ABSTRACT
Background
Mirikizumab demonstrated efficacy in moderately‐to‐severely active ulcerative colitis, including in patients with prior advanced therapy failure (PATF) (Phase 3: LUCENT‐1 [NCT03518086], LUCENT‐2 [NCT03524092]). This post hoc analysis evaluates mirikizumab efficacy by number/mechanism of PATF.
Methods
LUCENT‐1 patients received 300 mg mirikizumab or placebo; mirikizumab induction responders entered LUCENT‐2 and received 200 mg mirikizumab or placebo until week (W)52. Mirikizumab induction non‐responders received extended induction with open‐label 300 mg mirikizumab between W12 and W24. Extended induction responders received open‐label 200 mg mirikizumab between W24 and W52. In each population, efficacy was analyzed by subgroups based on PATF number (0, 1, ≥ 2 [2–3]) and mechanism (including difficult‐to‐treat [DTT]: anti‐TNF plus tofacitinib and/or vedolizumab).
Results
At baseline, 479/1162 patients (41.2%) had (≥ 1) PATF, of which 177 (37.0%) had DTT. Among mirikizumab‐treated patients (n = 868), W12 clinical response was achieved by 69.8%, 63.9%, 45.3%, and 41.9% of the 0‐PATF, 1‐PATF, ≥ 2‐PATF, and DTT subgroups, respectively. 42.1% (365/868) continued with maintenance treatment. Among W12 responders, 51.9% (0‐PATF), 44.2% (1‐PATF), 49.0% (≥ 2‐PATF), and 42.9% (DTT) achieved clinical remission at W52. Over half of the patients (54.0% [147/272]) in the extended induction population had PATF; 51.0% (75/147) were DTT. At W24, clinical response was achieved by 62.4%, 41.4%, 49.5%, and 49.3% of the 0‐PATF, 1‐PATF, ≥ 2‐PATF, and DTT subgroups. Of this 49.3% of the DTT subgroup (extended induction responders), 38.9% (14/36) achieved W52 clinical remission.
Conclusions
Mirikizumab induction and maintenance is efficacious in moderately‐to‐severely active ulcerative colitis with or without prior failure of advanced therapy, including difficult‐to‐treat disease.
Trail Registration
LUCENT‐1: NCT03518086; LUCENT‐2: NCT03524092
Keywords: advanced therapy, biologic, difficult‐to‐treat, mirikizumab, ulcerative colitis
Key Summary
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Summarize the established knowledge on this subject
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Multiple advanced therapy options have emerged for treating ulcerative colitis (UC), but concerns remain around the lack of treatment response and loss of response over time in some patients.
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Mirikizumab, a novel monoclonal antibody targeting the interleukin‐23 p19 subunit, is approved for adults with moderately‐to‐severely active UC. Phase 3 trial results suggested that mirikizumab is efficacious in patients with a history of advanced therapy failure.
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What are the significant and/or new findings of this study?
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Our post hoc analysis shows that mirikizumab is efficacious in patients with moderately‐to‐severely active UC regardless of the mechanism of action or the number of prior advanced therapy failures.
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Across patient subgroups with prior advanced therapy failure, mirikizumab was superior to placebo in achieving clinical response at week (W)12 and clinical remission at W52.
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With the option of standard or extended induction, almost 80% of patients with one previous anti‐TNF failure and 69% with difficult to treat UC achieved clinical response at W12 or W24 with mirikizumab; around 40% of difficult‐to‐treat extended induction responders achieved clinical remission at W52.
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1. Introduction
Advanced therapies have transformed the management of ulcerative colitis (UC), a progressive disease characterized by recurrent colonic inflammation that significantly impacts patients' quality of life [1, 2, 3, 4, 5]. Despite the growing armamentarium for UC [6, 7], clinical evidence demonstrates that many patients may not respond to induction therapy or experience a secondary loss of response over time [5, 8, 9, 10, 11, 12, 13, 14]. Treatment is often individualized based on disease activity, severity, risk of poor prognosis, and prior advanced therapy failure (PATF) [15]. Guidance for agent selection when optimising/switching therapy for refractory disease is unclear [9, 16]. It is unknown whether PATF reflects disease activity/duration or whether the type of PATF influences immune mechanisms that determine response to subsequent therapy.
Mirikizumab, an anti‐IL‐23p19 monoclonal antibody, is approved for adults with moderate‐to‐severely active UC [17]. In the Phase 3, randomized, double‐blind, placebo‐controlled LUCENT‐1 and LUCENT‐2 trials, mirikizumab was efficacious in patients with a history of conventional and/or advanced therapy failure [18], suggesting its potential therapeutic value for refractory UC. Furthermore, mirikizumab reduces the mucosal expression of genes associated with resistance to current therapies [19]. Non‐response to anti‐tumor necrosis factor (anti‐TNF) seems to be a clear predictor for subsequent therapy failure [16], which may be mediated by decreased leukocyte trafficking [20]. Notably, extended induction after limited/no response might be beneficial in clinical practice [21], and mirikizumab has demonstrated efficacy on extended induction [22].
This post hoc analysis assesses the clinical efficacy of mirikizumab versus placebo during induction and maintenance therapy and upon extended induction in patient subgroups based on PATF number/mechanism of action. This could support/inform decision‐making during treatment selection following treatment failure.
2. Materials and Methods
2.1. Ethics
Both LUCENT‐1 (NCT03518086) and LUCENT‐2 (NCT03524092) were conducted in compliance with international ethics guidelines, including the Declaration of Helsinki, the International Council for Harmonization, and applicable laws and regulations. All patients provided written informed consent before participating.
2.2. Study Design
The study design and protocols of the 12‐week LUCENT‐1 and 40‐week LUCENT‐2 studies have been previously described (Figure 1) [18, 22].
FIGURE 1.
Study design. IV, intravenous; MIRI, mirikizumab; non‐resp, non‐responders; OL, open‐label; PBO, placebo; Q4W, every 4 weeks; R, randomization; resp, responders; SC, subcutaneous; W, week. aLUCENT‐1 was a Phase 3, randomized, parallel‐arm, double‐blind, PBO‐controlled induction trial of mirikizumab in patients with moderately‐to‐severely active ulcerative colitis. bLUCENT‐2 was a Phase 3, randomized, double‐blind maintenance study. The figure does not include the full LUCENT‐2 program.
The modified intent‐to‐treat (mITT) population consisted of all patients who underwent randomization and received ≥ 1 dose of mirikizumab or placebo after excluding patients affected by an electronic clinical outcome assessment error.
In LUCENT‐1 (induction), patients were randomized to receive three intravenous (IV) doses of 300 mg mirikizumab or placebo at weeks (W)0, W4, and W8 (every 4W, Q4W). Patients who responded to mirikizumab induction at W12 entered LUCENT‐2 (W0 of maintenance) and were re‐randomized to receive 200 mg mirikizumab or placebo subcutaneously (SC) Q4W until W52. Patients who did not respond to mirikizumab induction at W12 received extended induction with open‐label 300 mg mirikizumab IV Q4W until W20 (extended induction). Patients responding to extended induction at W24 (W12 of LUCENT‐2) entered open‐label maintenance with 200 mg mirikizumab SC Q4W until W52 (extended induction responders). Treatment weeks indicated are cumulative (e.g., W52 corresponds to 40 weeks on the LUCENT‐2 maintenance trial).
2.3. Patient Subgroups
This post hoc analysis examines mITT patient subgroups by PATF, defined as inadequate response, loss of response, or intolerance to advanced therapy (anti‐TNF, vedolizumab or tofacitinib) prior to the LUCENT‐1 induction baseline. Reference product plus biosimilar were counted as 1 PATF. For the populations described above, efficacy outcomes were analyzed by subgroup:
Zero (no), 1, and ≥ 2 PATF subgroups: Patients with 0, 1 and ≥ 2 (in this study, 2 or 3) PATF, respectively.
Anti‐TNF, vedolizumab, and tofacitinib prior failure subgroups, and difficult‐to‐treat (DTT): Patients with prior failure to the respective therapy. Anti‐TNFs include infliximab, infliximab biosimilar, adalimumab, adalimumab biosimilar, and golimumab. Patients with prior anti‐TNF failure were separated into two subgroups (1 or ≥ 1) for efficacy analyses. The 1 anti‐TNF failure subgroup comprised all patients in the mITT population who experienced only 1 anti‐TNF failure and no other PATF before LUCENT‐1 induction baseline; other subgroups were not mutually exclusive.
Patients with DTT disease are defined as those who experienced failure of biologics and advanced small molecules with ≥ 2 different mechanisms of action [13]; in this study, DTT represented anti‐TNF failure plus vedolizumab and/or tofacitinib failure prior to LUCENT.
2.4. Outcome Measures
LUCENT‐1 and LUCENT‐2 primary and major secondary endpoints have been previously reported [18, 22]. The endpoints relevant to the current analyses are below. Endpoints were assessed at W12, W24, and W52, unless specified.
Clinical response: ≥ 2‐point and ≥ 30% decrease in Modified Mayo Score (MMS) from baseline, plus rectal bleeding subscore (RB) of 0 or 1 or RB ≥ 1‐point decrease from baseline.
Symptomatic remission: MMS stool frequency subscore (SF) of 0 or SF of 1 with ≥ 1‐point decrease from baseline, plus RB of 0.
Endoscopic remission: MMS endoscopic subscore (ES) of 0 or 1 (excluding friability).
Clinical remission: SF of 0, or 1 with ≥ 1‐point decrease from baseline, RB of 0, and ES of 0 or 1 (excluding friability).
Corticosteroid‐free remission: Clinical remission at W52, with no corticosteroid use for ≥ 12 weeks, and symptomatic remission at W40. Assessed at W52.
Histologic‐endoscopic mucosal remission: endoscopic remission and a Geboes subscore of 0 for grades 2b (lamina propria neutrophils), 3 (neutrophils in epithelium), 4 (crypt destruction), and 5 (erosion or ulceration). Assessed at W52.
2.5. Data Analysis
Baseline demographics and disease characteristics by PATF subgroup are presented with descriptive statistics. Baseline efficacy measures were based on the LUCENT‐1 baseline.
Efficacy outcomes in each subgroup were assessed at W12 (induction population), W24 (extended induction population), and W52 (maintenance population and extended induction responders). Missing data for the categorical efficacy endpoints were imputed using non‐responder imputation. Statistical testing for mirikizumab versus placebo used Fisher's exact test; for the 1 anti‐TNF subgroup, treatment differences were tested using the Cochran–Mantel–Haenszel test; p < 0.05 was considered significant. Statistical testing was not performed for the prior tofacitinib failure subgroups due to small sample size, nor for the extended induction population or extended induction responder population, where all patients received mirikizumab. No multiplicity adjustments were made for treatment comparisons.
3. Results
3.1. Patient Disposition and Baseline Characteristics
Overall patient disposition and baseline demographics and disease characteristics are reported elsewhere [18].
In the LUCENT‐1 induction population, 41.2% (479/1162) of patients had experienced (≥ 1) PATF. Of these, 245 had 1 PATF and 234 had ≥ 2 PATF. Among patients with 1 PATF, 77.6% (190/245; 16.4% of the overall LUCENT‐1 population) had anti‐TNF failure and 21.6% (53/245) had vedolizumab failure; only two patients had prior tofacitinib failure. Of those with ≥ 2 PATF, 99.1% (232/234) had anti‐TNF failure, 75.6% (177/234) were DTT, 70.5% (165/234) had vedolizumab failure, and 16.2% (38/234) had tofacitinib failure (Table 1).
TABLE 1.
Prior advanced therapy failure at baseline by subgroup.
| LUCENT‐1 induction | LUCENT‐2 maintenance (MIRI induction responders) | LUCENT‐2 extended induction (MIRI induction non‐responders) | LUCENT‐2 extended induction responders (delayed Responders) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 PATF | ≥ 2 PATF a | Total | 1 PATF | ≥ 2 PATF a | Total | 1 PATF | ≥ 2 PATF a | Total | 1 PATF | ≥ 2 PATF a | Total | |
| N = 245 | N = 234 | N = 1162 | N = 112 | N = 80 | N = 544 | N = 56 | N = 91 | N = 272 | N = 22 | N = 44 | N = 144 | |
| n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | |
| Number of PATF b | ||||||||||||
| 0 | — | — | 683 (58.8) | — | — | 352 (64.7) | — | — | 125 (46.0) | — | — | 78 (54.2) |
| 1 | 245 (100.0) | — | 245 (21.1) | 112 (100.0) | — | 112 (20.6) | 56 (100.0) | — | 56 (20.6) | 22 (100.0) | — | 22 (15.3) |
| 2 | — | 203 (86.8) | 203 (17.5) | — | 68 (85.0) | 68 (12.5) | — | 76 (83.5) | 76 (27.9) | — | 36 (81.8) | 36 (25.0) |
| > 2 a | — | 31 (13.2) | 31 (2.7) | — | 12 (15.0) | 12 (2.2) | — | 15 (16.5) | 15 (5.5) | — | 8 (18.2) | 8 (5.6) |
| PATF b | ||||||||||||
| DTT c | 0 (0.0) | 177 (75.6) | 177 (15.2) | 0 (0.0) | 55 (68.8) | 55 (10.1) | 0 (0.0) | 75 (82.4) | 75 (27.6) | 0 (0.0) | 36 (81.8) | 36 (25.0) |
| Anti‐TNF d | 190 (77.6) | 232 (99.1) | 422 (36.3) | 90 (80.4) | 80 (100.0) | 170 (31.3) | 46 (82.1) | 89 (97.8) | 135 (49.6) | 20 (90.9) | 43 (97.7) | 63 (43.8) |
| Vedolizumab | 53 (21.6) | 165 (70.5) | 218 (18.8) | 22 (19.6) | 48 (60.0) | 70 (12.9) | 9 (16.1) | 72 (79.1) | 81 (29.8) | 1 (4.5) | 35 (79.5) | 36 (25.0) |
| Tofacitinib | 2 (0.8) | 38 (16.2) | 40 (3.4) | 0 (0.0) | 16 (20.0) | 16 (2.9) | 1 (1.8) | 17 (18.7) | 18 (6.6) | 1 (4.5) | 7 (15.9) | 8 (5.6) |
Note: Failure was defined as prior treatment discontinuation due to loss of response, inadequate response, or intolerance to medication. Percentages were calculated using the N of each column as the denominator.
Abbreviations: DTT, difficult to treat; MIRI, mirikizumab; PATF, prior advanced therapy failure; TNF, tumor necrosis factor.
The maximum number of PATF reported was three.
Advanced therapy includes adalimumab, adalimumab biosimilar, golimumab, infliximab, infliximab biosimilar, ustekinumab, and vedolizumab. Reference product plus biosimilar were counted as 1 PATF.
DTT represents anti‐TNF failure plus vedolizumab and/or tofacitinib failure prior to LUCENT.
Includes infliximab, infliximab biosimilar, adalimumab, adalimumab biosimilar, and golimumab.
Of the patients who responded to mirikizumab induction at W12 and entered LUCENT‐2 (maintenance population), 35.3% (192/544) had PATF, of which 112 had 1 PATF and 80 had ≥ 2 PATF. Of patients with 1 PATF, 80.4% (90/112) had prior anti‐TNF failure, while 19.6% (22/112) had prior vedolizumab failure. All patients with ≥ 2 PATF (80/80) had anti‐TNF failure, and most were DTT (68.8% [55/80]) or had experienced vedolizumab failure (60.0% [48/80]); 20.0% (16/80) had tofacitinib failure (Table 1).
There were 272 patients treated with mirikizumab in LUCENT‐1 who did not achieve clinical response at W12 and entered the open‐label extended induction arm of LUCENT‐2 (extended induction population); of the 54.0% (147/272) who had PATF, 61.9% (91/147) had experienced ≥ 2 PATF. Finally, 144 patients were delayed responders by W24 (extended induction responder population); 45.8% (66/144) of them had experienced PATF, including 66.7% (44/66) with ≥ 2 PATF. In these two populations, similar to the induction and maintenance populations, anti‐TNF remained the most common PATF (82.1%–90.9% of patients with 1 PATF and 97.7%–97.8% of patients with ≥ 2 PATF); among those with ≥ 2 PATF, DTT (81.8%–82.4%) and vedolizumab failure (79.1%–79.5%) were also prominent (Table 1).
In both induction and maintenance populations, proportions of patients in each subgroup by PATF (0, 1, or ≥ 2) were similar between the mirikizumab and placebo arms (Supporting Information S1: Tables S1 and S2). Across populations, patients with PATF generally had longer durations of disease than those without PATF, and the ≥ 2 PATF subgroup generally had more severe disease based on numerically greater MMS, endoscopic subscore, and biomarker levels than the 0 and 1 PATF subgroups; they also had commonly higher corticosteroid use and lower immunomodulator use at baseline than the 0 and 1 PATF subgroups (Supporting Information S1: Tables S1–S4). In general, patients with 1 anti‐TNF failure had higher baseline rates of extensive colitis/pancolitis, severe endoscopic subscore, and immunomodulator use than those in the overall population. The demographic and baseline characteristics of each population by mechanism of action of PATF are presented in Supporting Information S1: Tables S5–S8.
3.2. Efficacy Outcomes
For the induction and maintenance populations, efficacy outcomes by subgroup are presented for mirikizumab versus placebo (Figures 2, 3, 4, 5). All patients in the extended induction population and extended induction responders (Figures 4 and 5) received mirikizumab.
FIGURE 2.
Efficacy endpoints at W12 (induction population). (A) Clinical remission defined as SF of 0, or 1 with ≥ 1‐point decrease from baseline, RB of 0, and ES of 0 or 1 (excluding friability). (B) Endoscopic remission defined as ES of 0 or 1 (excluding friability). (C) Clinical response defined as ≥ 2‐point and ≥ 30% decrease in MMS from baseline, plus RB of 0 or 1 or RB ≥ 1‐point decrease from baseline. (D) Symptomatic remission defined as SF of 0, or 1 with ≥ 1‐point decrease from baseline, plus RB of 0. DTT, difficult to treat; ES, endoscopic subscore; IV, Intravenous; MIRI, mirikizumab; MMS, Modified Mayo Score; PATF, prior advanced therapy failure; PBO, placebo; Q4W, every 4 weeks; RB, rectal bleeding subscore; SF, stool frequency subscore; TNF, tumor necrosis factor; TOFA, tofacitinib; VDZ, vedolizumab; W, week. aThe maximum number of PATF reported was three. bDTT represents anti‐TNF failure plus VDZ and/or TOFA failure prior to LUCENT. cAnti‐TNFs include infliximab, infliximab biosimilar, adalimumab, adalimumab biosimilar, and golimumab. Reference product plus biosimilar were counted as 1 PATF. *p < 0.05; **p < 0.01; ***p < 0.001. Statistical testing not performed for TOFA.
FIGURE 3.
Efficacy endpoints at W52 (maintenance population). (A) Clinical remission defined as SF of 0, or 1 with ≥ 1‐point decrease from baseline, RB of 0, and ES of 0 or 1 (excluding friability). (B) Endoscopic remission defined as ES of 0 or 1 (excluding friability). (C) CS‐free remission defined as clinical remission at W52, with no corticosteroid use for ≥ 12 weeks, and symptomatic remission at W40. (D) Histologic‐endoscopic mucosal remission defined as endoscopic remission and Geboes subscore of 0 for grades 2b (lamina propria neutrophils), 3 (neutrophils in epithelium), 4 (crypt destruction), and 5 (erosion or ulceration). (E) Clinical response defined as ≥ 2‐point and ≥ 30% decrease in MMS from baseline, plus RB of 0 or 1 or RB ≥ 1‐point decrease from baseline. (F) Symptomatic remission defined as SF of 0, or 1 with ≥ 1‐point decrease from baseline, plus RB of 0. CS, corticosteroid; DTT, difficult to treat; ES, endoscopic subscore; MIRI, mirikizumab; MMS, Modified Mayo Score; PATF, prior advanced therapy failure; PBO, placebo; Q4W, every 4 weeks; RB, rectal bleeding subscore; SC, subcutaneous; SF, stool frequency subscore; TNF, tumor necrosis factor; TOFA, tofacitinib; VDZ, vedolizumab; W, week. aThe maximum number of PATF reported was three. bDTT represents anti‐TNF failure plus VDZ and/or TOFA failure prior to LUCENT. cAnti‐TNFs include infliximab, infliximab biosimilar, adalimumab, adalimumab biosimilar, and golimumab. Reference product plus biosimilar were counted as 1 PATF. *p < 0.05; **p < 0.01; ***p < 0.001. Statistical testing not performed for TOFA.
FIGURE 4.
Efficacy endpoints at W24 (extended induction population). (A) Clinical remission defined as SF of 0, or 1 with ≥ 1‐point decrease from baseline, RB of 0, and ES of 0 or 1 (excluding friability). (B) Endoscopic remission defined as ES of 0 or 1 (excluding friability). (C) Clinical response defined as ≥ 2‐point and ≥ 30% decrease in MMS from baseline, plus RB of 0 or 1 or RB ≥ 1‐point decrease from baseline. (D) Symptomatic remission defined as SF of 0, or 1 with ≥ 1‐point decrease from baseline, plus RB of 0. DTT, difficult to treat; ES, endoscopic subscore; IV, intravenous; MIRI, mirikizumab; MMS, Modified Mayo Score; PATF, prior advanced therapy failure; RB, rectal bleeding subscore; SF, stool frequency subscore; TNF, tumor necrosis factor; TOFA, tofacitinib; VDZ, vedolizumab; W, week. aThe maximum number of PATF reported was three. bDTT represents anti‐TNF failure plus VDZ and/or TOFA failure prior to LUCENT. cAnti‐TNFs include infliximab, infliximab biosimilar, adalimumab, adalimumab biosimilar and golimumab. Reference product plus biosimilar were counted as 1 PATF.
FIGURE 5.
Efficacy endpoints at W52 (extended induction responders). (A) Clinical remission defined as SF of 0, or 1 with ≥ 1‐point decrease from baseline, RB of 0, and ES of 0 or 1 (excluding friability). (B) Endoscopic remission defined as ES of 0 or 1 (excluding friability). (C) CS‐free remission defined as clinical remission at W52, with no corticosteroid use for ≥ 12 weeks, and symptomatic remission at W40. (D) Histologic‐endoscopic mucosal remission defined as endoscopic remission and Geboes subscore of 0 for grades 2b (lamina propria neutrophils), 3 (neutrophils in epithelium), 4 (crypt destruction), and 5 (erosion or ulceration). (E) Clinical response defined as ≥ 2‐point and ≥ 30% decrease in MMS from baseline, plus RB of 0 or 1 or RB ≥ 1‐point decrease from baseline. (F) Symptomatic remission defined as SF of 0, or 1 with ≥ 1‐point decrease from baseline, plus RB of 0. CS, corticosteroid; DTT, difficult to treat; ES, endoscopic subscore; MIRI, mirikizumab; MMS, Modified Mayo Score; PATF, prior advanced therapy failure; RB, rectal bleeding subscore; SC, subcutaneous; SF, stool frequency subscore; TNF, tumor necrosis factor; TOFA, tofacitinib; VDZ, vedolizumab; W, week. aThe maximum number of PATF reported was three. bDTT represents anti‐TNF failure plus VDZ and/or TOFA failure prior to LUCENT. cAnti‐TNFs include infliximab, infliximab biosimilar, adalimumab, adalimumab biosimilar, and golimumab. Reference product plus biosimilar were counted as 1 PATF.
3.2.1. Efficacy Outcomes by Prior Advanced Therapy Failure Number
3.2.1.1. No Prior Advanced Therapy Failures
For both the induction population at W12 (Figure 2) and the maintenance population at W52 (Figure 3), patients receiving mirikizumab achieved all clinical endpoints at significantly higher rates (p < 0.001) than placebo. In the extended induction group (W24), 62.4% of patients (78/125) achieved clinical response and 15.2% (19/125) achieved clinical remission (Figure 4). Clinical remission was achieved by 37.2% (29/78) of the extended induction responders at W52 (Figure 5).
3.2.1.2. One Prior Advanced Therapy Failure
At W12, differences between mirikizumab and placebo were statistically significant for clinical response (63.9% [115/180] vs. 36.9% [24/65], respectively; p < 0.001), symptomatic remission (43.3% [78/180] vs. 26.2% [17/65]; p < 0.05), and endoscopic remission (30.0% [54/180] vs. 12.3% [8/65]; p < 0.01) in patients with 1 PATF (Figure 2). With maintenance (W52), differences between mirikizumab and placebo were statistically significant for clinical remission (44.2% [34/77]] vs. 17.1% [6/35]; p < 0.01), endoscopic remission (48.1% [37/77] vs. 25.7% [9/35]; p < 0.05), corticosteroid‐free remission (37.7% [29/77] vs. 17.1% [6/35], respectively; p < 0.05), clinical response (66.2% [51/77] vs. 40.0% [14/35]; p < 0.05), and symptomatic remission (63.6% [49/77] vs. 31.4% [11/35]; p < 0.01) (Figure 3). In the extended induction group (W24), 41.4% of patients (23/56) achieved clinical response and 3.6% (2/56) achieved clinical remission (Figure 4). Clinical remission was achieved by 27.3% of extended induction responders at W52 (Figure 5).
3.2.1.3. Two or More Prior Advanced Therapy Failures
At W12, differences between mirikizumab and placebo were statistically significant for clinical response (45.3% [82/181] vs. 20.8% [11/53], respectively; p < 0.01) and symptomatic remission (33.7% [61/181] vs. 9.4% [5/53]; p < 0.001) in patients with ≥ 2 PATF (Figure 2). With maintenance (W52), patients receiving mirikizumab achieved all clinical endpoints at statistically higher rates (p < 0.01) than placebo (Figure 3). In the extended induction group (W24), 49.5% of patients (45/91) achieved clinical response and 11.0% (10/91) achieved clinical remission (Figure 4). Clinical remission was achieved by 38.6% (17/44) of extended induction responders at W52 (Figure 5).
3.2.1.4. Difficult‐to‐Treat
Patients in the DTT subgroup receiving mirikizumab achieved all endpoints at significantly higher rates than placebo at W12 (p < 0.05), except for clinical remission (11.8% [16/136] with mirikizumab vs. 2.4% [1/41] with placebo). Among those receiving mirikizumab, 41.9% (57/136) achieved clinical response versus 17.1% (7/41) with placebo (p < 0.01; Figure 2). With maintenance (W52), differences between treatment arms were statistically significant for the following endpoints: clinical remission (42.9% [15/35] with mirikizumab vs. 10.0% [2/20] with placebo; p < 0.05), endoscopic remission (48.6% [17/35] vs. 10.0% [2/20]; p < 0.01), symptomatic remission (65.7% [23/35] vs. 25.0% [5/20]; p < 0.01), and clinical response (77.1% [27/35] vs. 25.0% [5/20]; p < 0.001; Figure 3). In the extended induction group (W24), 49.3% of patients (37/75) achieved clinical response and 10.7% (8/75) achieved clinical remission (Figure 4). Clinical remission was achieved by 38.9% (14/36) of the extended induction responders at W52 (Figure 5).
3.2.2. Efficacy Outcomes by Advanced Therapy Failure Mechanism
3.2.2.1. Prior Anti‐TNF Failure
Patients with only 1 anti‐TNF failure receiving mirikizumab achieved clinical response at a significantly higher rate than placebo at W12 (64.4% [94/146] with mirikizumab vs. 34.1% [15/44] with placebo; p < 0.01; Figure 2). With maintenance (W52), differences between treatment arms were statistically significant for clinical remission (44.3% [27/61] with mirikizumab vs. 17.2% [5/29] with placebo; p < 0.05), clinical response (67.2% [41/61] with mirikizumab vs. 44.8% [13/29] with placebo; p < 0.05), and symptomatic remission (63.9% [39/61] with mirikizumab vs. 34.5% [10/29] with placebo; p < 0.01; Figure 3). In the extended induction group (W24), 45.7% (21/46) achieved clinical response and 4.3% (2/46) achieved clinical remission (Figure 4). Clinical remission was achieved by 30.0% (6/20) of extended induction responders at W52 (Figure 5).
Patients with ≥ 1 anti‐TNF failure treated with mirikizumab achieved all endpoints at significantly higher rates than placebo (p < 0.05) at W12, except for clinical remission (15.7% [51/325] with mirikizumab vs. 9.3% [9/97] with placebo). Among those receiving mirikizumab, 54.2% (176/325) achieved clinical response versus 26.8% (26/97) with placebo (p < 0.001; Figure 2). W52 maintenance differences between treatment arms were statistically significant for all endpoints (p < 0.01; Figure 3). In the extended induction group (W24), 48.1% (65/135) achieved clinical response and 8.9% (12/135) achieved clinical remission (Figure 4). Clinical remission was achieved by 34.9% (22/63) of extended induction responders at W52 (Figure 5).
3.2.2.2. Prior Vedolizumab Failure
At W12, patients with vedolizumab failure receiving mirikizumab achieved all endpoints at significantly higher rates than placebo (p < 0.01), except for clinical remission (11.3% [18/159] with mirikizumab vs. 3.4% [2/59] with placebo). Among those receiving mirikizumab, 44.7% (71/159) achieved clinical response versus 23.7% (14/59) with placebo (p < 0.01; Figure 2). W52 maintenance differences between treatment arms were statistically significant for the following endpoints: clinical remission (44.7% [21/47] with mirikizumab vs. 13.0% [3/23] with placebo; p < 0.05), endoscopic remission (51.1% [24/47] vs. 13.0% [3/23]; p < 0.01), clinical response (72.3% [34/47] vs. 21.7% [5/23]; p < 0.001), and symptomatic remission (66.0% [31/47] vs. 17.4% [4/23]; p < 0.001; Figure 3). In the extended induction group (W24), 45.7% (37/81) achieved clinical response and 8.6% (7/81) achieved clinical remission (Figure 4). Clinical remission was achieved by 38.9% (14/36) of the extended induction responders at W52 (Figure 5).
3.2.2.3. Prior Tofacitinib Failure
Because of the small sample size, differences between mirikizumab and placebo were not statistically tested. Following mirikizumab induction, 47.1% (16/34) of patients achieved clinical response at W12 (Figure 2); 37.5% (3/8) achieved clinical remission with mirikizumab maintenance at W52 (Figure 3). In the extended induction population (W24), 44.4% (8/18) achieved clinical response (Figure 4). Clinical remission was achieved by 37.5% (3/8) of extended induction responders at W52 (Figure 5).
4. Discussion
This post hoc analysis of Phase 3 trial data supports the effectiveness of mirikizumab as an induction and maintenance therapy for patients with moderately‐to‐severely active UC, regardless of their PATF experience.
Baseline characteristics suggest that patients with PATF have longer mean disease duration and are more likely to have a severe endoscopic subscore than patients without PATF. These findings are consistent with the literature highlighting the progressive nature of UC and the need for early and effective treatment [4, 5, 13, 14]. Anti‐TNF failure was the most common PATF. This subgroup had a higher immunomodulator use at baseline than other subgroups, which is unsurprising considering that combined anti‐TNF plus immunomodulator treatment can improve efficacy [23]. Of note, a substantial proportion of patients had experienced failure with ≥ 2 different mechanisms of action, meeting the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) definition for “difficult to treat” [13]. Efficacy data are scarce for this patient group because of their underrepresentation in clinical trials [24]. Patients with DTT disease comprised 15% of the LUCENT‐1 population. These results could support clinicians in selecting an efficacious treatment for patients meeting this consensus criterion.
Significant mirikizumab‐to‐placebo differences were observed for most induction and maintenance endpoints in the PATF subgroups. At W12, clinical response was achieved across subgroups and clinical remission was the only endpoint without significant mirikizumab‐to‐placebo differences in PATF subgroups. Patients in the 1 anti‐TNF subgroup receiving mirikizumab had the most similar W12 clinical response to patients without PATF. Although direct comparisons between subgroups cannot be made, rates of clinical and endoscopic endpoints were numerically higher in the subgroup without PATF versus PATF subgroups. However, numerically greater mirikizumab‐to‐placebo differences were reported in PATF subgroups. The lower placebo endpoint achievement for subgroups with PATF highlights the challenge of treating UC with PATF and the importance of first‐treatment decisions. Numerical differences between PATF subgroups were more prominent at W12, whereas achievement of maintenance endpoints (W52) was more consistent across subgroups, suggesting that mirikizumab continues to be efficacious with time. These findings demonstrate that patients with prior PATF may take longer to achieve clinical and endoscopic endpoints [4, 5, 13, 14]. The effectiveness of mirikizumab with time was also observed in the extended induction population, where most patients had PATF and many had DTT. Nearly half of the DTT patients showed a clinical response at W24 following extended induction. Considering induction plus extended induction, over 75% of patients who had 1 PATF at baseline achieved clinical response by W24 with mirikizumab induction for 12 or 24 weeks; achievement was particularly high (78.8%) for the 1 anti‐TNF subgroup (comparable to the induction plus extended induction LUCENT population (80.3%) [22]).
This study provides insight into the treatment of moderately‐to‐severely active UC with mirikizumab following PATF. However, some limitations warrant caution with direct interpretation of these results in clinical practice. Analyses were not powered to demonstrate statistical significance between PATF subgroups, and some were descriptive due to the small sample size; re‐randomization of induction responders to mirikizumab maintenance or placebo affected sample size. Besides the 1 anti‐TNF subgroup, PATF subgroups by mechanism of action were not mutually exclusive. Anti‐TNF drugs (infliximab, adalimumab, golimumab, branded, or biosimilar) were not individually analyzed. Additionally, important details regarding prior therapy (e.g., treatment duration, order of drug use, dose optimization, primary vs. secondary loss of response as the reason for PATF, and reasons for discontinuation) were unknown. Examination of the impact of concomitant drugs (e.g., corticosteroids and immunomodulators) was prevented by limited sample sizes. Furthermore, the study did not include patients with prior failure to interleukin‐23, interleukin‐12/23, or other novel advanced therapies. Further research is needed to better inform clinical decision‐making during treatment selection, including head‐to‐head as well as long‐term real‐world evidence of the effectiveness, safety, and durability of new advanced therapies.
In conclusion, mirikizumab was efficacious and may provide an effective treatment for moderately‐to‐severely active UC with or without PATF. Across subgroups, mirikizumab was superior to placebo in achieving symptomatic remission and clinical response at W12, as well as clinical and endoscopic remission with maintenance (W52). These results underscore the potential of mirikizumab as an effective option for patients who have not responded/lost response to first‐line anti‐TNF therapy, and the added value of extended treatment for patients who are slower to respond.
Author Contributions
Eli Lilly and Company contributed to the study design, data collection, data analysis, data interpretation, preparation of the manuscript, and the decision to submit the paper for publication. A.H., K.H.S., E.D., and I.R. contributed to conception of the work and the study design. S.B. contributed to the conception of the work. G.D. contributed to data acquisition. R.A., K.H.S., E.D., I.R., and S.B. contributed to data analysis. All authors contributed to the interpretation of data. All authors had full access to all the data in the study, reviewed drafts, and approved the final version of the manuscript.
Funding
Eli Lilly and Company funded this study.
Ethics Statement
Both LUCENT‐1 (NCT03518086) and LUCENT‐2 (NCT03524092) were conducted in compliance with international ethics guidelines, including the Declaration of Helsinki, the International Council for Harmonization, and applicable laws and regulations. All patients provided written informed consent before participating.
Consent
All patients provided written informed consent before participating.
Conflicts of Interest
A.H. has served as a consultant, advisory board member or speaker for AbbVie, Arena, Atlantic, Bristol‐Myers Squibb, Celgene, Celltrion, Falk, Galapogos, Lilly, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda. She also serves on the Global Steering Committee for Genentech. S.N. has served as an advisor for Eli Lilly and Company, Pfizer, and Madrigal and as a speaker for Eli Lilly and Company, Pfizer, and Johnson and Johnson. G.D. has served as adviser and/or speaker for Abbvie, Alimentiv, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Prometheus Laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx. K.M. has received grants or contracts from Janssen, Abbvie, Tanabe Mitsubishi, EA Pharma, Mochida Pharmaceutical, Nippon Kayaku, Zeria, and JIMRO; consulting fees from Eli Lilly, Takeda, Pfizer, Abbvie, Tanabe Mitsubishi, Janssen, Bristol‐Myers Squibb, and EA Pharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen, Mitsubishi Tanabe, Abbvie, Pfizer, EA Pharma, Gilead, Eli Lilly, Takeda, Mochida Pharmaceutical, Kyorin Pharmaceutical, Zeria, Kissei Pharmaceutical, Nippon Kayaku, and Celltrion. M.D.M.‐A. has served as a speaker or has received research or educational funding or advisory fees from: AbbVie, Eli Lilly and Company, Faes Farma, Ferring Pharmaceuticals, Janssen, Merck Sharp & Dohme, Pfizer, Shire Pharmaceuticals, Takeda, Galápagos, and Tillots Pharma. R.A. has served as a speaker or consultant, or received research grants from AbbVie, Abivax, AlfaSigma, AstraZeneca, Biogen, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Gilead, Janssen‐Cilag, Lilly, MSD, Pfizer, Roche Pharma, and Takeda. K.H.S., E.D., I.R., and B.Z. are Eli Lilly and Company employees and stockholders. J.P. was a contractor for Eli Lilly and Company through Syneos Health. L.Z.‐P. is a contractor for Eli Lilly and Company through HaaPACS. S.B. was an employee and shareholder of Eli Lilly and Company. J.L. reports consultancy and speaker fees from: AbbVie, Arena, Bristol Myers Squibb, BioHit, Celltrion, Eli Lilly, Ferring, Galapagos, Janssen, MSD, Pfizer, Takeda, and Tillotts; Research grants from: AbbVie, Galapagos, and Takeda. D.L. has received consulting, boards, transports, or fees from: AbbVie, Amgen, Biogaran, Biogen, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Janssen, Merck Sharp & Dohme, Pfizer, Prometheus, Roche, Takeda, and Theradiag. S.D. has received consulting fees from: AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Gilead Sciences, Hospira, Inotrem, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB Pharma and Vifor Pharma; and receiving lecture fees from: AbbVie, Amgen, Ferring Pharmaceuticals, Gilead Sciences, Janssen, Mylan, Pfizer and Takeda.
Supporting information
Supporting Information S1
Acknowledgments
Statistical analysis was provided by Xingyuan Li and Vipin Arora of Eli Lilly and Company. Medical writing support was provided by Pablo Izquierdo of the PPD clinical research business of Thermo Fisher Scientific, and by Agni Dhanabal and Alexandre Chappard of Eli Lilly and Company. Medical writing was provided in accordance with Good Publication Practice guidelines and was funded by Eli Lilly and Company. This study was previously presented at the European Crohn's and Colitis Organization (ECCO 2023) and United European Gastroenterology Week (UEGW 2023). Mayo Scoring System to Assess Activity of Ulcerative Colitis Symptoms. Copyright Mayo Clinic.
Data Availability Statement
Data are available on reasonable request. Lilly provides access to all individual participant data collected during the trial, after anonymization. Data are available to request after primary publication acceptance. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information S1
Data Availability Statement
Data are available on reasonable request. Lilly provides access to all individual participant data collected during the trial, after anonymization. Data are available to request after primary publication acceptance. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.