ABSTRACT Background Etrasimod is an oral, once‐daily (q.d.), selective sphingosine 1‐phosphate (S1P) 1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Unlike the S1P receptor modulator ozanimod, etrasimod does not have a molecular structure to inhibit monoamine oxidase (MAO). Coadministration of drugs that inhibit MAO with opioids and antidepressants may increase the risk of adverse events (AEs). Aims This post hoc analysis evaluated the incidence of AEs potentially related to serotonin syndrome in patients taking etrasimod and concomitant opioids or antidepressants in the Phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. Methods Safety data pooled from both trials were analysed in subgroups of patients receiving etrasimod 2 mg q.d. (up to 52 weeks of exposure) with/without concomitant opioids or antidepressants. We report the proportions of patients who had ≥ 1 concurrent AE potentially associated with serotonin syndrome, including hypertension‐related events. Results Among 527 patients receiving etrasimod, 77 (14.6%) and 35 (6.6%) were taking concomitant opioids or antidepressants, respectively. The incidence of AEs potentially related to serotonin syndrome, including hypertension‐related AEs, was low (≤ 8.6%) and generally comparable in all subgroups. No reported AEs were serious or led to treatment discontinuation among patients taking these concomitant medications. Conclusions The incidence of AEs was low and comparable in patients receiving etrasimod with or without concomitant opioids or antidepressants. This analysis further supports the low likelihood of clinically relevant drug–drug interactions between etrasimod and medications commonly prescribed to patients with UC, such as opioids or antidepressants. ( ClinicalTrials.gov : NCT03945188; NCT03996369).

BACKGROUND & AIMS:Histologic remission, a potentially important treatment target in ulcerative colitis (UC), is associated with favorable long-term outcomes. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. This post-hoc analysis of the ELEVATE UC program evaluated the efficacy of etrasimod according to histologic and composite (histologic/endoscopic/symptomatic) endpoints and examined their prognostic value. METHODS:Patients with moderately to severely active UC were randomized 2:1 to once-daily oral etrasimod 2 mg or placebo. Histologic and composite endpoints, including disease clearance (endoscopic/histologic/symptomatic remission), were assessed at Weeks 12 (ELEVATE UC 52; ELEVATE UC 12) and 52 (ELEVATE UC 52). Logistic regressions examined associations between baseline and Week 12 histologic/composite endpoints and Week 52 outcomes. RESULTS:At Weeks 12 and 52, significant improvements with etrasimod vs placebo were observed in histologic/composite outcomes, including endoscopic improvement-histologic remission and disease clearance. The proportion of patients treated with etrasimod achieving clinical remission at Week 52 was higher among those with disease clearance at Week 12 vs those without disease clearance (73.9% [17/23] vs 28.3% [71/251]). Histologic improvement and endoscopic improvement at Week 12 were moderately and strongly associated with clinical remission at Week 52 (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.27-4.41; and OR, 6.36; 95% CI, 3.47-11.64, respectively). Histologic remission and endoscopic improvement at Week 12 were strongly associated with endoscopic improvement-histologic remission at Week 52 (OR, 3.21; 95% CI, 1.70-6.06 and OR, 5.47; 95% CI, 2.89-10.36, respectively). CONCLUSIONS:Etrasimod was superior to placebo for achievement of stringent histologic and composite endpoints. CLINICALTRIALS:gov, Number: NCT03945188; ClinicalTrials.gov, Number: NCT03996369.

Background: Biomarkers offer potential alternatives to endoscopies in monitoring ulcerative colitis (UC) progression and therapeutic response. This post hoc analysis of the ELEVATE UC clinical program assessed potential predictive values of fecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) as biomarkers and associated responses to etrasimod, an oral, once-daily, selective sphingosine 1-phosphate (S1P)(1,4,5) receptor modulator for the treatment of moderately to severely active UC, in 2 phase 3 clinical trials. Methods: In ELEVATE UC 52 and ELEVATE UC 12, patients were randomized 2:1 to 2 mg of etrasimod once daily or placebo for 52 or 12 weeks, respectively. Fecal calprotectin/hsCRP differences between responders and nonresponders for efficacy end points (clinical remission, clinical response, endoscopic improvement-histologic remission [EIHR]) were assessed by Wilcoxon P-values. Sensitivity and specificity were presented as receiver operating characteristics (ROC) curves with area under the curve (AUC). Results: In ELEVATE UC 52 and ELEVATE UC 12, 289 and 238 patients received etrasimod and 144 and 116 received placebo, respectively. Baseline fCAL/hsCRP concentrations were generally balanced. Both trials had lower week-12 median fCAL levels in week-12 responders vs nonresponders receiving etrasimod for clinical remission, clinical response, and EIHR (all P < .001), with similar trends for hsCRP levels (all P < .01). For etrasimod, AUCs for fCAL/hsCRP and EIHR were 0.85/0.74 (week 12; ELEVATE UC 52), 0.83/0.69 (week 52; ELEVATE UC 52), and 0.80/0.65 (week 12; ELEVATE UC 12). Conclusions: Fecal calprotectin/hsCRP levels decreased with etrasimod treatment; ROC analyses indicated a prognostic correlation between fCAL changes during induction and short-/long-term treatment response.

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). We present data from the ELEVATE UC 52 and ELEVATE UC 12 phase 3 clinical trials1 assessing etrasimod efficacy and safety in patients (pts) who were biologic/Janus kinase inhibitor (JAKi)-naïve and previously took 5-aminosalicylic acid (5-ASA) and/or thiopurines. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), eligible pts were randomised 2:1 to etrasimod 2 mg once daily or placebo (PBO). Pts in this post hoc analysis were naïve to prior biologic and/or JAKi treatments, and included regardless of prior/concomitant corticosteroids (CS). Pts in Cohort A were previously exposed to or currently taking 5-ASA, but naïve to prior thiopurines; pts in Cohort B were previously exposed to a thiopurine with/without prior/concomitant 5-ASA. Efficacy endpoints included clinical remission and endoscopic improvement (Weeks [Wks] 12 and 52), CS-free remission and sustained clinical remission (Wk 52) and symptomatic response (Wks 2, 4, 8 and 12). Data up to Wk 12 were pooled from both trials; Wk 52 data were from ELEVATE UC 52. Safety was assessed up to 52 wks. Results In Cohort A, 135 and 62 pts were randomised to etrasimod and PBO, respectively; more pts in the etrasimod vs PBO arm achieved clinical remission (Wks 12 and 52), endoscopic improvement (Wks 12 and 52), CS-free remission (Wk 52) and sustained clinical remission (Wk 52; all p<0.05; Figure 1A). In Cohort B, 69 and 35 pts were randomised to etrasimod and PBO, respectively; significantly more pts in the etrasimod vs PBO arm achieved clinical remission and endoscopic improvement (Wk 12) and sustained remission (Wk 52; all p<0.05; Figure 1B). In both cohorts, numerical differences in the etrasimod vs PBO arm in pts achieving symptomatic response were seen starting at Week 2. In both cohorts, safety findings were consistent with the overall population, with no increases in incidence rates of serious AEs or serious infections in the etrasimod vs PBO arm. Conclusion This post hoc analysis further characterises the efficacy and safety of etrasimod as a first-line advanced treatment after conventional 5-ASA and/or thiopurine therapy, and is consistent with previous results in the cohort of pts naïve to biologic/JAKi which showed greater treatment effects than in pts experienced with advanced treatments.2 Limitations included post hoc analysis and small cohort sample sizes. References 1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171. 2. Feagan B et al. United European Gastroenterol J 2022; 10: 388–389.

Abstract Background Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Unlike the other S1P receptor modulator approved for UC, etrasimod and its metabolites do not have a molecular structure to inhibit monoamine oxidase (MAO).1 Coadministration of drugs that inhibit MAO with opioids and antidepressants may increase the risk of adverse events (AEs), including hypertension.2 This post hoc analysis evaluated the incidence of AEs potentially related to serotonin syndrome in patients taking etrasimod and concomitant opioids or antidepressants in the phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials. Methods Safety data pooled from both trials were analysed in patients receiving etrasimod 2 mg QD (up to 52 weeks of exposure) with/without concomitant opioids or antidepressants. We report the proportions of patients who had ≥1 concurrent AE potentially related to serotonin syndrome, consisting of one standardised MedDRA Query, one query based on the Hunter Criteria and supplemental preferred terms (pyrexia, tachycardia and hypertension-related AEs).3 Results Among 527 patients receiving etrasimod, 77 (14.6%) and 35 (6.6%) patients were taking concomitant opioids or antidepressants, respectively. Most patients on concomitant opioids or antidepressants were White (80.0–88.3%); male (50.6–51.4%); their median age was 35.0 (18.0–70.0) and 41.0 (19.0–74.0) years, respectively. More patients with vs without concomitant opioids or antidepressants, respectively, consumed alcohol (40.3% vs 24.7% and 48.6% vs 25.4%) and used tobacco (40.3% vs 20.9% and 34.3% vs 23.0%). The incidence of other AEs potentially related to serotonin syndrome was low and generally comparable in all subgroups; reported rates of pyrexia and tachycardia were similar in patients with/without concomitant opioids or antidepressants (Table). Hypertension-related AEs were infrequent and generally balanced. No AEs per the Hunter Criteria were reported in patients on concomitant opioids or antidepressants (Table). No reported AEs were serious or led to treatment discontinuation among patients taking these concomitant medications. Conclusion The incidence of AEs was low and comparable in patients receiving etrasimod with or without concomitant opioids or antidepressants. This analysis supports the low likelihood of clinically relevant drug–drug interactions between etrasimod and medications commonly prescribed to patients with UC, such as opioids or antidepressants. References 1. Lee CA et al. Clin Pharmacol Drug Dev 2023; 12: 553–571. 2. Sands BE et al. J Crohns Colitis 2023; online ahead of print. 3. Dunkley EJC et al. QJM 2003; 96: 635–642.

Background and Aims: Infections are a safety concern in patients with ulcerative colitis [UC]. Etrasimod is an oral, once daily [QD], selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE programme. Methods: Proportions, incidence rates [IRs; per 100 patient-years], and descriptive analyses of all serious, severe, herpes zoster and opportunistic infections are reported in the Pivotal UC cohort [ELEVATE UC 52 and ELEVATE UC 12]. Cox regression models evaluated potential baseline risk factors. Results: In this analysis [n = 787], proportions [IRs] of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three [0.6%] and five [1.9%] patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group [etrasimod: 0.4%; placebo: 0.8%], all localised and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count [ALC] < 0.2 x 10(9)/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred. Conclusions: Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC < 0.5 x 10(9)/L and infection events was observed. Longer-term follow-up will further characterise the etrasimod safety profile.

Background Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we evaluate the impact of etrasimod 2 mg QD on health-related quality of life (HRQoL) in patients with UC.Methods This post hoc analysis used data from the Phase 3 randomized controlled trials, ELEVATE UC 52 and ELEVATE UC 12. HRQoL measures included: Inflammatory Bowel Disease Questionnaire (IBDQ), 36-Item Short Form Survey (SF-36), and Work Productivity and Activity Impairment Questionnaire: Ulcerative Colitis (WPAI:UC) completed at baseline, Week 12 (both trials), and Week 52 (ELEVATE UC 52 only). For IBDQ analyses, patients were stratified by prior exposure to biologics/Janus kinase inhibitors (JAKi) and baseline modified Mayo score (MMS; 4-6 or 7-9).Results Generally, significantly greater proportions of patients receiving etrasimod (N = 527) vs placebo (N = 260) achieved IBDQ remission (IBDQ total score >= 170) and IBDQ response (IBDQ total score increase from baseline >= 16), with significant improvement in all IBDQ domain scores at Week 12 and maintained through Week 52. Significant differences in IBDQ remission and IBDQ response rates between etrasimod and placebo were more consistent among biologic/JAKi-naive patients vs those who were biologic/JAKi-experienced and in those with baseline MMS 7-9 vs 4-6. Significant improvements were observed in several SF-36 domain and summary scores and WPAI:UC domain scores at Week 12 and Week 52.Conclusions Etrasimod 2 mg QD demonstrated significant and clinically meaningful improvements across multiple HRQoL measures, including WPAI, vs placebo.Clinical Trial Registration ClinicalTrials.gov: NCT03945188; NCT03996369 In this analysis of ELEVATE UC 52 and ELEVATE UC 12, we show that etrasimod 2 mg once daily vs placebo demonstrated significant and clinically meaningful improvements in patients' health-related quality of life measured by various instruments. Graphical Abstract

Introduction: Abdominal pain (AP) and bowel urgency (BU) are ulcerative colitis (UC) symptoms that result in quality of life impairment.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. Efficacy was demonstrated in the ELEVATE UC clinical program. Methods: The treatment effect of etrasimod vs placebo (PBO) on AP and BU was assessed as a post hoc analysis of the ELEVATE UC program. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (pts) were randomized 2:1 to once-daily etrasimod 2 mg or PBO. ELEVATE UC 52 had a treat-through design with a 12-week (wk) induction followed by a 40-wk maintenance period. ELEVATE UC 12 was a 12-wk induction study. In both trials, AP and BU data were assessed as pt-reported outcomes (PROs) at baseline (BL), Wks12 (both trials) and 52 (ELEVATE UC 52 only) using two 11-point numeric rating scales (NRS). The NRSs measured the worst AP and the severity of urgency to have a bowel movement in the past 24 hours and ranged from 0 (no pain or urgency) to 10 (pain as bad as can imagine or worst possible urgency). Endpoints included AP NRS=0, and, for pts with BL BU score ≥ 3: BU NRS clinically meaningful improvement (≥ 3 point decrease from BL) or remission (BU NRS ≤ 1).2 Results: At BL, the mean NRS scores ranged from 4.2 to 4.6 for AP and from 6.4 to 6.8 for BU across treatment arms and studies (Table 1). Significantly greater proportions of etrasimod- vs PBO-treated pts had no AP at Wk12 (ELEVATE UC 12: 33.2% vs 18.1%; ELEVATE UC 52: 27.7% vs 15.3%) and Wk52 (ELEVATE UC 52: 22.8% vs 10.4%) (all P< 0.01; Table 1). Similarly, significantly greater proportions of etrasimod- vs PBO-treated pts had no BU in both trials at Wk12 (18.1% vs 9.8%; 16.9% vs 6.7%, all P< 0.05), the difference did not meet statistical significance at Wk52 (ELEVATE UC 52: 17.3% vs 10.1%, P=0.0573; Table 1). In both trials, a significantly greater proportion of etrasimod- vs PBO-treated pts reported a BU NRS score of ≤ 1 and a decrease from BL of ≥ 3 points at Wk12 (both ELEVATE UC trials) and Wk52 (ELEVATE UC 52; all P< 0.05; Figure 1). Conclusion: Etrasimod improved AP and BU scores compared to PBO; a numerically greater proportion of etrasimod-treated pts reported no AP or no BU or had clinically meaningful decreases in BU at Wks12 and 52. References: 1. Hibi T et al. Inflamm Intest Dis 2020; 5: 27–35. 2. Dubinsky MC et al. J Patient Rep Outcomes 2022; 6: 114. Table 1. - AP and BU in ELEVATE UC 52 and ELEVATE UC 12 (FAS; BL MMS 4–9) ELEVATE UC 52 ELEVATE UC 12 PBO QD (N=144) Etrasimod 2 mg QD (N=289) Diff (95% CI) p value [a],[b] PBO QD (N=116) Etrasimod 2 mg QD (N=238) Diff (95% CI) p value [a],[b] Worst AP (NRS) in past 24 hr at BL, N1 Mean (SD) 1314.4 (2.83) 2724.6 (2.74) NA 1114.4 (2.75) 2214.2 (2.74) NA AP NRS=0Wk 12, n/N (%) 22/144 (15.3) 80/289 (27.7) 12.45 (4.64, 20.26)0.0018 21/116 (18.1) 79/238 (33.2) 14.97 (5.81, 24.13)0.0014 AP NRS=0Wk 52, n/N (%) 15/144 (10.4) 66/289 (22.8) 12.27 (5.39, 19.15)0.0005 NA NA NA Severity of urgency (NRS) in past 24 hr at BL, N1 Mean (SD) 1316.8 (2.61) 2726.8 (2.43) NA 1116.4 (2.48) 2216.4 (2.64) NA BU NRS=0Wk 12, n/N2 (%) 8/119 (6.7) 43/255 (16.9) 10.50 (3.99, 17.02)0.0016 10/102 (9.8) 36/199 (18.1) 8.18 (0.45, 15.9)0.0380 BU NRS=0Wk 52, n/N2 (%) 12/119 (10.1) 44/255 (17.3) 7.06 (-0.22, 14.34)0.0573 NA NA NA Missing responses are considered as non-responses.[a]Difference in response proportion (etrasimod vs PBO) is based on Cochran-Mantel-Haenszel method.[b]Two-sided nominal p values are reported without adjustment for multiple comparisons.AP, abdominal pain; BL, baseline; BU, bowel urgency; CI, confidence interval; Diff, difference; FAS, full analysis set; hr, hours; MMS, modified Mayo score; n, number of responders; N, number of patients in the FAS; N1, number of patients with observations at baseline; N2: number of patients with BL BU NRS score ≥ 3 points included in the analysis of BU NRS=0; NA, not applicable; NRS, numerical rating scale; PBO, placebo; QD, once daily; SD, standard deviation; Wk, week. Figure 1.: Proportions of Patients with (A) BU Remission (BU NRS of ≤ 1) and (B) a Clinically Meaningful Improvement (BU NRS ≥ 3 Point Decrease from BL) in BU Among Patients with a BL BU NRS Score ≥ 3 in ELEVATE UC 52 and ELEVATE UC 12. Missing responses are considered as non-responses Δ: adjusted difference in response rates for etrasimod vs PBO; BL, baseline; BU, bowel urgency; CI, confidence internal; PBO, placebo; n, number of responders; N2: number of patients with BL BU NRS score ≥ 3 points included in the analyses of BU NRS ≤ 1 and decrease from BL in BU NRS ≥ 3 points; NRS, numerical rating scale, QD, once daily; UC, ulcerative colitis; Wk, week.

Abstract Background In ulcerative colitis (UC), persistent histological activity is associated with higher rates of relapse and long-term complications, even when endoscopic remission is achieved; therefore, histological healing is a potentially important treatment target. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator for the treatment of moderately to severely active UC. This post hoc analysis of the phase 3 ELEVATE programme evaluated the efficacy of etrasimod according to different histologic and composite endpoints. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (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. A key secondary endpoint was the achievement of endoscopic improvement-histologic remission (EIHR). In this post hoc analysis (baseline MMS 5-9), efficacy of etrasimod was compared to PBO at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12 using additional histologic and composite endpoints defined in Table 1. Results At week 12 and at week 52, significant improvements with etrasimod were observed in histologic outcomes, including EIHR (with and without eosinophils), histologic remission, histologic-endoscopic mucosal improvement (HEMI), endoscopic normalization-histologic remission (with and without eosinophils), and disease clearance (Figure 1). In both studies, etrasimod was superior to PBO in achievement of HEMI at week 12 (ELEVATE UC 52 and UC 12: 27.7% vs 8.9%, and 25.7% vs 10.7%, both P<0.001) and at week 52 (ELEVATE UC 52: 32.8% vs 8.9%; P<0.001). Etrasimod was also superior to PBO in achievement of histologic remission at week 12 (33.9% vs 9.6%) and at week 52 (30.7% vs 14.1%, both P<0.001) in ELEVATE UC 52, but not ELEVATE UC 12. Etrasimod was superior to PBO using the more stringent endpoints of endoscopic normalization-histologic remission (week 12 ELEVATE UC 52 and UC 12: 10.6% vs 1.5%, P<0.001 and 10.4% vs 4.5%, P=0.030; week 52 ELEVATE UC 52: 18.2% vs 5.2%; P<0.001) and disease clearance (week 12 ELEVATE UC 52 and UC 12: 8.4% vs 1.5%, P<0.001 and 9.9% vs 4.5%, P=0.042; week 52 ELEVATE UC 52: 18.6% vs 3.7%; P<0.001). Conclusion In this post hoc analysis, etrasimod was superior to PBO for achievement of stringent composite endpoints including EIHR, endoscopic normalization-histologic remission, and disease clearance in both ELEVATE UC 52 and ELEVATE UC 12.

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.

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). Prior analyses demonstrated etrasimod efficacy in UC1 and greater improvement from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) total score and domains vs placebo (PBO).2 Methods: This post hoc subgroup analysis examined the effect of prior and concomitant therapies on IBDQ scores in the phase 3 ELEVATE UC clinical program. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), eligible patients (pts) with modified Mayo scores of 4–9 completed the 32-item IBDQ at Weeks (Wks)12 (both trials) and 52 (ELEVATE UC 52). In this analysis, pts were stratified by prior biologic/Janus kinase inhibitor (bio/JAKi) and baseline corticosteroid (CS) use. Least squares (LS) mean change from baseline in IBDQ total and domain scores were compared for etrasimod vs PBO (data as observed). Proportions of pts with IBDQ remission (total score ≥ 170) were analyzed (nonresponder imputation). Results: Among all randomized patients, there were 304/433 and 236/354 pts without prior bio/JAKi use and 298/433 and 255/354 pts without baseline CS use in ELEVATE UC 52 and ELEVATE UC 12, respectively. Overall, mean baseline IBDQ total scores were similar in pts with and without prior bio/JAKi or baseline CS use. At Wks12 (both trials) and 52 (ELEVATE UC 52), LS mean change from baseline in IBDQ total and domain scores was higher (p < 0.05) for etrasimod vs PBO in pts without prior bio/JAKi and pts without baseline CS use (Table 1). IBDQ remission was generally achieved by significantly higher proportions of pts receiving etrasimod vs PBO regardless of prior bio/JAKi or baseline CS use at Wk52 (prior bio/JAKi use: No, 46.8% vs 21.2% [p < 0.001] and Yes, 25.0% vs 11.1% [P=0.043]; baseline CS use: No, 41.3% vs 15.7% [p < 0.001] and Yes, 38.7% vs 23.8% [P=0.087]). Conclusion: Pts receiving etrasimod had improvements in IBDQ total score and in all 4 domains at Wk12, maintained at Wk52. Significant differences were shown in these outcomes with etrasimod vs PBO in pts without prior bio/JAKi and without baseline CS use. IBDQ remission was generally achieved by higher proportions of pts without vs with prior bio/JAKi or without vs with baseline CS use. References 1. Sandborn WJ et al. Lancet 2023; 401: 1159-1171. 2. Armuzzi A et al. J Crohns Colitis 2023: 17; i593–i594. Table 1. - LS Mean Change from Baseline in IBDQ Total Score and Domains by Prior Bio/JAKi and Baseline CS Use (Full Analysis Set) [n], LS mean change from baseline [a], (SE) Without prior bio/JAKi use With prior bio/JAKi use Without baseline CS use With baseline CS use Etrasimod 2 mg QD PBO Etrasimod 2 mg QD PBO Etrasimod 2 mg QD PBO Etrasimod 2 mg QD PBO ELEVATE UC 52 N=205 N=99 N=84 N=45 N=196 N=102 N=93 N=42 Wk12 [n=168] [n=79] [n=64] [n=35] [n=151] [n=77] [n=81] [n=37] IBDQ total score 47.44 (2.888)*** 27.74 4.144) 33.98 5.183) 34.27 7.099) 41.48 3.035)** 24.97 4.185) 44.45 4.537) 35.51 6.576) Bowel symptoms 17.10 0.941)*** 9.55 1.350) 12.79 1.645) 12.62 2.262) 15.39 0.999)*** 8.69 (1.380) 15.60 (1.459) 12.51 (2.113) Systemic symptoms 6.52 (0.467)*** 3.58 (0.670) 4.77 (0.843) 5.21 (1.161) 5.98 (0.475)** 3.52 (0.656) 5.75 (0.773) 4.66 (1.120) Emotional health 15.77 (1.090)*** 9.14 (1.563) 11.34 (1.970) 10.83 (2.697) 13.76 (1.149)** 8.59 (1.583) 15.15 (1.683) 11.10 (2.437) Social function 8.01 (0.548)** 5.56 (0.785) 5.06 (0.989) 5.47 (1.354) 6.38 (0.589)* 4.28 (0.811) 7.87 (0.842) 7.16 (1.217) Wk52 [n=116] [n=31] [n=27] [n=10] [n=97] [n=24] [n=46] [n=17] IBDQ total score 58.66 (3.209)** 39.75 (5.611) 47.11 (6.797) 29.54 (10.705) 55.75 (3.544)*** 30.64 (6.563) 51.84 (5.113) 46.70 (7.772) Bowel symptoms 20.70 (1.057)** 14.17 (1.877) 17.55 (2.217) 11.88 (3.526) 19.79 (1.177)*** 11.48 (2.203) 18.70 (1.690) 16.44 (2.591) Systemic symptoms 7.86 (0.520)* 5.63 (0.912) 5.96 (1.080) 4.24 (1.687) 7.67 (0.550)** 4.13 (1.009) 6.46 (0.891) 6.94 (1.365) Emotional health 20.25 (1.218)* 14.28 (2.146) 16.03 (2.618) 9.28 (4.144) 19.83 (1.354)** 11.58 (2.530) 16.88 (1.903) 15.46 (2.891) Social function 10.22 (0.612)** 6.47 (1.074) 7.90 (1.312) 4.85 (2.074) 8.70 (0.683)** 4.12 (1.253) 10.38 (0.974) 8.49 (1.495) ELEVATE UC 12 N=159 N=77 N=79 N=39 N=173 N=82 N=65 N=34 Wk12 [n=129] [n=64] [n=60] [n=31] [n=145] [n=67] [n=44] [n=28] IBDQ total score 42.17 (3.321)*** 22.29 (4.598) 51.13 (4.408)* 35.64 (6.038) 44.85 (2.929)*** 24.79 (4.268) 50.71 (5.343) 39.72 (6.596) Bowel symptoms 16.21 (1.134)*** 8.46 (1.565) 18.26 (1.456) 13.45 (1.996) 16.85 (1.003)*** 9.37 (1.462) 18.37 (1.781) 14.38 (2.197) Systemic symptoms 5.55 (0.545)** 2.75 (0.756) 6.89 (0.761) 4.51 (1.043) 6.02 (0.492)** 3.29 (0.718) 6.94 (0.910) 4.96 (1.123) Emotional health 13.66 (1.265)** 7.24 (1.747) 17.25 (1.653)* 11.11 (2.264) 14.69 (1.102)*** 7.72 (1.605) 16.98 (2.002) 13.08 (2.478) Social function 6.81 (0.591)** 3.78 (0.820) 8.66 (0.848) 6.63 (1.161) 7.33 (0.526)*** 4.30 (0.767) 8.44 (1.008) 7.29 (1.243) [a] For ELEVATE UC 52, estimates are from a mixed-effect model with repeated measures model for change from baseline with a covariate for baseline score, and factors for naive to bio/JAKi therapy (Yes or No, for with or without baseline CS use subgroups only) or baseline CS use (Yes or No, for with or without prior bio/JAKi use subgroups only), baseline disease activity (MMS: 4–6 or 7–9), treatment, visit, and treatment by visit interaction. For ELEVATE UC 12, estimates are from an analysis of covariance model for change from baseline, with a covariate for baseline score, and factors for naive to bio/JAKi therapy (Yes or No, for with or without baseline CS use subgroups only) or baseline CS use (Yes or No, for with or without prior bio/JAKi use subgroups only), baseline disease activity (MMS: 4–6 or 7–9), and treatment.The IBDQ evaluates disease-related quality of life using 32 items examined with 4 domains: bowel symptoms (score range, 10–70), systemic symptoms (score range, 5–35), emotional health (score range, 12–84) and social function (score range, 5–35). For the total score (range, 32–224) and each domain, a higher score indicates a better quality of life. Responses after intercurrent events and missing responses were considered as nonresponses.*P < 0.05; **P < 0.01; ***P < 0.001. Presented P values are for etrasimod 2 mg once daily vs PBO. P values are presented without adjustment for multiplicity.bio/JAKi, biologic/Janus kinase inhibitor; CS, corticosteroid; IBDQ, Inflammatory Bowel Disease Questionnaire; LS mean, least squares mean; MMS, modified Mayo score; N, total number of pts in the full analysis set; n, number of pts with available IBDQ data at the specified time point; PBO, placebo; pt; patient; QD, once daily; SE, standard error; UC, ulcerative colitis; Wk, week.

Abstract Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator (S1P1,4,5) in development for the treatment of moderately to severely active ulcerative colitis (UC). ELEVATE UC 52 and ELEVATE UC 12 were two phase 3 studies that demonstrated efficacy and safety of etrasimod in patients with UC in which several patient-reported outcomes were collected. Health-related quality of life (HRQoL) was assessed in a post hoc analysis of the ELEVATE programme with the validated Inflammatory Bowel Disease Questionnaire (IBDQ).1 Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). Patients in the full analysis set with modified Mayo Scores 5-9 with a completed 32-item IBDQ questionnaire at baseline, week 12 (both trials) and week 52 (ELEVATE UC 52 only) were included in this analysis. Least squares mean (LSM) change from baseline for IBDQ total score and IBDQ domain scores were compared between etrasimod and PBO arms in both trials at each time point (data as observed), along with the proportion of patients who achieved IBDQ remission (IBDQ total score ≥170; nonresponder imputation). Results At baseline, a total of 237 and 191 etrasimod-treated patients and 112 and 96 PBO-treated patients completed the IBDQ for ELEVATE UC 52 and ELEVATE UC 12, respectively. LSM change from baseline in IBDQ total scores for etrasimod vs PBO were 42.8 vs 27.4 (difference [95% CI] 15.4 [6.5, 24.4]; P<0.001) and 55.8 vs 38.1 (difference [95% CI] 17.7 [6.6, 28.6]; P=0.002) at week 12 and week 52, respectively, in ELEVATE UC 52, and 47.5 vs 30.2 (difference [95% CI] 17.3 [8.5, 26.2]; P<0.001) at week 12 in ELEVATE UC 12 (Figure 1A). A greater proportion of etrasimod-treated patients achieved IBDQ remission at week 12 in both trials and week 52 in ELEVATE UC 52 (Figure 1B). Etrasimod-treated patients demonstrated significant improvements from baseline vs PBO in all 4 IBDQ domains in both trials (Figure 2). Across all IBDQ domains, improvements were seen at 12 weeks and the LSM change from baseline was greatest among etrasimod-treated patients at all time points. Conclusion Patients treated with etrasimod demonstrated greater improvement from baseline in total and all 4 domain scores of the IBDQ at the end of the 12-week induction phase and 52-week maintenance phase in comparison with PBO. These findings demonstrate the benefits of etrasimod on disease-specific HRQoL and support the clinical findings from the ELEVATE programme. Reference: 1. Chen XL, et al. Health Qual Life Outcomes. 2017;15:1-13.

Abstract Background Infections are an important safety concern in patients with IBD and may be due to its therapies, such as corticosteroids. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). The biologic effect of etrasimod leads to selective and reversible lymphocyte retention in lymph nodes with a decrease in peripheral lymphocyte count. We report the infection events from the phase 3 ELEVATE programme. Methods Infection events were evaluated in the pivotal UC pooled safety analyses set comprising two phase 3 studies: ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369). Subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). We report the n (%) and exposure-adjusted incidence rate (EAIR) of infections including serious infections, severe infections, opportunistic infections (including tuberculosis), and herpes infections. Infections were considered adverse events of special interest (AESI) if they were severe (≥ CTCAE Grade 3), were opportunistic infections, or were herpes zoster or herpes simplex infections. Results From the pooled ELEVATE UC 12 and ELEVATE UC 52 trials, 527 subjects received ≥1 dose of etrasimod 2 mg (265.6 subject-years of exposure) and 260 subjects were randomised to PBO (103.0 subject-years of exposure). Infections were similar between treatment groups (etrasimod: 99 [18.8%], EAIR=0.41; PBO: 46 [17.7%], EAIR=0.52). The most frequent infections in both groups were COVID-19, urinary tract infections, and nasopharyngitis (Table 1). Serious infections occurred in 3 (0.6%) subjects in the etrasimod arm (EAIR=0.01) and 5 (1.9%) in PBO arm (EAIR=0.05). Two cases of herpes zoster were reported in each treatment group (etrasimod: 0.4%, EAIR<0.01; PBO: 0.8%, EAIR=0.02); these were localised and nonserious. One opportunistic infection was reported in each arm (etrasimod: subject withdrew from the study on day 20, the AE of Cytomegalovirus infection [Grade 2] was reported on day 36; PBO: tuberculosis [Grade 2]). Overall, 3 cases of infection led to discontinuation: 2 in the etrasimod arm (both mild) and 1 in the PBO arm (Table 2). No subject with an absolute lymphocyte count <0.2×109/L subsequently reported a serious/severe or opportunistic infection. There were no deaths. Conclusion In these trials, etrasimod-treated subjects reported no increase in infections relative to PBO. Serious infections and herpes zoster were more commonly reported in the PBO-treated group. Longer-term follow-up data from the ongoing 5-year open-label extension will further characterize the etrasimod safety profile.