Impact of Prior Biologic/Janus Kinase Inhibitor Therapy on the Efficacy of Etrasimod: Subgroup Analysis From 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: The study design for phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials has been described previously.1 ELEVATE UC 52 comprised a 12-week (wk) induction period followed by a 40-wk maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12-wk induction period. Patients (pts) had a documented history of inadequate response/loss of response/intolerance to ≥ 1 treatment for UC. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo (PBO) in adults with UC by prior exposure to advanced (biologic/Janus kinase inhibitor [bio/JAKi]) therapy. We present subgroup efficacy analyses of the primary and select 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 bio/JAKi therapy. Additional symptomatic endpoints were analyzed by study visit to Wk 12 (pooled ELEVATE UC 52 and ELEVATE UC 12). Results: In ELEVATE UC 52 and ELEVATE UC 12, respectively, 274 and 222 pts with a baseline modified Mayo score 5–9 were treated with etrasimod, and 135 and 112 pts with PBO. Pts treated with etrasimod vs PBO, in both bio/JAKi-naïve and -exposed subgroups, achieved statistically significant improvements in clinical remission, clinical response and endoscopic improvement at Wks 12 and 52 in ELEVATE UC 52 (Table 1). In ELEVATE UC 12, bio/JAKi-naïve pts achieved statistically significant improvements in all endpoints, while pts in both subgroups achieved statistically significant improvements in clinical response (Table 1). In bio/JAKi-naïve and -exposed pts, respectively, pooled data showed the earliest significant improvements were during Wks 2 and 12 for symptomatic response and Wks 4 and 2 for symptomatic remission (Table 1). Conclusion: In ELEVATE UC 52, both bio/JAKi-naïve and -exposed pts treated with etrasimod showed statistically significant improvements in induction and maintenance efficacy endpoints vs PBO. In ELEVATE UC 12, etrasimod demonstrated statistically significant improvements vs PBO in induction in bio/JAKi-naïve pts. For symptomatic response in the pooled analysis, a significant treatment difference occurred later for bio/JAKi-exposed than -naïve pts. Reference: 1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171. Table 1. - Subgroup Analysis of the Proportion of Patients Achieving the Primary and Select Secondary Efficacy and Symptomatic Endpoints in the ELEVATE UC 52 and ELEVATE UC 12 Trials Stratified by Prior Bio/JAKi Exposure [a] ELEVATE UC 52, Wk 12 ELEVATE UC 52, Wk 52 ELEVATE UC 12, Wk 12 Endpoint, n/N (%) [b] by prior bio/JAKi exposure PBO (N=135) Etrasimod 2 mg once daily (N=274) % difference (95% CI) p value [c] PBO (N=135) Etrasimod 2 mg once daily (N=274) % difference (95% CI) p value [c] PBO (N=112) Etrasimod 2 mg once daily (N=222) % difference (95% CI) p value [c] Clinical remission [d] [e] Naïve 9/93 (9.7) 60/194 (30.9) 21.5 (12.67, 30.30)< 0.001 7/93 (7.5) 71/194 (36.6) 28.8 (19.89, 37.67) < 0.001 12/74 (16.2) 41/148 (27.7) 11.9 (0.98, 22.73)0.033 Exposed 1/42 (2.4) 14/80 (17.5) 14.7 (4.82, 24.62)0.004 2/42 (4.8) 17/80 (21.3) 14.6 (3.36, 25.82)0.011 5/38 (13.2) 14/74 (18.9) 6.6 (-7.18, 20.29)0.349 Clinical response [f] Naïve 35/93 (37.6) 132/194 (68.0) 29.6 (17.77, 41.45)< 0.001 25/93 (26.9) 103/194 (53.1) 26.1 (14.65, 37.58)< 0.001 32/74 (43.2) 97/148 (65.5) 22.3 (8.63, 35.89)0.001 Exposed 11/42 (26.2) 39/80 (48.8) 19.9 (2.95, 36.92)0.021 6/42 (14.3) 29/80 (36.3) 19.7 (5.32, 34.07)0.007 14/38 (36.8) 41/74 (55.4) 20.1 (1.14, 39.12)0.038 Endoscopic improvement [g] Naïve 17/93 (18.3) 76/194 (39.2) 21.2 (11.07, 31.36)< 0.001 12/93 (12.9) 78/194 (40.2) 28.1 (18.60, 37.60)< 0.001 14/74 (18.9) 51/148 (34.5) 16.2 (4.90, 27.40)0.005 Exposed 2/42 (4.8) 20/80 (25.0) 19.1 (7.20, 30.95)0.002 2/42 (4.8) 24/80 (30.0) 23.1 (10.77, 35.32)< 0.001 7/38 (18.4) 17/74 (23.0) 5.5 (-10.00, 20.97)0.487 Endpoint, n/N (%) [b] by prior bio/JAKi exposure Pooled ELEVATE UC 52 and ELEVATE UC 12, up to Wk 12PBO Pooled ELEVATE UC 52 andELEVATE UC 12, up to Wk 12Etrasimod 2 mg once daily Pooled ELEVATE UC 52 andELEVATE UC 12, up to Wk 12% difference (95% CI) p value [c] Symptomatic response [h] at the earliest visit with significant difference Naïve (Wk 2) 49/167 (29.3) 141/342 (41.2) 12.1 (3.47, 20.69)0.0060 Exposed (Wk 12) 31/80 (38.8) 85/154 (55.2) 16.0 (2.79, 29.19)0.0176 Symptomatic remission [i] at the earliest visit with significant difference Naïve (Wk 4) 24/167 (14.4) 105/342 (30.7) 16.7 (9.67, 23.79)< 0.0001 Exposed (Wk 2) 7/80 (8.8) 28/154 (18.2) 9.0 (0.54, 17.54)0.0371 [a] This is a subgroup analysis of the full analysis set; therefore, only patients with a baseline MMS score between 5 and 9 were included. Patients with a baseline MMS of 4 were excluded.[b] Patients missing an assessment at the specified analysis visit were considered non-responders.[c] Difference (%) is for etrasimod minus PBO and is based on estimated common risk difference using Mantel–Haenszel weights, stratified by baseline corticosteroid use (Yes/No) and baseline disease activity (MMS: ≤ 6 or ≥ 7). The 2-sided nominal p value is to test the hypothesis of the common risk difference being 0; P < 0.05 is considered statistically significant.[d] SFS=0 (or =1 with ≥ 1-point decrease from baseline), RBS=0 and ES ≤ 1 (excluding friability).[e] Patients in clinical remission at Wk 52 were also in clinical remission without corticosteroids if they had not been receiving corticosteroids for at least 12 wks immediately prior to Wk 52.[f] A ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS of ≤ 1.[g] ES of ≤ 1 (excluding friability).[h] Decrease from baseline ≥ 30% in composite RBS and SFS.[i]SFS=0 (or =1 with ≥ 1-point decrease from baseline), RBS=0.Bio, biologic; CI, confidence interval; ES, endoscopic subscore; JAKi, Janus kinase inhibitor; MMS, modified Mayo score; N, the number of unique patients achieving each endpoint; 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; Wk, week.