Clinical effect of mirikizumab treatment on bowel urgency in patients with moderately to severely active ulcerative colitis and the clinical relevance of bowel urgency improvement for disease remission

Background: Bowel urgency reduces ulcerative colitis patients' quality of life. Mirikizumab, a p19-directed anti-IL-23 antibody, demonstrates ulcerative colitis efficacy. Mirikizumab efficacy to reduce bowel urgency and bowel urgency association with other endpoints were analyzed in 2 Phase 3 trials. Methods: LUCENT-1 (Induction): 1162 patients randomized 3:1 to intravenous 300 mg mirikizumab or placebo every 4 weeks for 12 weeks. LUCENT-2 (Maintenance): 544 mirikizumab responders during induction were re-randomized 2:1 to subcutaneous mirikizumab 200 mg or placebo every 4 weeks for 40 weeks (52 weeks of continuous treatment). Bowel urgency was measured using the Urgency Numeric Rating Scale (0–10); for patients with LUCENT-1 baseline score ≥3, bowel urgency clinically meaningful improvement (≥3-point decrease) and remission (score ≤1) rates in mirikizumab versus placebo groups were compared at Weeks 12 and 52. Associations between bowel urgency and other efficacy endpoints were assessed at Weeks 12 and 52. Results: A significantly higher proportion of mirikizumab patients versus placebo achieved clinically meaningful improvement in bowel urgency and remission at Weeks 12 and 52. Significantly higher percentages of patients achieving bowel urgency clinically meaningful improvement or remission, compared with those who did not, also achieved endpoints for clinical, corticosteroid-free, endoscopic, and symptomatic remission; clinical response; normalized fecal calprotectin and C-reactive protein; and improved quality of life. Conclusions: In patients with ulcerative colitis, bowel urgency improvement was associated with better clinical outcomes than in patients without improvement during induction and maintenance. A greater proportion of mirikizumab patients achieved sustainable bowel urgency improvement and remission compared to placebo patients

Patient interpretations of patient-reported outcome measures to assess bowel urgency: qualitative interviews in ulcerative colitis

Objectives: Bowel urgency is an impactful core symptom of ulcerative colitis (UC). Patient-reported outcome (PRO) questionnaires have been developed and used to assess the patient experience of this important symptom. The objective of this paper is to present evidence from qualitative research conducted to support the use and interpretation of select PRO questionnaires to assess bowel urgency related to the UC patient experience. Methods: Qualitative interviews were conducted with ten adults with a clinician-confirmed diagnosis of moderately to severely active UC. Interviews aimed to document patient interpretation of modified recall periods for the Urgency Numeric Rating Scale (Urgency NRS), two global assessments (i.e., the Patient Global Impression of Severity [PGIS] and Patient Global Impression of Change [PGIC]), and four items (Items 11, 16, 23, and 26) of the Inflammatory Bowel Disease Questionnaire (IBDQ), and explore the patient perspective of meaningful change on these questionnaires. Results: Both modified Urgency NRS versions (with 7-day or 3-day recall period) were interpreted as intended by most patients (≥ 88.9%), and slightly more than half of patients (60.0%) reported that the 7-day recall period was more relevant to their bowel urgency experience. Patients reported thinking of bowel urgency (≥ 80.0%) or bowel urgency-related accidents (70.0% of patients) when interpreting the global assessments and IBDQ items. Most patients reported a 1- to 3-point change as the smallest meaningful improvement that would be meaningful on the Urgency NRS (similar to findings on other questionnaires). Conclusion: Adults with UC can understand and respond to the Urgency NRS with modified recall periods (i.e., 7-day or 3-day), interpret the conceptual content of the PGIS, PGIC, and select IBDQ items to be inclusive of bowel urgency and bowel urgency-related accidents, and select answers representing meaningful improvements on the Urgency NRS, PGIS, PGIC, and IBDQ item response scales. These results further contribute patient-centered data to existing UC and bowel urgency research

Patient and Health Care Professional Perceptions of the Experience and Impact of Symptoms of Moderate-to-Severe Crohn’s Disease in US and Europe: Results from the Cross-Sectional CONFIDE Study

Background: Crohn’s disease (CD) significantly affects patients’ health-related quality of life and well-being. Aims: Communicating Needs and Features of IBD Experiences (CONFIDE) survey explores the experience and impact of moderate-to-severe CD symptoms on patients’ lives and identifies communication gaps between patients and health care professionals (HCPs). Methods: Online, quantitative, cross-sectional surveys of patients, and HCPs were conducted in the United States (US), Europe (France, Germany, Italy, Spain, United Kingdom), and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. US and Europe data are presented as descriptive statistics. Results: Surveys were completed by 215 US and 547 European patients and 200 US and 503 European HCPs. In both patient groups, top three symptoms currently (past month) experienced were diarrhea, bowel urgency, and increased stool frequency, with more than one-third patients wearing diaper/pad/protection at least once a week in past 3 months due to fear of bowel urgency-related accidents. HCPs ranked diarrhea, blood in stool, and increased stool frequency as the most common symptoms. Although 34.0% US and 27.2% European HCPs ranked bowel urgency among the top five symptoms affecting patient lives, only 12.0% US and 10.9% European HCPs ranked it among top three most impactful symptoms on treatment decisions. Conclusion: Bowel urgency is common and impactful among patients with CD in the US and Europe. Differences in patient and HCP perceptions of experiences and impacts of bowel urgency exist, with HCPs underestimating its burden. Proactive communication between HCPs and patients in clinical settings is crucial for improving health outcomes in patients with CD

Early and Sustained Symptom Control with Mirikizumab in Patients with Ulcerative Colitis in the Phase 3 LUCENT Program

Ulcerative colitis (UC), a chronic inflammatory bowel disease, may manifest with symptoms of increased stool frequency (SF), rectal bleeding (RB), bowel urgency (BU), abdominal pain (AP), and fatigue. Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately to severely active UC in the LUCENT Phase 3 trials. We evaluated mirikizumab's efficacy in achieving symptom control and time to symptom improvement during induction, maintenance of sustained symptom control, "comprehensive symptom control", defined according to a combination of individual patient-reported outcomes, and prognostic baseline indicators of early symptomatic remission at week 4.BACKGROUND AND AIMSUlcerative colitis (UC), a chronic inflammatory bowel disease, may manifest with symptoms of increased stool frequency (SF), rectal bleeding (RB), bowel urgency (BU), abdominal pain (AP), and fatigue. Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately to severely active UC in the LUCENT Phase 3 trials. We evaluated mirikizumab's efficacy in achieving symptom control and time to symptom improvement during induction, maintenance of sustained symptom control, "comprehensive symptom control", defined according to a combination of individual patient-reported outcomes, and prognostic baseline indicators of early symptomatic remission at week 4.The results of LUCENT-1/-2 have previously been reported. Treatment differences for symptomatic endpoints were compared over 52 weeks versus placebo (PBO) and comprehensive symptomatic endpoints at 12 and 52 weeks of continuous treatment. Subgroup analyses were conducted for prior biologic or tofacitinib treatment failure. Prognostic analyses were run using regression analysis.METHODSThe results of LUCENT-1/-2 have previously been reported. Treatment differences for symptomatic endpoints were compared over 52 weeks versus placebo (PBO) and comprehensive symptomatic endpoints at 12 and 52 weeks of continuous treatment. Subgroup analyses were conducted for prior biologic or tofacitinib treatment failure. Prognostic analyses were run using regression analysis.By Week (W)2, mirikizumab-treated patients achieved greater reductions in SF, RB, BU, and fatigue versus PBO. At W4, there was a higher rate of AP improvement. At W12, a greater proportion of mirikizumab-treated patients achieved symptomatic remission, RB remission, SF remission, and BU remission/clinically meaningful improvement. Mirikizumab-treated patients sustained symptom control versus placebo patients in maintenance until W52. This treatment effect was shown in patients regardless of prior biologic or tofacitinib failure. Additionally, mirikizumab achieved comprehensive symptom control versus PBO at W12 and W52.RESULTSBy Week (W)2, mirikizumab-treated patients achieved greater reductions in SF, RB, BU, and fatigue versus PBO. At W4, there was a higher rate of AP improvement. At W12, a greater proportion of mirikizumab-treated patients achieved symptomatic remission, RB remission, SF remission, and BU remission/clinically meaningful improvement. Mirikizumab-treated patients sustained symptom control versus placebo patients in maintenance until W52. This treatment effect was shown in patients regardless of prior biologic or tofacitinib failure. Additionally, mirikizumab achieved comprehensive symptom control versus PBO at W12 and W52.Mirikizumab demonstrated efficacy in achieving and sustaining symptom control and comprehensive symptom control over 52 weeks. [NCT03518086; NCT03524092].CONCLUSIONSMirikizumab demonstrated efficacy in achieving and sustaining symptom control and comprehensive symptom control over 52 weeks. [NCT03518086; NCT03524092]

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

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. 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). Among W52 mirikizumab responders, clinical response at W104 was 74.5%, 87.2%, and 96.7% and clinical remission was 76.6%, 89.0%, and 98.3% for NRI, mNRI, and OC, respectively. Among W52 mirikizumab remitters, clinical response at W104 was 54.0%, 62.8%, and 70.1% 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. 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

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

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.BACKGROUNDMirikizumab, 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.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.METHODSOf 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.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.RESULTSUsing 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.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.CONCLUSIONSSymptomatic, 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.ClinicalTrials.gov: NCT03518086; NCT03524092; NCT03519945.CLINICAL TRIAL REGISTRYClinicalTrials.gov: NCT03518086; NCT03524092; NCT03519945