Three-Year Efficacy and Safety of Mirikizumab Following 152 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study

Abstract

Background: Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, has demonstrated induction of clinical remission at week 12 with maintenance through week 104 in patients with moderately-to-severely active ulcerative colitis (UC). Results are presented from the LUCENT-3 open-label extension study through week 152.

Methods: Of 868 LUCENT clinical trial program mirikizumab-treated induction patients, 544 were responders of whom 365 were rerandomized to mirikizumab maintenance. Of these, 324 completed week 52 and 316 entered extension treatment (286 week 52 responders; 179 week 52 remitters). Efficacy and safety outcomes are reported for mirikizumab-treated LUCENT-3 participants, including biologic-failed patients, with data for week 52 maintenance responders/remitters. Discontinuations or missing data were handled by nonresponder imputation, modified nonresponder imputation (mNRI), and observed cases.

Results: Using mNRI, 81.6% of week 52 responders demonstrated clinical response at week 152. Week 152 remission rates for week 52 responders included clinical (56.1%), corticosteroid-free (CSF; 54.5%), endoscopic (61.0%), histologic-endoscopic mucosal remission (HEMR; 52.6%), symptomatic (74.9%), and bowel urgency (BU; 58.6%). At week 152, 53.3% of week 52 responders achieved histologic-endoscopic mucosal improvement (HEMI) and 74.3% achieved BU clinically meaningful improvement (CMI). Among week 52 remitters, 85.4% showed a clinical response at week 152, with clinical (70.1%), CSF (68.9%), endoscopic (72.0%), HEMR (63.4%), symptomatic (81.4%), and BU (60.8%) remission. At week 152, among week 52 remitters, 64.0% of patients achieved HEMI and 75.6% achieved BU CMI. Stool frequency, rectal bleeding, BU, and abdominal pain score reductions from induction baseline to maintenance week 52 were sustained through week 152 for week 52 completers. Overall, in the safety population, 7.4% of patients reported severe adverse events (AEs); 5.3% discontinued treatment due to AEs. AEs of special interest included opportunistic infection (1.8%), hepatic disorders (3.2%), cerebrocardiovascular events (1.5%), and malignancy (0.3%). Patients with antidrug antibodies reduced over time from 23.6% in year 1 to 3.2% in year 3.

Conclusions: Symptomatic, clinical, endoscopic, histologic, and quality-of-life outcomes support long-term sustained benefit of mirikizumab treatment up to 152 weeks in patients with UC, including biologic-failed patients, with no new safety concerns.

Clinical trial registry: ClinicalTrials.gov: NCT03518086; NCT03524092; NCT03519945.

Keywords: interleukin-23 p19 antibody; long-term extension; mirikizumab; ulcerative colitis; week 152 results.

Figure 1.

LUCENT-3 rates at 152 weeks of continuous treatment in LUCENT-2 week 52 responders and remitters for (A) alternate clinical remission, (B) endoscopic remission, (C) clinical response, (D) clinical remission, (E) symptomatic remission, and (F) corticosteroid-free remission (nonresponder imputation [NRI], modified NRI [mNRI], observed case [OC]). The modified intention-to-treat population was used with NRI, mNRI, and OC methods for missing data. Responders: ≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of endoscopic subscore (ES), stool frequency (SF) subscore, and rectal bleeding (RB) subscore, and RB of 0 or 1, or a ≥1-point decrease from baseline. Remitters: modified Mayo score (MMS) SF of 0 or SF of 1 with a ≥1-point decrease from baseline; RB of 0; and ES of 0 or 1. Symptomatic remission: SF of 0 or SF of 1 with a ≥1-point decrease in MMS from baseline; and RB of 0. Corticosteroid-free remission: clinical remission with no corticosteroid use for ≥12 weeks. Alternate clinical remission: SF of 0 or 1; RB of 0; and ES of 0 or 1 (excluding friability). Endoscopic remission: ES of 0 or 1 (excluding friability). Abbreviations: CI, confidence interval.

Figure 2.

LUCENT-3 rates at 152 weeks of continuous treatment in LUCENT-2 week 52 responders and remitters for (A) histologic-endoscopic mucosal improvement (HEMI), (B) histologic-endoscopic mucosal remission (HEMR), (C) bowel urgency (BU) clinically meaningful improvement (CMI), and (D) BU remission (nonresponder imputation [NRI], modified NRI [mNRI], observed case [OC]). The modified intention-to-treat population was used with NRI, mNRI, and OC methods for missing data. Responders: ≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of endoscopic subscore (ES), stool frequency (SF) subscore, and rectal bleeding (RB) subscore, and RB of 0 or 1, or a ≥1-point decrease from baseline. Remitters: modified Mayo score (MMS) SF of 0 or SF of 1 with a ≥1-point decrease from baseline; RB of 0; and ES of 0 or 1. Bowel urgency remission: Urgency Numeric Rating Scale (NRS) score of 0 or 1. CMI: change from baseline in Urgency NRS score ≥ 3 in patients with Urgency NRS score ≥ 3 at induction baseline. HEMI: Geboes score ≤ 3.1 and ES of 0 or 1 (excluding friability). HEMR: Geboes score ≤ 2B.0 and ES of 0 or 1 (excluding friability). Abbreviations: CI, confidence interval.

Figure 3.

LUCENT-3 rates at 152 weeks of continuous treatment in LUCENT-2 week 52 responders and remitters by biologic-failed and not biologic-failed treatment status for (A) clinical response, (B) clinical remission, (C) symptomatic remission, and (D) histologic-endoscopic mucosal remission (HEMR; nonresponder imputation). The modified intention-to-treat population was used with nonresponder imputation methods for missing data. Responders: ≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of endoscopic subscore (ES), stool frequency (SF) subscore, and rectal bleeding (RB) subscore, and RB of 0 or 1, or a ≥1-point decrease from baseline. Remitters: modified Mayo score (MMS) SF of 0 or SF of 1 with a ≥1-point decrease from baseline; RB of 0; and ES of 0 or 1. Biologic failed refers to patients with prior inadequate response, loss of response, or intolerance to biologic therapy or Janus kinase inhibitors (tofacitinib) at LUCENT-1 induction baseline. Not biologic failed refers to patients not meeting the biologic-failed definition at LUCENT-1 induction baseline. Symptomatic remission: SF of 0 or SF of 1 with a ≥1-point decrease in MMS from baseline; and RB of 0. HEMR: Geboes score ≤ 2B.0 and ES of 0 or 1 (excluding friability). Abbreviations: CI, confidence interval.

Figure 4.

Change from induction baseline in UC symptoms by visit through week 152 of continuous mirikizumab treatment in the modified intention-to-treat (mITT) population (LUCENT-1), mirikizumab induction responders (LUCENT-2), and maintenance completers (LUCENT-3, open-label) for (A) bowel urgency, (B) stool frequency, and (C) rectal bleeding (RB; mixed-effects model for repeated measures [MMRM]). The mITT population was used with MMRM to estimate the least squares mean (LSM) change from baseline. The LUCENT program is 3 separate studies with different study designs, and patients flow from one study to the next; thus, the patient population is changing across studies: LUCENT-1 (mITT), LUCENT-2 (mirikizumab induction responders), LUCENT-3 (mirikizumab maintenance completers). See Figure 1 for patient flow and the current examined population that follows mirikizumab induction responders through the LUCENT clinical program. The Urgency Numeric Rating Scale (0- to 10-point severity scale with 0 denoting no urgency and 10 denoting the worst possible urgency, with a ≥3-point decrease considered a CMI), modified Mayo score (MMS) stool frequency subscore (0 to 3 score; 0 = normal; 1 = 1-2 stools more than normal; 2 = 3-4 stools more than normal; 3 = ≥5 stools more than normal), and MMS RB subscore (0-3 score; 0 = normal; 1 = streaks of blood with stool less than half the time; 2 = obvious blood with stool most of the time; 3 = blood alone passed) measure changes in the respective symptom from the induction baseline. LSM was reported for each treatment group except for week 0 of maintenance (‡; week 12). Abbreviations: CMI, clinically meaningful improvement; IV, intravenous; MIRI, mirikizumab; SC, subcutaneous; W, week.

Figure 5.

Remission rates at weeks 12, 52, 104, and 152 for (A) symptomatic remission, (B) clinical response, (C) clinical remission, and (D) endoscopic remission in the modified intention-to-treat (mITT) population (overall efficacy population; LUCENT-1), mirikizumab induction responders (LUCENT-2; nonresponder imputation [NRI]), and LUCENT-2 maintenance responders (LUCENT-3; modified NRI [mNRI]). *Based upon study designs, after induction, responders are being followed over time; thus, the population changes and the week (W) 152 percentages are based on the noted population not the original LUCENT-1 baseline population. Missing data are not a factor for LUCENT-1 and LUCENT-2, and mNRI data for these studies are not available; thus, NRI data are shown. For LUCENT-3, to address missingness and allow for better over-time comparison, mNRI data are shown. ^aDatabase lock (DBL)-1 and DBL-2 are interim DBLs with differences in the number of patients included due to some study sites not being included for DBL-1. ^bLUCENT-1 MIRI induction responders rerandomized to MIRI or PBO (MIRI withdrawal). ^cResponder population (n = 285) of LUCENT-2 MIRI blinded maintenance completers population (n = 316). ^dCI for LUCENT-1. ^eCI for LUCENT-2 and LUCENT-3. Symptomatic remission: stool frequency (SF) of 0 or SF of 1 with ≥1-point decrease in modified Mayo score (MMS) from baseline; and rectal bleeding (RB) of 0. Endoscopic remission: endoscopic subscore (ES) of 0 or 1 (excluding friability). Clinical response: ≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of ES, SF, and RB subscores, and RB of 0 or 1, or a ≥1-point decrease from baseline. Clinical remission: MMS SF of 0 or SF of 1 with a ≥1-point decrease from baseline; RB of 0; and ES of 0 or 1. Endoscopic remission: ES of 0 or 1 (excluding friability). Treatment comparison was made with the Cochran-Mantel-Haenszel test adjusted for stratification factors. Abbreviations: CI, confidence interval; IV, intravenous; MIRI, mirikizumab; N, number of patients in the analysis population; PBO, placebo; Q4W, every 4 weeks; SC, subcutaneous.

Figure 6.

Incidence of ADA+ events in evaluable patients over time. Year 1 (weeks 0 to 52); year 2 (weeks 52 to 104); year 3 (weeks 104 to 152). Abbreviations: ADA, antidrug antibody; N, denominator, number of ADA+ evaluable patients for each time point.