinical response (other secondary efficacy endpoint) was defined as a ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS ≤ 1.BL, baseline; CI, confidence interval; CS, corticosteroid; ES, endoscopic subscore; Etra, etrasimod; MMS, modified Mayo score; n, number of responding patients; N, the number of patients in the subgroup in the analysis set by treatment; PBO, placebo; RBS, rectal-bleeding subscore; SFS, stool-frequency subscore; UC ulcerative colitis.

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