Early and sustained symptom control with mirikizumab in patients with moderately to severely active ulcerative colitis in the LUCENT phase 3 clinical trial program

Introduction Mirikizumab (miri), an IL-23p19 monoclonal antibody, demonstrated improved symptom control and induction of clinical remission at week (W) 12 and maintenance of clinical remission at W40 in adult patients with moderately to severely active ulcerative colitis (UC) in LUCENT Phase 3 trials (NCT03518086, NCT03524092).

Objectives To assess the early onset of symptom improvement in the LUCENT-1 induction phase and sustained symptom control in the LUCENT-2 maintenance phase at W40 (W52 of continuous treatment) in patients induced into clinical response with miri.

Methods Patients with moderately to severely active UC and inadequate/loss of response or intolerance to conventional/biologic/tofacitinib therapy were randomised to receive intravenous miri 300mg (Q4W) or PBO (12W induction LUCENT-1). Patients who achieved clinical response to miri by W12 (end of induction) were re-randomised 2:1 to blinded maintenance treatment with subcutaneous miri 200mg or PBO Q4W in the 40W maintenance study (LUCENT-2). Clinical assessed outcomes in the induction and maintenance phase were rectal bleeding (RB), stool frequency (SF) and symptomatic remission, bowel urgency (BU) severity and BU remission. BU clinically meaningful improvement (CMI) and symptomatic response were assessed in the induction phase. Stable maintenance of symptomatic remission (symptomatic remission for≥7 of 9 visits from W4 to W36 and at Week 40) was assessed in the maintenance phase.

Results Patient cohort size and outcomes are shown in [Table 1] (induction W12) and [Table 2] (maintenance W40). As early as W2, patients receiving miri experienced significant reductions in SF (p=0.035), RB (p=0.001) and BU severity (p=0.004), with greater symptomatic response (p=0.003) compared to PBO. A significantly greater percentage of miri- vs PBO-treated patients achieved SF remission by W2; RB remission, symptomatic remission (p<0.001) and BU CMI by W4 (p=0.044), and BU remission at W7 onwards (p=0.002). The rate of stable maintenance of symptomatic remission was significantly higher in miri- vs PBO-treated patients (p<0.001) at W40.

Table 1 Assessment of improvement for ulcerative colitis symptomatic components in patients treated with miri vs PBO at W12 (LUCENT-1).

Endpoint (W12)	PBO IV Q4W N=294	Miri 300 mg IV Q4W N=868	Risk difference vs PBO (95% CI)*	P-value
RB remission, n (%)	129 (43.9)	555 (63.9)	20.6 (14.2, 27.0)	<0.001
SF remission, n (%)	117 (39.8)	495 (57.0)	17.1 (10.7, 23.6)	<0.001
Symptomatic response, n (%)	154 (52.4)	625 (72.0)	20.2 (13.8, 26.6)	<0.001
Symptomatic remission, n (%)	82 (27.9)	395 (45.5)	17.5 (11.4, 23.6)	<0.001
BU CMI, n (%)	N=276** 89 (32.2)	N=811.395 (48.7)	16.2 (9.7, 22.7)	<0.001
BU remission, n (%)	N=276** 34 (12.3)	N=811**179 (22.1)	9.7 (4.9, 14.5)	<0.001
BU severity, LSM change from baseline (SE)***	−1.63 (0.14)	−2.59 (0.08)	−0.95 (−1.47, −0.44)	<0.001

*The Cochran-Mantel-Haenszel (CMH) test, with missing data imputed as nonresponse, was used to assess the outcomes. The risk difference and CMH test were both adjusted for the stratification factors of prior biologic or tofacitinib failure, baseline corticosteroid use, region, and baseline modified mayo score.; **Baseline population differs according to definition of each endpoint.; *** Mixed model for repeated measures was used to assess BU severity.; Abbreviations: BU, bowel movement urgency; CI, confidence interval; CMI, Clinical Meaningful Improvement; IV, intravenous; LSM, least square mean; miri, mirikizumab; n, number of patients in the specified category; PBO, placebo; Q4W, every 4 weeks; RB, rectal bleeding; SE, standard error; SF, stool frequency; W, week.; Definitions: BU CMI, improvement of≥3 points in BU severity in patients with baseline BU severity≥3; BU remission, BU severity 0 or 1 in patients with baseline BU severity≥3; RB remission, RB sub score of 0; Symptomatic response, at least a 30% decrease from baseline in the sum of SF and RB sub scores; SF remission, SF sub score 0 or 1 with≥1-point decrease from baseline; Symptomatic remission, SF sub score 0 or 1 with≥1-point decrease from baseline and RB sub score of 0.

Table 2 Proportion of patients with ulcerative colitis with sustained symptom control at W40 (LUCENT-2).

Endpoint (W40)	PBO SC Q4W N=179	Miri 200 mg SC Q4W N=365	Risk difference vs PBO (95% CI)*	P-value
RB remission, n (%)	89 (49.7)	291 (79.7)	29.1 (20.8, 37.4)	<0.001
SF remission, n (%)	80 (44.7)	274 (75.1)	29.6 (21.2, 38.0)	<0.001
Symptomatic remission n (%)	71 (39.7)	259 (71.0)	30.2 (21.9, 38.6)	<0.001
Stable maintenance of symptomatic remission, n (%)	N=112**43 (38.4)	N=264**184 (69.7)	31.0 (20.7, 41.2)	<0.001
BU remission, n (%)	N=172**43 (25.0)	N=336**144 (42.9)	18.1 (9.8, 26.4)	<0.001
BU severity, LSM change from baseline (SE)	−2.74 (0.20)	−3.80 (0.14)	−1.06 (−1.51, −0.61)	<0.001

*The Cochran-Mantel-Haenszel (CMH) test, with missing data imputed as nonresponse, was used to assess the outcomes. The risk difference and CMH test were both adjusted for the stratification factors of prior biologic or tofacitinib failure, baseline corticosteroid use, region, and clinical remission status at the end of induction study.;**Baseline population differs according to definition of each endpoint.;*** Mixed model for repeated measures was used to assess BU severity.; Abbreviations: BU, bowel movement urgency; CI, confidence interval; LSM, least square mean; miri, mirikizumab; n, number of patients in the specified category; PBO, placebo; Q4W, every 4 weeks; RB, rectal bleeding; SC, subcutaneous; SE, standard error; SF, stool frequency; W, week, Definitions: BU remission, BU severity 0 or 1 in patients with BU severity≥3 at baseline; SF remission, SF=0 or 1 with a≥1-point decrease from induction baseline; RB remission, RB=0; Symptomatic remission, both SF and RB remission; Stable maintenance of symptomatic remission, patients in symptomatic remission for≥7 of 9 visits from W4 to W36 and also at Week 40 among patients in symptomatic remission and clinical response at the end of LUCENT-1.

Conclusion Compared with PBO, miri provides rapid control of UC symptoms during induction, including BU as early as W2, with control of BU, RB and SF sustained for a further 40 weeks of maintenance therapy in adult patients with moderately to severely active UC who are continuously treated ([Abb. 1]).

Abb. 1  

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Artikel online veröffentlicht:
28. August 2023