S1493 The Impact of Mirikizumab Induction, Maintenance, and Long-Term Treatment on Disease Clearance in Patients With Moderately to Severely Active Ulcerative Colitis: Post-Hoc Analysis of LUCENT Trials

Introduction: Disease clearance (DC) has been proposed as an aspirational target in ulcerative colitis (UC). Mirikizumab (miri) has demonstrated strong efficacy in LUCENT Phase 3 trials. This analysis evaluated the impact of miri on DC during LUCENT-1, -2 and long-term LUCENT-3 trials and the association between DC and other clinical and patient-reported outcomes (PROs). Methods: DC: symptomatic remission [Mayo stool frequency (SF)=0, 1 with ≥1 point decrease from baseline + rectal bleeding (RB)=0] and histologic-endoscopic mucosal remission [HEMR: Mayo endoscopic remission (ER: endoscopy subscore of 0 or 1, excluding friability) + Geboes score ≤2B.0]. PROs: Fatigue NRS, IBDQ remission, SF-36, WPAI:UC, PGRS and PGRC (see table footer). Clinical outcomes: clinical remission, corticosteroid-free remission, ER, HEMR, bowel urgency (BU) remission, SF remission and RB remission. Patient proportion achieving DC was assessed at W12, 52 and 104. Associations between the PROs and DC were evaluated at W12 and 52 and those between clinical outcomes and early DC achievement in miri-treated patients at W12 and W52 were evaluated at W52 and W104, respectively. Results: Significantly higher proportion of miri-treated patients achieved DC vs PBO at W12 (N=868 miri, 294 PBO; DC: 16.0% vs 7.1%, P < 0.0001) and W52 (N=365 miri, 179 PBO; DC: 36.4% vs 19.6%, P =0.0002). Similar trends were seen for biologic failure subgroups at W12 (bio/JAKi-failed DC: 9.1% miri vs 5.9% PBO; bio&JAKi-naïve DC: 20.9% miri vs 7.6% PBO) and W52 (bio/JAKi-failed DC: 31.3% miri vs 12.5% PBO; bio&JAKi-naïve DC: 39.3% miri vs 23.7% PBO). At W104 (N=239 miri), 40.6% patients achieved DC with 2-year of treatment. 38.4% bio/JAKi-failed (n=73) and 40.9% bio&JAKi-naïve (n=159) patients achieved DC. Significantly greater improvement in all PROs was seen at W12 for miri-treated patients who achieved DC vs those who did not at W12. Similar associations were observed at W52, except in WPAI: UC overall work productivity (Table 1A). Patients achieving DC at W12 were more likely to achieve all clinical outcomes, except BU remission, at W52 vs those who did not achieve W12 DC. This trend repeated in those who achieved DC at W52 and continued to W104 (Table 1B). Conclusion: Miri consistently demonstrated DC across induction, maintenance and long-term studies. Over 36% patients achieved DC after 1 year of miri treatment. DC attainment was associated with improvement in PROs in LUCENT-1 and -2. Early DC was associated with better long-term clinical outcomes. Table 1. - Association between disease clearance achievement and improvement in patient-reported outcomes in miri-treated patients, and association of early disease clearance and subsequent achievement of long-term positive clinical outcomes in miri-treated patients A. Association Between Disease Clearance Achievement and Improvement in Patient-Reported Outcomes in Miri-treated Patients B. Association of Early Disease Clearance and Subsequent Achievement of Long-term Positive Clinical Outcomes in Miri-treated Patients W12 W12 DC: (Y/N)[N=139 vs 729] W52 W52 DC: (Y/N)[N=133 vs 232] W52 W12 DC: (Y/N)[N=93 vs 272] W104 W52 DC: (Y/N)[N=111 vs 128] Fatigue NRS change from baseline, LSM (std) -2.5 (0.2) vs-1.8 (0.1)*** Fatigue NRS change from baseline, LSM (std) -3.2 (0.2) vs-2.3 (0.2)** Clinical Remission,n (%) 59 (63.4) vs 123 (45.2)** Clinical Remission, n (%) 73 (65.8) vs56 (43.8)*** IBDQ remission,n (%) 114 (82.0) vs385 (52.8)*** IBDQ remission,n (%) 116 (87.2) vs148 (63.8)*** CS-free Remission,n (%) 55 (59.1) vs 109 (40.1)** CS-free Remission, n (%) 71 (64.0) vs55 (43.0)** SF-36 PCS change from baseline, LSM (std) 8.8 (0.6) vs5.4 (0.3)*** SF-36 PCS change from baseline, LSM (std) 10.7 (0.6) vs8.0 (0. 5)*** Endoscopic Remission,n (%) 64 (68.8) vs 150 (55.1)* Endoscopic Remission, n (%) 87 (78.4) vs69 (53.9)*** SF-36 MCS change from baseline, LSM (std) 6.9 (0.7) vs4.7 (0.3)** SF-36 MCS change from baseline, LSM (std) 8.0 (0.7) vs6.3 (0.6)* HEMR,n (%) 55 (59.1) vs 103 (37.9)** HEMR,n (%) 68 (61.3) vs46 (35.9)*** WPAI:UC Overall Work Productivity change from baseline, LSM (std) -29.0 (2.5) vs-18.0 (1.3)*** WPAI Overall Work Productivity change from baseline, LSM (std) -34.9 (2.4) vs-29.0 (2.1) BU Remission,n (%) 44 (47.3) vs 114 (41.9) BU Remission,n (%) 58 (52.3) vs62 (48.4) PGRS change from baseline, LSM (std) -1.9 (0.1) vs-1.0 (0.04)*** PGRS change from baseline, LSM (std) -2.3 (0.1) vs-1.7 (0.1)*** SF Remission,n (%) 83 (89.2) vs 203 (74.6)** SF Remission,n (%) 103 (92.8) vs 106 (82.8)* PGRC, LSM (std) 1.7 (0.1) vs2.4 (0.05)*** PGRC, LSM (std) 1.5 (0.1) vs1.8 (0.1)** RB Remission,n (%) 87 (93.5) vs 224 (82.4)* RB Remission,n (%) 106 (95.5) vs 109 (85.2)** Note: * P < 0.05; ** P < 0.01; ***P < 0.001.DC = Symptomatic Remission & HEMR.Fatigue Numeric Rating Scale (NRS) = a single item patient-reported outcome measure that assesses fatigue on an 11-point NRS scale ranging from 0 (no fatigue) to 10 (fatigue as bad as you can imagine).Inflammatory Bowel Disease Questionnaire (IBDQ) = A 32-item patient-completed questionnaire that assesses 4 domains of IBD-related quality of life: "Bowel Symptoms", "Systemic Symptoms", "Emotional Function", and "Social Function". A higher total score of all 32-items combined indicates better IBD-related quality of life. An IBDQ score equal or greater than 170 points has been suggested for disease remission.Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Standard (SF-36) = a 36-item patient-reported outcome measure designed to assess health-related quality of life in 8 domains: physical functioning, role-physical, role-emotional, bodily pain, vitality, social functioning, mental health, and general health. The mental and physical well-being domains ladder to the Mental Component Summary (MCS) score and the Physical Component Summary (PCS) score. The MCS and PCS summary scores range from 0 to 100, where higher scores indicate better levels of function and/or better health.WPAI:UC = Work Productivity and Activity Impairment Questionnaire-Ulcerative Colitis (WPAI-UC) is a 6-item patient-reported outcome measure that assesses UC-related impairment of daily activity and work productivity over the past 7 days. Scores are represented as impairment percentages, with higher numbers indicating greater impairment and less productivity. (change from baseline).PGRS = A 1-item patient-rated questionnaire designed to assess the patients’ rating of their disease symptom severity over the past 24 hours. Responses are graded on a 6-point scale in which a score of 1 indicates the patient has no symptoms (that is, “none”) and a score of 6 indicates that the patient’s symptom(s) are “very severe.”PGRC = A patient-rated instrument designed to assess the patients’ rating of change in their symptom(s). Responses are graded on a 7-point Likert scale in which a score of 1 indicates that the subject’s symptom(s) is “very much better,” a score of 4 indicates that the subject’s symptom has experienced “no change,” and a score of 7 indicates that the subject’s symptom(s) is “very much worse.”Symptomatic remission = MMS SF=0 or SF = 1 with a ≥ 1 point decrease from baseline and RB = 0.HEMR =endoscopic remission (MMS ES = 0 or 1 (excluding friability)) and a Geboes subscore of 0 for grades 2b (lamina propria neutrophils), 3 (neutrophils in epithelium), 4 (crypt destruction), and 5 (erosion or ulceration).Clinical remission = MMS SF = 0 or 1 with a ≥ 1 point decrease from baseline, RB = 0, and ES = 0 or 1 (excluding friability).CS-free remission = At LUCENT-2 W40 (W52 of continuous treatment), clinical remission at W40, symptomatic remission at W28, and no CS use for ≥12 weeks prior to W40. At LUCENT-3 W52 (W104 of continuous treatment), corticosteroid-free remission is defined as clinical remission at W52 and no corticosteroid use for at least 12 weeks prior to W52.Endoscopic remission = MMS ES = 0 or 1 (excluding friability).BU remission = Urgency NRS Score = 0 or 1.SF remission = MMS SF=0, or SF=1 with a >= 1-point decrease from induction baseline.RB remission = MMS RB=0.Associations between DC and categorical outcomes were analyzed using a CMH test adjusted for randomization factors, and corresponding odds ratios were determined. Non-responder imputation was used to impute missing values. For continuous outcomes, associations were analyzed using analysis of covariance with mBOCF using a model that included baseline outcome value and randomization factors. Relative effect sizes were determined.Abbreviations: BU = Bowel Urgency; CS = corticosteroid; CMH = Cochran-Mantel-Haenszel; HEMR = histologic-endoscopic mucosal remission; IBDQ = inflammatory bowel disease questionnaire; LSM = least squares mean; MCS = mental component score; MMS = modified Mayo score; N = number of patients in the analysis population; n = number of patients in the specified category; NRS = numeric rating scale; PCS = physical component score; PGRC = patient global rating of change; PGRS = patient global rating of severity; RB = Rectal Bleeding; SF = Stool Frequency; SF-36 = 36-item short-form health survey; std = standard error; UNRS = Urgency Numeric Rating Scale; W = week; mBOCF = modified baseline observation carried forward; WPAI = work productivity activity impairment questionnaire.

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