Etrasimod 2mg Once Daily as Treatment for Patients With Moderately to Severely Active Ulcerative Colitis: Topline and Subgroup Analysis From ELEVATE UC 52 and ELEVATE UC 12

Introduction: Etrasimod (ETR), is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). We report a subgroup analysis according to prior exposure to advanced (biologic/Janus kinase inhibitor [JAKi]) therapy from the phase 3 trials ELEVATE UC 52 and ELEVATE UC 12 that evaluated efficacy and safety of ETR vs placebo (PBO) in adults with UC. Methods: In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), adults (16-80 years) with moderately to severely active UC (based on modified Mayo Score of 4-9 with endoscopic subscore ≥2 and rectal bleeding subscore ≥1) and history of inadequate response, loss of response, or intolerance to ≥1 UC treatment were randomized 2:1 to once-daily ETR 2mg or PBO. ELEVATE UC 52 utilized a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. ELEVATE UC 12 comprised a 12-week induction period. Patients (pts) were stratified by prior exposure to biologic/JAKi therapy, baseline corticosteroid use, and baseline disease activity. Subgroup analyses were performed on primary and key secondary endpoints at Wk 12 and Wk 52 in ELEVATE UC 52, and Wk 12 in ELEVATE UC 12 in pts naïve to, or with prior exposure to, 1 or >1 biologic/JAKi. Results: In ELEVATE UC 52, ETR-treated pts achieved statistically significant improvements vs PBO in the co-primary and all key secondary efficacy endpoints at Wks 12 and 52. Significant improvements vs PBO in all endpoints were observed in the biologic/JAKi-naïve and 1 prior biologic/JAKi subgroups (Table). In pts with >1 prior biologic/JAKi, efficacy was demonstrated across all endpoints, generally with lower rates vs PBO. In ELEVATE UC 12, ETR-treated pts achieved statistically significant improvements vs PBO in the co-primary and all key secondary efficacy endpoints at Wk 12. Significant improvements vs PBO in all endpoints were observed in biologic/JAKi-naïve subgroup, and in clinical remission in 1 prior biologic/JAKi subgroup. Efficacy was less evident in the >1 biologic/JAKi experienced subgroup. Conclusion: In ELEVATE UC 52 and ELEVATE UC 12, ETR was shown to be efficacious vs PBO in moderate to severe UC. While limited by small sample sizes, these subgroup analyses demonstrate consistent benefit of ETR vs PBO in biologic/JAKi-naïve and 1 prior biologic/JAKi subgroups with less evident benefit in the >1 biologic/JAKi subgroup Table 1. - Subgroup Analysis of the Proportion of Patients Achieving the Primary and Key Secondary Efficacy Endpoints in the ELEVATE UC 52 and ELEVATE UC 12 Trials in the Overall Population and Stratified by Prior Biologic/JAKi Exposurea ELEVATE UC 52 (treat-through)Week 12 ELEVATE UC 52 (treat-through)Week 52 ELEVATE UC 12 (induction only)Week 12 Endpoint, n (%) by no. of prior bio/ JAKis PBO (n=144) ETR 2 mg (n=289) % diff. from PBO (95% CI) [P value] PBO (n=144) ETR 2 mg (n=289) % diff. from PBO (95% CI) [P value] PBO (n=116) ETR 2 mg (n=238) % diff. from PBO (95% CI) [P value] Clinical remission b Overall 10/135 (7.4) 74/274 (27.0) 19.8 (12.9 - 26.6) [< .001] 9/135 (6.7) 88/274 (25.4) 25.4 (18.4 - 32.4) [< .001] 17/112 (15.2) 55/222 (24.8) 9.7 (1.1 - 18.2) [.026] Naïve 9/99 (9.1) 66/205 (32.2) 23.3 (14.7 - 31.8) [< .001] 8/99 (8.1) 75/205 (36.6) 29.0 (20.5 - 37.5) [< .001] 12/77 (15.6) 46/159 (28.9) 13.8 (3.3 - 24.4) [.010] 1 bio/JAKi 1/25 (4.0) 8/44 (18.2) 15.9 (1.6 - 30.2) [.029] 2/25 (8.0) 13/44 (29.5) 19.7 (3.2 - 36.2) [.020] 2/20 (10.0) 12/36 (33.3) 21.9 (2.4 - 41.3) [.028] >1 bio/JAKi 2/20 (10.0) 7/40 (17.5) 4.4 (−12.7 - 21.5) [.613] 1/20 (5.0) 6/40 (15.0) 9.8 (−6.0 - 25.6) [.224] 3/19 (15.8) 4/43 (9.3) −7.5 (−26.2 - 11.2) [.433] Endoscopic improvement c Overall 19/135 (14.1) 96/274 (35.0) 21.1 (13.0 - 29.3) [< .001] 14/135 (10.4) 102/274 (37.2) 26.7 (19.0 - 34.4) [< .001] 21/112 (18.8) 68/222 (30.6) 12.1 (3.0 - 21.2) [.009] Naïve 20/99 (20.2) 86/205 (42.0) 22.1 (12.1 - 32.2) [< .001] 16/99 (16.2) 86/205 (42.0) 26.8 (17.3 - 36.4) [< .001] 14/77 (18.2) 58/159 (36.5) 18.9 (7.9 - 29.8) [.001] 1 bio/JAKi 1/25 (4.0) 12/44 (27.3) 24.2 (9.3 - 39.0) [.001] 2/25 (8.0) 15/44 (34.1) 24.8 (7.9 - 41.8) [.004] 4/20 (20.0) 13/36 (36.1) 13.3 (−10.2 - 36.8) [.267] >1 bio/JAKi 3/20 (15.0) 10/40 (25.0) 7.7 (−12.6 - 28.0) [.456] 1/20 (5.0) 12/40 (30.0) 24.0 (5.7 - 42.3) [.010] 4/19 (21.1) 7/43 (16.3) −4.1 (−25.6 - 17.3) [.706] Mucosal healing d Overall 6/135 (4.4) 58/274 (21.2) 16.9 (10.8 - 23.0) [< .001] 11/135 (8.1) 73/274 (26.6) 18.4 (11.4 - 25.4) [< .001] 10/112 (8.9) 36/222 (16.2) 7.4 (0.5 - 14.4) [.036] Naïve 9/99 (9.1) 54/205 (26.3) 17.0 (8.6 - 25.5) [< .001] 13/99 (13.1) 60/205 (29.3) 16.9 (8.0 - 25.8) [< .001] 8/77 (10.4) 31/159 (19.5) 9.5 (0.5 - 18.5) [.039] 1 bio/JAKi 0/25 (0.0) 6/44 (13.6) 13.8 (3.1 - 24.5) [.012] 2/25 (8.0) 11/44 (25.0) 16.1 (0.1 - 32.0) [.048] 1/20 (5.0) 6/36 (16.7) 10.8 (−5.3 - 26.8) [.189] >1 bio/JAKi 0/20 (0.0) 6/40 (15.0) 14.2 (3.0 - 25.5) [.013] 0/20 (0.0) 8/40 (20.0) 21.5 (8.4 - 34.6) [.001] 1/19 (5.3) 4/43 (9.3) 5.1 (−8.3 - 18.5) [.458] bio, biologic; CI, confidence interval; ES, endoscopic subscore; ETR, etrasimod; JAKi, Janus kinase inhibitor; MMS, modified Mayo score; PBO, placebo; RB, rectal bleeding; SF, stool frequency.aData based on Cochran–Mantel–Haenszel analysis of Full Analysis Set (all randomized patients who received ≥1 dose of study drug) and non-responder imputation method with baseline MMS 5-9 as the primary analysis and baseline MMS 4-9 as supplemental analysis. P values are 2-sided.bSF subscore = 0 (or = 1 with ≥1-point decrease from baseline), RB subscore = 0, and ES ≤1.cES ≤1.dES ≤1 with histologic remission measured by Geboes index score < 2.0 .