Two-Year Efficacy and Safety of Mirikizumab Following 104 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, is efficacious in inducing clinical remission at week 12 (W12) and maintaining clinical remission at W52 in patients with moderately to severely active ulcerative colitis. Results are presented from the open-label extension study through W104.

Methods: Clinical, symptomatic, quality-of-life, and adverse event outcomes are reported for mirikizumab induction responders and extended 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 nonresponder imputation (NRI), modified NRI (mNRI), and observed case (OC).

Results: Among W52 mirikizumab responders, clinical response at W104 was 74.5%, 87.2%, and 96.7% and clinical remission was 54.0%, 62.8%, and 70.1% for NRI, mNRI, and OC, respectively. Among W52 mirikizumab remitters, clinical response at W104 was 76.6%, 89.0%, and 98.3% and clinical remission was 65.6%, 76.1%, and 84.2%. Using mNRI, remission rates at W104 for W52 clinical remitters were 74.7% corticosteroid-free, 79.5% endoscopic, 63.9% histologic-endoscopic mucosal remission, 85.9% symptomatic, 59.8% bowel urgency, 80.5% Inflammatory Bowel Disease Questionnaire (using NRI), 71.2% histologic-endoscopic mucosal improvement, and 77.5% bowel urgency improvement. Previous biologic-failed vs not-biologic-failed patient data were generally similar. Extended induction mNRI clinical response was 81.9%. Serious adverse events were reported in 5.2% of patients; 2.8% discontinued treatment due to adverse events.

Conclusions: Endoscopic, histologic, symptomatic, and quality-of-life outcomes support the long-term benefit of mirikizumab treatment up to 104 weeks in patients with ulcerative colitis, including biologic-failed patients, with no new safety concerns.

Keywords: IL-23 p19 antibody; long-term extension; mirikizumab; ulcerative colitis; week 104 results.

Figure 1.

LUCENT clinical trial program with LUCENT-3 patient flow pathways for analyzed populations. Response is defined as achieving ≥2-point and ≥30% decrease in the modified Mayo score (MMS) from induction baseline with rectal bleeding (RB) = 0 or 1, or ≥1-point decrease from baseline. DBL, data base lock; IV, intravenous; LOR, loss of response; MIRI, mirikizumab; OL, open-label; Q4W, every 4 weeks; SC, subcutaneous; W, week.

Figure 4.

LUCENT-3 rates at 104 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) (Geboes ≤2B.0 + endoscopic subscore [ES] = 0 or 1 [excluding friability]), 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 ES and stool frequency (SF) and rectal bleeding (RB) subscores, and RB = 0 or 1, or ≥1-point decrease from baseline. Remitters: modified Mayo score SF = 0 or SF = 1 with ≥1-point decrease from baseline; RB = 0; ES = 0 or 1. Biologic failed refers to those biologic-failed patients at LUCENT-1 induction baseline: prior inadequate response, loss of response, or intolerance to biologic therapy or Janus kinase inhibitors (tofacitinib). Not biologic failed refers to not-biologic-failed patients at LUCENT-1 induction baseline: patients not meeting biologic-failed definition. Symptomatic remission: SF = 0 or SF = 1 with ≥1-point decrease in modified Mayo score from baseline; RB = 0. CI, confidence interval.

Figure 2.

LUCENT-3 rates at 104 weeks of continuous treatment in LUCENT-2 week 52 responders and remitters for (A) clinical response, (B) clinical remission, (C) symptomatic remission, and (D) corticosteroid-free remission, nonresponder imputation (NRI), modified NRI (mNRI), observed case. The modified intention-to-treat population was used with the NRI, mNRI, and observed case methods for missing data. Responders: ≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of endoscopic subscore (ES) and stool frequency (SF), and rectal bleeding (RB) subscores, and RB = 0 or 1, or ≥1-point decrease from baseline. Remitters: modified Mayo score SF = 0 or SF = 1 with ≥1-point decrease from baseline; RB = 0; ES = 0 or 1. Symptomatic remission: SF = 0 or SF = 1 with ≥1-point decrease in modified Mayo score from baseline; RB = 0. Corticosteroid-free remission refers to clinical remission with no corticosteroid use for ≥12 weeks. For the mNRI method, for week 52 responders for endpoints: treatment discontinuation, 23 (9.6%); sporadic missing 32 (13.4%). For the mNRI method, for week 52 remitters: treatment discontinuation, 14 (9.1%); sporadic missing 20 (13.0%). CI, confidence interval.

Figure 3.

LUCENT-3 rates at 104 weeks of continuous treatment in LUCENT-2 week 52 responders and remitters for (A) histologic-endoscopic mucosal improvement (HEMI) (Geboes ≤3.1 + endoscopic subscore [ES] = 0 or 1 [excluding friability]), (B) histologic-endoscopic mucosal remission (HEMR) (Geboes ≤2B.0 + ES = 0 or 1 [excluding friability]), (C) bowel urgency clinically meaningful improvement (CMI) (change from baseline in Urgency Numeric Rating Scale [NRS] ≥3 in patients with Urgency NRS ≥3 at induction baseline), and (D) bowel urgency remission, nonresponder imputation (NRI), modified NRI (mNRI), observed case. The modified intention-to-treat population was used with the NRI, mNRI, and observed case methods for missing data. Responders: ≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of ES and stool frequency (SF) and rectal bleeding (RB) subscores, and RB = 0 or 1, or ≥1-point decrease from baseline. Remitters: modified Mayo score SF = 0 or SF = 1 with 2:1-point decrease from baseline; RB = 0; ES = 0 or 1. Bowel urgency remission: Urgency NRS = 0 or 1. For the mNRI method, HEMI/HEMR- week 52 responders: treatment discontinuation, 23 (9.6%); sporadic missing, 13 (5.4%). For the mNRI method, HEMI/HEMR week 52 remitters: treatment discontinuation, 14 (9.1%); sporadic missing, 9 (5.8%). For the mNRI method, bowel urgency CMI week 52 responders: treatment discontinuation, 22 (9.8%); sporadic missing, 29 (12.9%). For the mNRI method, bowel urgency CMI week 52 remitters: treatment discontinuation, 14 (9.5%); sporadic missing, 18 (12.2%). For the mNRI method, bowel urgency remission week 52 responders: treatment discontinuation, 23 (9.6%); sporadic missing, 33 (13.8%). For the mNRI method, bowel urgency remission week 52 remitters: treatment discontinuation, 14 (9.1%); sporadic missing, 20 (13.0%). CI, confidence interval.

Figure 5.

LUCENT-3 change from induction baseline in ulcerative colitis symptoms from weeks 52 through 104 (LUCENT-3 weeks 0-52) of continuous mirikizumab treatment in LUCENT-2 week 52 completers for (A) stool frequency (change in stool frequency modified Mayo score subscore from induction baseline), (B) rectal bleeding (change in rectal bleeding modified Mayo score subscore from induction baseline), (C) Abdominal Pain Numeric Rating Scale (NRS), and (D) Urgency NRS, mixed models for repeated measures. The modified intention-to-treat population was used with mixed models for repeated measures to estimate the mean change from baseline. The Abdominal Pain NRS measures change in abdominal pain score from induction baseline. The Urgency NRS measures change in bowel Urgency NRS score from induction baseline. LSM = least-squares mean.

Figure 6.

LUCENT-3 rate at 104 weeks of continuous treatment in LUCENT-2 week 52 responders and remitters by biologic-failed and not-biologic-failed treatment status for Inflammatory Bowel Disease Questionnaire (IBDQ) remission (IBDQ total score ≥170), nonresponder imputation. The modified intention-to-treat population was used with modified baseline observation carried forward and nonresponder imputation methods for missing data for continuous and categorical endpoints, respectively. Baseline was defined as the last nonmissing assessment recorded on or prior to the date of the first study drug administration at week 0 in the LUCENT-1 induction study. Inflammatory Bowel Disease Questionnaire remission rates are based on IBDQ total score ≥170; categorical data. Responders: ≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of endoscopic subscore and stool frequency (SF) and rectal bleeding (RB) subscores, and RB = 0 or 1, or ≥1-point decrease from baseline. Remitters: modified Mayo score SF = 0 or SF = 1 with ≥1-point decrease from baseline; RB = 0; endoscopic subscore = 0 or 1. Biologic failed refers to biologic-failed patients at LUCENT-1 induction baseline: prior inadequate response, loss of response, or intolerance to biologic therapy or Janus kinase inhibitors (tofacitinib). Not biologic failed refers to not-biologic-failed patients at LUCENT-1 induction baseline: patients not meeting the biologic-failed definition. CI, confidence interval.