Efficacy and Safety of Mirikizumab in the Treatment of Moderately to Severely Active Ulcerative Colitis Regardless of Baseline Modified Mayo Score: Results From the Phase 3 LUCENT Trials

Abstract

Background: The modified Mayo score (mMS) is a measure for ulcerative colitis (UC) disease activity. Recent US Food and Drug Administration guidance for moderately to severely active UC trials suggests that patients should have baseline mMS of 5-9 including an endoscopy score of at least 2, as opposed to the previous range of 4-9. This disclosure reports results from patients with UC with baseline mMS of 5-9 who received mirikizumab, a monoclonal antibody directed against the interleukin-23 p19 subunit, or placebo in the phase 3 LUCENT trials.

Methods: Mirikizumab was evaluated in the randomized, double-blind, placebo-controlled LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) trials, and the ongoing long-term LUCENT-3 (NCT03519945) trial, which use mMS 4-9. Analyses for patients with baseline mMS of 5-9 (excluding patients with mMS of 4) were conducted according to LUCENT trial statistical analysis plans. Categorical efficacy endpoints were summarized using proportions and confidence intervals. Continuous efficacy endpoints are presented as least-squares mean (standard error) changes from baseline.

Results: Mirikizumab demonstrated efficacy for the primary endpoint of clinical remission and major secondary endpoints including clinical response, endoscopic improvement, histologic-endoscopic mucosal improvement/remission, bowel urgency remission, and corticosteroid-free remission. Importantly, mirikizumab exhibited greater improvements versus placebo in the Inflammatory Bowel Disease Questionnaire, fatigue, symptomatic remission, and work productivity. Finally, mirikizumab demonstrated long-term (104-week) sustained, durable efficacy across all studied endpoints. No new safety signals were identified during the 2-year follow-up.

Conclusions: Mirikizumab delivered significant clinical benefit for patients with baseline mMS of 5-9 and demonstrated a favorable safety profile.

Keywords: fatigue; mirikizumab; modified Mayo score; ulcerative colitis; urgency.

Graphical Abstract

Figure 1.

The primary endpoint (clinical remission) and major secondary endpoints at week 12 of the LUCENT-1 induction trial (A) and week 52 of the LUCENT-2 maintenance trial (B) among patients with induction baseline mMS of 5–9. Error bars indicate the upper limit of the 95% confidence intervals for each outcome unless otherwise specified. *P < .01, **P = .001, ***P < .001. ^aClinical remission is defined as an SF of 0 or 1, with a ≥1-point decrease from baseline, RB of 0, and ES of 0 or 1 (excluding friability). ^bClinical response is defined as a ≥2-point and ≥30% decrease in mMS from baseline, RB of 0 or 1, or RB ≥1-point decrease from baseline. ^cEndoscopic improvement is defined as an ES of 0 or 1 (excluding friability). ^dHEMI is defined as both endoscopic improvement (centrally read ES of 0 or 1, excluding friability) and histologic improvement (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue based on the Geboes scoring system). ^eBowel urgency remission is defined as an Urgency NRS weekly average score of 0 to 1 among subjects with a baseline Urgency NRS of ≥3. At week 12: placebo N = 245, mirikizumab N = 728; at week 52: placebo N = 160, mirikizumab N = 307. ^fClinical remission maintenance is defined as achievement of clinical remission at Week 52 in patients who were in clinical remission at Week 12; Placebo N = 62, Mirikizumab N = 128. ^gCSF clinical remission is defined as clinical remission at week 40 and no corticosteroid use for ≥12 weeks prior to the week 40 assessment. ^hHEMI is defined as both endoscopic improvement (centrally read ES of 0 or 1, excluding friability) and histologic improvement (no neutrophils in crypts or lamina propria, no crypt destruction, and no erosions, ulcerations, or granulation tissue based on the Geboes scoring system). CSF, corticosteroid-free; ES, endoscopic subscore; HEMI, histologic–endoscopic mucosal improvement; IV, intravenous; mMS, modified Mayo score; NRS, numeric rating scale; RB, rectal bleeding; SC, subcutaneous; SF, stool frequency.

Figure 2.

Efficacy by prior types of biologic/JAKi therapies at week 12 in LUCENT-1 in patients with baseline mMS of 5–9: clinical remission (A), endoscopic improvement (B), and HEMI (C). Error bars on the figures represent the upper 95% confidence intervals for each outcome. The definitions for each endpoint remained consistent with those outlined in Figure 1 or as otherwise annotated. *P < .05, **P < .01, ***P < .001. ^aTofacitinib was the only JAKi available at the time of the study. HEMI, histologic–endoscopic mucosal improvement; JAKi, Janus kinase inhibitor; mMS, modified Mayo score; TNFi, tumor necrosis factor inhibitor.

Figure 3.

Efficacy by prior types of biologic/JAKi therapies at week 52 in LUCENT-2: clinical remission (A), endoscopic improvement (B), CSF clinical remission (C), and HEMI (D). Error bars on the figures represent the upper 95% confidence intervals for each outcome. The definitions for each endpoint remained consistent with those outlined in Figure 1 or as otherwise annotated. *P < .05, **P < .01, ***P < .001. ^aTofacitinib was the only JAKi available at the time of the study. ^bHEMI is defined as both endoscopic improvement (centrally read ES of 0 or 1, excluding friability) and histologic improvement (no neutrophils in crypts or lamina propria, no crypt destruction, and no erosions, ulcerations, or granulation tissue based on the Geboes scoring system). CSF, corticosteroid-free; HEMI, histologic–endoscopic mucosal improvement; JAKi, Janus kinase inhibitor; mMS, modified Mayo score; TNFi, tumor necrosis factor inhibitor.

Figure 4.

Patient-reported outcomes from LUCENT-1 (A) and LUCENT-2 (B) for patients with induction baseline mMS of 5–9. Error bars on the figure represent the upper limit of the 95% confidence intervals (left) and standard error (center and right). *P < .05, **P < .01, ***P < .001. IBDQ remission, IBDQ response, and systematic remission were analyzed with a Cochran-Mantel-Haenszel test with adjustment for stratification factors (corticosteroid use [yes/no] at LUCENT-1 baseline, prior biologic or tofacitinib failure [yes/no], baseline disease activity [mMS: 5–6, 7–9], and geographic region [North America, Europe, and Other]). For LUCENT-2, clinical remission at LUCENT-1 week 12 (yes/no) replaces baseline disease activity. WPAI and fatigue outcomes were analyzed with an analysis of covariance model that included trial group, baseline value, corticosteroid use (yes/no) at LUCENT-1 baseline, prior biologic or tofacitinib failure (yes/no), baseline disease activity (mMS: [5–6] or [7–9]), and geographic region (North America, Europe, and Other). For LUCENT-2, clinical remission at LUCENT-1 week 12 (yes/no) replaces baseline disease activity. Presenteeism, absenteeism, and work impairment are in patients with baseline employment. Overall work impairment score, aggregate of absenteeism and presenteeism. IBDQ, Inflammatory Bowel Disease Questionnaire; LSM, least square means; mMS, modified Mayo score; NRS, numeric rating scale; Presenteeism, reduced productivity while at work; WPAI-UC, Work Productivity and Activity Impairment Questionnaire Ulcerative Colitis

Figure 5.

Efficacy at 104 weeks (2 years) of continuous treatment for clinical remission, CSF clinical remission, endoscopic improvement, HEMI, and bowel urgency remission (mMS of 5–9 at LUCENT-1 baseline, mNRI) for maintenance responders in LUCENT-3. Error bars on the figure represent the upper 95% confidence intervals for each outcome. The outcome definitions remained consistent with those outlined in Figure 1 or as otherwise specified below. ^aHEMI is defined as both endoscopic improvement (centrally read endoscopic subscore of 0 or 1, excluding friability) and histologic improvement (no neutrophils in crypts or lamina propria, no crypt destruction, and no erosions, ulcerations, or granulation tissue based on the Geboes scoring system). ^bBowel urgency remission is defined as an Urgency NRS weekly average score of 0–1. CSF, corticosteroid-free; HEMI, histologic–endoscopic mucosal improvement; mMS, modified Mayo Score; mNRI, modified nonresponder imputation; NRS, numeric rating scale.