S1018 Early Disease Clearance With Etrasimod and Correlation With Week 52 Outcomes and Biomarkers: A Post Hoc Analysis of the Phase 3 ELEVATE UC Trials

Introduction: The concept of disease clearance (DC), which includes symptomatic, endoscopic and histologic remission, has been proposed as the ultimate goal in ulcerative colitis (UC) treatment. However, the prognostic value of this endpoint remains uncertain.1 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 UC. Methods: We report a post hoc analysis from the ELEVATE UC trials to assess relationships between histological/composite endpoints, biomarkers and efficacy outcomes in etrasimod-treated patients (pts). 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). DC was defined as Nancy Histological Index=0, Mayo endoscopic subscore (ES)=0, rectal bleeding subscore=0, stool frequency subscore=0 or 1 (if 1, must have ≥ 1 point decrease from baseline). Other endpoints are defined in Table 1. Kappa correlation coefficients2 were estimated between histological endpoints at Wk 12 and efficacy outcomes at Wk 52, and between histological endpoints and biomarkers at Wks 12 and 52. Results: At Wk 12 in both trials, DC was achieved by more etrasimod- than PBO-treated pts (8.4% [23/274] vs 1.5% [2/135] and 9.9% [22/222] vs 4.5% [5/112], P < 0.001 and P=0.042, respectively). The proportion of pts with clinical remission at Wk 52 was higher among pts who achieved DC at Wk 12 (17/23; 74%) vs pts who did not (71/251; 28%). Histologic-endoscopic mucosal improvement at Wk 12 had the highest correlation with efficacy outcomes at Wk 52 (κ 0.357–0.438; Table 1). Fecal calprotectin and C-reactive protein normalization showed slight/fair to substantial agreement with histologic endpoints (κ 0.223–0.630; 0.075–0.6, respectively; Table 1). Absolute lymphocyte count < 0.5x109/L showed no agreement (κ -0.100–0.216; Table 1). Conclusion: Early achievement of DC showed only fair correlation with Wk 52 efficacy outcomes. Correlation of fecal calprotectin < 150 mg/kg with histological endpoints was most often moderate and improved from Wks 12 to 52. A different approach is needed for development of robust predictive models. References 1. D’Amico F et al. United Eur Gastroenterol J 2022; 10: 777–784. 2. Cohen JA et al. Educ Psychol Meas 1960; 20: 37–46. Table 1. - Correlations Between Histological and Efficacy Endpoints in ELEVATE UC 52, and Histological Endpoints and Biomarker Status in ELEVATE UC 52 and 12 Among Patients (With Baseline Modified Mayo Score of 5 to 9) Receiving Etrasimod 2 mg QD Correlations with Wk 12 histological endpoints and efficacy endpoints at Wk 52 of ELEVATE UC 52 ELEVATE UC 52 – Wk 12 endpoint (N=274) Definition Clinical remission [d] at Wk 52 CS-free clinical remission [e] at Wk 52 Symptomatic remission [f] at Wk 52 Endoscopic improvement [g] at Wk 52 Endoscopic improvement-histologic remission [h] at Wk 52 Histologic remission [a] Geboes < 2.0 0.266 0.266 0.299 0.292 0.365 Histologic-endoscopic mucosal improvement [a] Geboes ≤ 3.1 + ES 0–1 0.392 0.392 0.357 0.423 0.438 Endoscopic improvement-histologic remission [b] Geboes < 2.0 + ES 0–1 0.338 0.338 0.297 0.367 0.431 Endoscopic normalization-histologic remission [c] Geboes < 2.0 + ES 0 0.217 0.217 0.169 0.223 0.307 Disease clearance [c] NHI=0, ES=0, RBS=0, SFS=0 or 1 (if 1, must have ≥ 1-point decrease from baseline) 0.200 0.200 0.164 0.194 0.260 Correlations with biomarker status at the same visit (Wk 12 and Wk 52) ELEVATE UC 12 – Wk 12 endpoint (N=222)ELEVATE UC 52 – Wk 12 or Wk 52 endpoints (N=274) Absolute lymphocyte count (< 0.5 x 109/L) Fecal calprotectin normalization (< 150 mg/kg) hsCRP normalization (< 5 mg/L) Histologic remission [a]Histologic-endoscopic mucosal improvement [a]Endoscopic improvement-histologic remission [b]Endoscopic normalization-histologic remission [c]Disease clearance [c] ELEVATEUC 12 (Wk 12)0.0600.1240.0410.004−0.022 ELEVATE UC 52 (Wk 12)−0.006−0.100−0.0550.0360.014 ELEVATE UC 52 (Wk 52)0.2160.1320.1600.0980.067 ELEVATEUC 12 (Wk 12)0.3700.5350.2900.2270.236 ELEVATE UC 52 (Wk 12)0.2680.4970.2980.2570.223 ELEVATE UC 52 (Wk 52)0.5710.6300.5380.4580.431 ELEVATEUC 12 (Wk 12)0.1990.1800.3860.0750.084 ELEVATEUC 52 (W12)0.1930.2670.2870.0890.094 ELEVATE UC 52 (Wk 52)0.4970.5330.6000.3730.365 Kappa correlation coefficients are shown, ≤ 0 indicate no agreement, 0.01–0.20 indicate none to slight agreement, 0.21–0.40 indicate in fair agreement, 0.41–0.60 indicate in moderate agreement, 0.61–0.80 indicate substantial agreement, and coefficients 0.81–1.00 indicate an almost perfect agreement.[a] Pre-specified exploratory endpoint; [b] Pre-specified key secondary endpoint subject to type I error control; [c] Post hoc endpoint; [d] Clinical remission was defined as SFS=0 (or =1 with a ≥ 1-point decrease from baseline), RBS=0, and ES ≤ 1 (excluding friability); [e] CS-free clinical remission was defined as the proportion of patients in clinical remission at Wk 52 and who had not been receiving CS for ≥ 12 wks prior to Wk 52; [f] Symptomatic remission was defined as SFS=0 (or =1 with a ≥ 1-point decrease from baseline) and RBS=0; [g] Endoscopic improvement was defined as an ES ≤ 1 (excluding friability); [h] Endoscopic improvement-histologic remission was defined as ES ≤ 1 (excluding friability) with histologic remission measured by a Geboes Index score < 2.0.CS, corticosteroid; ES, endoscopic subscore; hsCRP, high-sensitivity C-reactive protein; NHI, Nancy Histological Index; QD, once daily; RBS, rectal bleeding subscore; SFS, stool frequency subscore; Wk, week.

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