Introduction
Mirikizumab is an anti-IL-23p19 antibody with demonstrated efficacy compared to placebo in the treatment of moderately to severely active ulcerative colitis (UC) (LUCENT-1: NCT03518086; LUCENT-2: NCT03524092). Corticosteroid (CS)-free remission is a treatment goal for patients with UC. Mirikizumab’s CS-sparing effect was assessed in the LUCENT-2 maintenance trial among patients receiving CS at baseline.
Aims & Methods
In LUCENT-1, patients on mirikizumab or placebo who entered the study on CS remained on their stable baseline dose (≤20 mg/day prednisone equivalent) during induction (Week [W] 0 to W12). Patients randomized to mirikizumab induction and achieving clinical response (N=365) at W12 were re-randomized 2:1 in LUCENT-2 to mirikizumab (200 mg/4 weeks) or placebo for maintenance (W12-52). LUCENT-1 responders began a CS taper upon entering LUCENT-2 by tapering the >10 mg daily dose by 5 mg/week until receiving 10 mg/day, and then 2.5 mg/week until 0 mg/day. For those receiving ≤10 mg/day, the daily dose was tapered by 2.5 mg/week until 0 mg/day. Clinical remission was defined as a Mayo stool frequency subscore of 0 or 1 with ≥1-point decrease from W0 baseline, a rectal bleeding subscore of 0, and an endoscopic subscore of 0 or 1 (excluding friability). Descriptive statistics were calculated with non-responder imputation used for missing data. The common risk difference between mirikizumab and placebo was calculated and adjusted for the following stratification factors: prior biologic/tofacitinib failure, region, and W12 clinical remission status. Risk difference confidence intervals were calculated with the Mantel-Haenszel-Sato method. P-values were calculated with the Cochran-Mantel-Haenszel test adjusted by prior biologic/tofacitinib failure and W0 CS use.
Results
Of the mirikizumab induction responders who were re-randomized in LUCENT-2, 33% (59/179) of placebo patients were baseline CS users compared with 34% (125/365) of mirikizumab patients. The median baseline CS dose was 20 mg/day. At W52, a significantly greater proportion of patients treated with mirikizumab in maintenance achieved clinical remission while off CS at W52 vs placebo, clinical remission while off CS for ≥12 weeks, and clinical remission with symptomatic remission at W40 while off CS for ≥12 weeks (Table; all p≤0.01). A significantly greater proportion of patients treated with mirikizumab had discontinued CS by W24, W40, and W52 compared to placebo (Table; all p<0.001). Among patients who completed W52 of mirikizumab treatment, 95.2% had discontinued CS.
| | Mirikizumab
N=125 | Placebo
N=59 | Common risk difference
(95% CI) | P-value |
| Patients achieving clinical remission and off CS at Week 52 | 52 (41.6%) | 9 (15.3%) | 22.3 (9.9–34.6) | p=0.002 |
| Patients achieving clinical remission at Week 52 and off CS for ≥12 weeks | 51 (40.8%) | 9 (15.3%) | 21.2 (8.9–33.4) | p=0.003 |
| Patients achieving clinical remission at Week 52 with symptomatic remission at Week 40 and off CS for ≥12 weeks | 48 (38.4%) | 7 (11.9%) | 21.9 (10.7–33.2) | p=0.002 |
| Patients off CS at Week 52 among treatment completers | 99/104 (95.2%) | 26/30 (86.7%) | NA* | NA* |
| Patients permanently off CS at Week 52** | 99 (79.2%) | 26 (44.1%) | 34.2 (19.2–49.2) | p<0.001 |
| Patients permanently off CS at Week 40** | 96 (76.8%) | 25 (42.4%) | 33.1 (18.0–48.3) | p<0.001 |
| Patients permanently off CS at Week 24** | 88 (70.4%) | 23 (39.0%) | 30.5 (15.2–45.8) | p<0.001 |
Abbreviations: CI = confidence interval; CS = corticosteroid; N = number of patients in group.
Non-responder imputation was used for missing data. Patients who discontinued study treatment or received rescue treatment were defined as treatment failures (i.e., remaining on CS).
*NA = not available. Formal treatment comparison for this endpoint not performed because this is an as-observed analysis.
**Patients were off CS and did not discontinue study treatment or re-initiate CS use for the remainder of the study period. |
Conclusion
Among patients on CS at baseline, mirikizumab induction responders who were re-randomized to mirikizumab maintenance achieved CS-free clinical remission at W52 at higher rates than mirikizumab induction responders who were re-randomized to placebo maintenance. Mirikizumab’s CS-sparing effect in patients with moderately to severely active UC is clinically meaningful and aligned with long-term treatment goals of CS discontinuation.
Disclosure
David Laharie declares counseling, boards, transports, or fees from AbbVie, Biogaran, Biogen, Ferring, HAC-pharma, Janssen, MSD, Novartis, Pfizer, Prometheus, Roche, Takeda, Theradiag, and Tillots. Corey Siegel has served as a consultant to AbbVie, BMS, Eli Lilly, Janssen, Pfizer, Prometheus, Takeda, and Trellus Health, as a speaker for AbbVie, Janssen, Pfizer, and Takeda, and received grant support from AbbVie, Janssen, Pfizer, and Takeda. Karen Samaan, Deborah A. Fisher, Nathan Morris, and Isabel Redondo are employees and shareholders of Eli Lilly and Company. Parambir S. Dulai has received research support and/or consulting fees from Takeda, Janssen, Pfizer, AbbVie, Gilead, Eli Lilly, BMS, Novartis; owns stock options and has served as a board member for DigbiHealth; and owns licensing royalties from Precidiag. Vipul Jairath has received consulting fees from AbbVie, Alimentiv Inc (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pendopharm, Pfzer, Roche, Sandoz, Takeda, Topivert; speaker’s fees from Abbvie, Ferring, Janssen, Pfzer, Shire, and Takeda. Javier P. Gisbert has served as a speaker, a consultant, and advisory member for, or has received research funding from MSD, AbbVie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Sandoz, Celgene, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma. Katsuyoshi Matsuoka reports receiving personal fees from Mitsubishi Tanabe Pharma, AbbVie, Takeda Pharmaceutical, EA Pharma, Janssen Pharmaceutical, and Pfizer, research grants from Janssen Pharmaceutical, and scholarship grants from Mitsubishi Tanabe Pharma, AbbVie, EA Pharma, and Mochida Pharmaceutical.
