S1450 Long-Term Efficacy and Safety of Mirikizumab Following 152 Weeks of Continuous Treatment: Results From the LUCENT-3 Open-Label Extension Study

Introduction: Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, is efficacious in inducing clinical remission at Week(W) 12 and maintaining clinical remission through W52 and W104 in patients with moderately-to-severely active ulcerative colitis (UC) (LUCENT-1, LUCENT-2, LUCENT-3). Here we present efficacy and safety results through W152 of mirikizumab treatment from the open-label extension LUCENT-3 study. Methods: Clinical, symptomatic, quality-of-life, and adverse event outcomes are reported for mirikizumab induction responders, including biologic failed patients, who entered LUCENT-3, with data shown for W52 maintenance responders or remitters. Discontinuations or missing data were handled by non-responder imputation (NRI), modified NRI (mNRI), and observed case (OC). mNRI uses multiple imputation for missing data and balances bias of NRI and OC. Table provides endpoint and population definitions and abbreviations. Results: Using mNRI, among W52 miri responders, 82% demonstrated clinical response at W152. Remission rates at W152 for W52 clinical responders were: 56% clinical, 55% corticosteroid-free (CSF), 61% endoscopic, 53% histologic-endoscopic mucosal remission (HEMR), 75% symptomatic, and 59% bowel urgency. Patients achieving histologic-endoscopic mucosal improvement (HEMI) and bowel urgency clinically meaningful improvement (CMI) at W152 were 53% and 74%, respectively. For W52 miri remitters, 85% demonstrated clinical response at W152. Remission rates at W152 for W52 clinical remitters were: 70% clinical, 69% CSF, 72% endoscopic, 63% HEMR, 82% symptomatic, and 61% bowel urgency. Patients achieving HEMI and bowel urgency CMI at W152 were 64% and 76%, respectively. Biologic Failed/Non-failed subgroup data were generally similar (Table 1). Stool frequency, rectal bleeding, bowel urgency, and abdominal pain symptom score reductions from induction baseline at W52 were sustained through W152. Severe adverse events (AEs) were reported in 7.4% of patients, while 5.3% discontinued treatment due to an AE. AEs of special interest included: opportunistic infection (1.8%); cerebrocardiovascular events (1.5%); malignancy (0.3%). Elevated liver enzymes ≥3ULN included: ALT (0.9%); AST (1.2%); TBL (1.8%); none ≥5ULN. Conclusion: Symptomatic, clinical, endoscopic, histologic, and quality-of-life outcomes support the long-term sustained benefit of mirikizumab treatment up to 152 W in patients with UC, including biologic failed patients, with no new safety concerns. Table 1. - Efficacy and safety results through week 152 of mirikizumab treatment Endpoints atWeek 152 In Week 52 Responders1 n=285% All (95% CI3) In Week 52 Responders1 n=195% Not Biologic Failed (95% CI3) In Week 52 Responders1 n=91% Biologic Failed (95% CI3) In Week 52 Remitters2 n=179% All (95% CI3) In Week 52 Remitters2 n=120% Not Biologic Failed (95% CI3) In Week 52 Remitters2 n=59% Biologic Failed (95% CI3) Clinical Response4 71.6(66.1, 76.5) 76.4(70.0, 81.8) 60.4(50.2, 69.9) 72.6(65.7, 78.6) 79.2(71.1, 85.5) 59.3(46.6, 70.9) Clinical Remission5 49.5(43.7, 55.2) 52.3(45.3, 59.2) 42.9(33.2, 53.1) 60.3(53.0, 67.2) 65.8(57.0, 73.7) 49.2(36.8, 61.6) Symptomatic Remission6 CSF Remission7 66.3(60.6, 71.6) 48.1(42.3, 53.9) 71.3(64.6, 77.2) 50.8(43.8, 57.7) 54.9(44.7, 64.8)41.8(32.2, 52.0) 69.8(62.7, 76.1)59.2(51.9, 66.1) 75.8(67.4, 82.6)65.0(56.1, 72.9) 57.6(44.9, 69.4)47.5(35.3, 60.0) HEMR8 49.3 (43.6, 55.1) 51.3 (44.3, 58.2) 45.1 (35.2, 55.3) 59.2(51.9, 66.1) 63.3(54.4, 71.4) 50.8(38.4, 63.2) Endoscopic Remission9 59.1(53.3, 64.6) 59.5(52.5, 66.1) 58.2(48.0, 67.8) 69.8(62.7, 76.1) 73.3(64.8, 80.4) 62.7(50.0, 73.9) HEMI10 50.3(44.6, 56.1) 51.8(44.8, 58.7) 47.3(37.3, 57.4) 59.8(52.5, 66.7) 64.2(55.3, 72.2) 50.8(38.4, 63.2) Bowel Urgency Remission11 51.6(45.8, 57.3) 55.4(48.4, 62.2) 42.9(33.2, 53.1) 52.5(45.2, 59.7) 60.0(51.1, 68.3) 37.3(26.1, 50.0) Bowel Urgency CMI12 n=266 13 65.4(59.5, 70.9) n=180 13 69.4(62.4, 75.7) n=87 13 56.3(45.9, 66.3) n=169 13 63.9(56.4, 70.8) n=112 13 68.8(59.7, 76.6) n=57 13 54.4(41.6, 66.6) Abbreviations: AE=Adverse event; ALT=alanine aminotransferase; AST=aspartate transaminase; CI=Confidence Interval; CMI= clinically meaningful improvement; CSF= corticosteroid-free; HEMI= histologic-endoscopic mucosal improvement; HEMR=histologic-endoscopic mucosal remission ES=Endoscopic Subscore; mITT=Modified Intent-to-Treat; mRNI=modified NRI; NRI=Nonresponder Imputation; NRS = Numeric Rating Scale; OC = observed case; TBL=total bilirubin.Definitions: Biologic Failed: Inadequate response, loss of response, or intolerant to a biologic therapy or the Janus kinase inhibitors for UC. Cerebrocardiovascular events: atrial fibrillation (N=2), angina unstable (N=1), coronary arterial stent insertion (N=1), hypertensive crisis (N=1), ventricular tachycardia (N=1) – angina and stint were same patient. Not Biologic Failed: failed conventional treatments (i.e., immunomodulators/corticosteroids); may include some participants who were exposed to but did not fail biologic treatment. Malignancy: thyroid cancer metastatic (N=1). mNRI: patients who discontinue treatment treated as nonresponders and patients who are otherwise missing endpoint data imputed using multiple imputation. NRI: patients who discontinue treatment treated as nonresponders and patients who are otherwise missing endpoint data tagged as nonresponders. OC: patients who discontinue treatment or are otherwise missing data are excluded from analyses. Opportunistic infection: herpes zoster (N=4), candidiasis (N=3) – one patient had each.1Responders = (≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of endoscopic (ES), stool frequency (SF) and rectal bleeding (RB) subscores, and RB = 0 or 1, or ≥1 pt decrease from baseline).2Remitters = (Mayo Modified Score [MMS] SF = 0 or SF = 1 with ≥ 1-point decrease from baseline; RB = 0; ES = 0 or 1) cohort of LUCENT-2 at W52.3Response confidence intervals are constructed using Wilson method, without continuity correction.4Clinical response: ≥2-point and ≥30% decrease in MMS from baseline; RB=0 or 1 or, RB ≥1-point decrease from baseline.5Clinical remission: SF=0 or SF=1 with ≥1-point decrease in MMS from baseline; RB=0; and ES=0 or 1 (excluding friability).6Symptomatic remission: SF=0 or SF=1 with ≥1-point decrease in MMS from baseline; RB=0.7Corticosteroid-free (CSF) remission: Defined as clinical remission, and no corticosteroid use for at least 12 weeks prior to Week 52; SF = 0, or SF = 1 with a ≥1-point decrease from induction baseline; RB = 0; ES = 0 or 1 (excluding friability).8Histologic-Endoscopic Mucosal Remission (HEMR): Endoscopic subscore=0 or 1 (excluding friability) + Geboes≤2.0.9Endoscopic remission: ES=0 or 1 (excluding friability); score ranges 0 to 4; a lower score indicates less mucosal damage.10Histologic-Endoscopic Mucosal Improvement (HEMI): Endoscopic subscore=0 or 1 (excluding friability) + Geboes≤3.1.11Bowel urgency remission: UNRS=0 or 1.12Bowel urgency Clinically Meaningful Improvement (CMI): Change from baseline in UNRS≥3 in patients with UNRS≥3 at induction baseline.13In patients who had BU NRS≥3 at induction baseline.

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