Mirikizumab Improves Quality of Life in Patients With Moderately-to-Severely Active Ulcerative Colitis: Results From the Phase 3 LUCENT-1 Induction and LUCENT-2 Maintenance Studies

Abstract Background Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy in phase 3, randomized, double-blind, placebo-controlled LUCENT-1 (induction/NCT03518086) and LUCENT-2 (maintenance/NCT03524092) ulcerative colitis (UC) studies. We evaluated the effect of mirikizumab on quality-of-life (QoL) outcomes in these studies. Methods In LUCENT-1, 1162 patients with moderately-to-severely active UC were randomized 3:1 to receive mirikizumab 300 mg intravenous or placebo every 4 weeks (Q4W) for 12 weeks. In LUCENT-2, mirikizumab induction responders (N = 544) were re-randomized 2:1 to receive mirikizumab 200 mg subcutaneous or placebo Q4W through week (W) 40 (W52 of treatment). QoL was assessed at W12 and W52 using patient-reported outcomes. Treatments were statistically compared using analysis of covariance model (continuous outcomes) and Cochran–Mantel–Haenszel test (binary outcomes). Results At W12 and W52, mirikizumab showed significant improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) total and domain scores (P < .001); 36-Item Short Form Health Survey (SF-36) Physical Component Summary (PCS), Mental Component Summary (MCS), and domain scores (P < .05); EQ-5D-5L scores (P < .001); Work Productivity and Activity Impairment Questionnaire (UC) scores (P < .05); Patient Global Rating of Severity (P < .001); and Patient Global Rating of Change (P < .01) scores. A significantly higher proportion of mirikizumab-treated patients achieved IBDQ response (W12: 72.7% vs 55.8%; W52: 79.2% vs 49.2%; P < .001), IBDQ remission (W12: 57.5% vs 39.8%; W52: 72.3% vs 43.0%; P < .001), and clinically important improvements in PCS (W12: 50.6% vs 41.5%; W52: 61.9% vs 36.9%; P < .01) and MCS (W12: 44.2% vs 37.8%; W52: 51.2% vs 34.6%; P < .05) scores. Conclusions Mirikizumab improved QoL in patients with moderately-to-severely active UC in phase 3 LUCENT-1 and LUCENT-2 studies. Clinical trials registration number LUCENT-1: NCT03518086; LUCENT-2: NCT03524092


Introduction
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by mucosal inflammation of the colon.The disease exhibits a relapsing-remitting course; symptoms include diarrhea, rectal bleeding (RB), bowel urgency, and tenesmus. 1,2tients with UC experience increased morbidity across all quality-of-life (QoL) domains.Moderately-to-severely active UC has been shown in previous studies to be associated with anxiety and depression, 3,4 impaired social interactions, leisure activities, and work productivity. 5,6][11] Mirikizumab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that inhibits interleukin (IL)-23 by binding to an epitope on the p19 subunit. 12In a phase 2 study (NCT02589665) in patients with UC, mirikizumab improved QoL relative to placebo as assessed by Inflammatory Bowel Disease Questionnaire (IBDQ) scores and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Physical and Mental Component Summary (PCS and MCS, respectively) scores and domain scores at Weeks 12 and 52.Response rates for clinically meaningful improvements in IBDQ, PCS and MCS scores, and IBDQ remission were also higher in mirikizumab-treated patients at Weeks 12 and 52. 13 In the phase 3, LUCENT-1 induction (NCT03518086) and LUCENT-2 maintenance (NCT03524092) studies in moderately-to-severely active UC, mirikizumab demonstrated efficacy across clinical, symptomatic, endoscopic, and histologic measures of disease, even after the failure of conventional immunosuppressives, biologic therapies, and/or tofacitinib. 14erein, we present the effect of mirikizumab versus placebo on QoL outcomes in phase 3 LUCENT-1 and LUCENT-2 studies.
Detailed study design, eligibility criteria, and endpoints for LUCENT-1 and LUCENT-2 studies have been published previously. 14tudy protocols and informed consent forms were approved by the ethical review board supervising each site.The study was compliant with International Conference on Harmonization Good Clinical Practice guidelines, Declaration of Helsinki, and Council for International Organizations of Medical Sciences International Ethical Guidelines.Written informed consent was provided by all patients.

Randomization and Treatments
In the LUCENT-1 induction study, patients were randomized 3:1 to receive mirikizumab 300 mg or placebo intravenously (IV) every 4 weeks (Q4W) up to Week 12. Mirikizumab induction responders (patients who achieved ≥2 points and ≥30% decrease from baseline in MMS and had ≥1 point decrease from baseline in the RB subscore or an RB score of 0/1) at Week 12 (LUCENT-1) were re-randomized 2:1 to receive mirikizumab 200 mg or placebo subcutaneously Q4W up to Week 40 in the LUCENT-2 maintenance study.
LUCENT-1 and LUCENT-2 together comprised a total of 52 weeks of continuous mirikizumab treatment, with Week 12 representing the end of the induction study and the start (Week 0) of the 40-week maintenance study.
Detailed randomization stratification criteria have been reported previously. 14
Prespecified exploratory endpoints included assessment of (1) Patient Global Rating of Severity (PGRS) up to Weeks 12 and 52 and (2) Patient Global Rating of Change (PGRC) at Weeks 12 and 52.
A detailed description of PROs is provided in Supplementary Table 1.For all the secondary and exploratory endpoints, responses were collected electronically at respective time points using an eDiary (PGRS) or a tablet device.

Statistical Analyses
The statistical analyses were performed using SAS® Version 9.4 or higher.
Modified Intent-to-Treat (mITT) population included all randomized patients who received any amount of study treatment excluding patients impacted by the electronic clinical outcome assessment transcription error in Poland and Turkey. 14atient demographics and baseline characteristics were summarized by treatment for the mITT population.Descriptive statistics were used to summarize continuous variables and frequency counts and percentages were used to summarize categorical variables.
All PRO analyses for LUCENT-1 were carried out in the mITT population.For LUCENT-2, all PRO analyses were performed in the subpopulation of patients who responded to mirikizumab induction therapy at Week 12. Baseline for both LUCENT-1 and LUCENT-2 studies was defined as the last nonmissing assessment recorded on or prior to the date of the first study drug administration at Week 0 in LUCENT-1.
For prespecified continuous endpoints, treatments were compared (mirikizumab versus placebo) using analysis of covariance (ANCOVA) model (for PGRC, ANCOVA as observed was used).Type III sums of squares for least squares (LS) means were reported for each treatment group.The ANCOVA model included treatment, baseline value, and stratification factors in the model.The LS mean difference, standard error, P-value, and 95% confidence interval (CI), unless otherwise specified, were reported.Missing data were imputed using modified baseline observation carried forward (mBOCF) method: Patients had their last post-baseline value carried forward, with the exception that patients who discontinued due to an adverse event had their baseline value carried forward.
Cochran-Mantel-Haenszel (CMH) test was used to compare the proportion of patients who achieved binary endpoints (PCS and MCS MCID response rates, and IBDQ response and remission rates) in the two treatment groups, while adjusting for the stratification factors.Estimated common risk differences with 95% CI (calculated using Mantel-Haenszel-Sato method 25 ) and P-value (calculated using CMH) were reported.Missing data were imputed using nonresponder imputation (NRI) method.
The reported PRO measures were not included in the multiplicity-controlled testing scheme.Reported P-values are unadjusted for multiple testing and should not be interpreted as confirmatory.

Patient Disposition and Characteristics
In the LUCENT-1 study, 1162 patients comprising the mITT population were randomized to mirikizumab 300 mg IV (N = 868) or placebo IV (N = 294). 14In the LUCENT-2 study, 544 mirikizumab clinical responders were re-randomized to mirikizumab 200 mg SC (N = 365) or placebo SC (N = 179). 14atient demographics and baseline disease characteristics were generally balanced between the two treatment groups in the LUCENT-1 and LUCENT-2 studies (Table 1).

Patient Global Rating of Severity
In the induction study, significant improvement in PGRS scores was observed in the mirikizumab group versus placebo as early as Week 2 (P < .05)and scores continued to   improve up to Week 12 (−1.16vs −0.69; P < .001)(Figure 5A).Improvement in PGRS scores in mirikizumab-versus placebo-treated patients was sustained throughout the maintenance period, with significant improvements seen at Week 52 (−1.88 vs −1.07; P < .001)(Figure 5B).

Patient Global Rating of Change
Patients in the mirikizumab group showed significant improvement in PGRC at Weeks 12 (P < .001; Figure 5C) and 52 (P = .009;Figure 5D) compared to placebo.

Discussion
In the phase 3 LUCENT-1 and LUCENT-2 studies, mirikizumab showed significant and clinically meaningful improvement in QoL of patients with moderately-to-severely active UC.There is a lack of validated PROs specifically for UC; however, our study assessed improvement in both disease-related (IBDQ and WPAI:UC) and diverse (SF-36, EQ-5D-5L, PGRS, and PGRC) PROs.The improvements seen in these outcomes during the induction study (Week 12) were sustained through the maintenance period (Week 40; ie, 52 weeks of continuous therapy).
IBDQ is commonly used to assess disease-specific QoL. 26 In the current study, ~80% of mirikizumab-treated patients who were induction responders at Week 12 achieved IBDQ response, and ~70% of patients achieved IBDQ remission at Week 52.A recent study evaluating sensitivity of IBDQ reported treatment efficacy as a positive predictor of IBDQ outcomes and showed strong association between IBDQ and changes in clinical health in response to treatment. 27F-36 has been used in several UC clinical trials to detect changes in QoL with respect to treatment efficacy [28][29][30][31][32] ;  treatments that induce and maintain remission have shown to normalize and restore mental and physical well-being. 33linical remission rates in LUCENT-1 (Week 12) and LUCENT-2 (Week 40) studies were significantly higher in the mirikizumab group versus placebo. 14Consistent with these findings, a significantly greater proportion of mirikizumabtreated patients achieved clinically important improvement in PCS and MCS scores at Weeks 12 and 52 compared to placebo.
UC-related symptoms increase absenteeism and have a negative impact on patients' productivity at work (i.e., presenteeism), leading to unemployment and use of disability compensation. 34,35A recent systematic review reported that UC is associated with high annual absenteeism costs in North America ($1443 per person; range: $85-$2350) and Europe ($2394 per person; range: $651-$5992). 36In comparison to patients without IBD, patients with UC reported higher work loss-related costs per patient per year ($5307 vs $3165; P < .001) in the United States. 37Mirikizumab treatment significantly improved all WPAI:UC scores, except absenteeism, at Week 52 versus placebo.The impact on absenteeism may be explained by the majority of patients reporting zero absence due to UC in the past 7 days, findings in agreement with previously reported studies. 34n the current study, EQ-5D-5L VAS 38 scores improved significantly with mirikizumab versus placebo during the induction and maintenance studies.Compared to placebo, mirikizumab-treated patients reported significant improvement in PGRS scores as early as Week 2, with ~2-point improvement in mean PGRS score at Week 52.Similarly, mirikizumab significantly improved mean PGRC scores at Weeks 12 and 52 versus placebo.
1][32]39 In addition to clinical remission, treatment effect needs to be assessed from the patients' perspectives.The STRIDE-II recommendations include absence of disability and normalized health-related QoL as long-term treatment targets for moderate-to-severe UC and suggest changing treatment if these targets are not achieved. 8The current study utilized a broad range of PROs to evaluate the effect of mirikizumab on various dimensions of QoL including UC symptoms, change in severity of symptoms, physical and mental well-being, and work productivity and daily activities.

Conclusions
Mirikizumab demonstrated significant and clinically important improvement across all domains of QoL in patients with moderately-to-severely active UC during LUCENT-1 induction and LUCENT-2 maintenance studies.