Introduction
Mirikizumab (miri), an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately-to-severely active ulcerative colitis (UC) in LUCENT Phase 3 trials.1,2 Bowel urgency (BU) clinically meaningful improvement (CMI) and BU remission were associated with clinical response and remission and also contributed to the improvement in Work Productivity and Activity Impairment Questionnaire UC (WPAI:UC) scores.3,4 This analysis evaluated if the addition of BU improvement to clinical response or remission was associated with better work productivity.
Aims & Methods
In LUCENT-1 (NCT03518086), patients were randomized 3:1 to induction miri 300mg intravenous or placebo every four weeks (Q4W). Patients who achieved clinical response to miri at week 12 (W12) were re-randomized 2:1 to maintenance subcutaneous injection of miri 200mg or placebo Q4W for 40 weeks in LUCENT-2 [52 weeks (W52) continuous treatment] (NCT03524092). Clinical response and remission were assessed along with change from baseline in WPAI:UC domain scores (activity impairment, absenteeism, presenteeism, and overall work impairment).5 BU was assessed using the Urgency Numeric Rating Scale (UNRS), an 11-point scale ranging from 0 (“no urgency”) to 10 (“worst possible urgency”), with both BU CMI (≥3-point change) and BU remission (UNRS score of 0 or 1), measured in patients with a baseline UNRS of ≥3.6 The association between BU (CMI or remission) with the change of WPAI:UC was evaluated using analysis of variance among patients with baseline UNRS ≥3 who achieved clinical response. This analysis was repeated among patients who achieved clinical remission.
Results
The addition of BU CMI was positively associated with reduction of activity impairment, presenteeism, and overall work impairment in patients who achieved clinical response or remission at both W12 and W52 (p<0.005) (Table 1). Achieving clinical response and BU remission was significantly associated with greater reduction of activity impairment, presenteeism, and overall work impairment compared to patients with clinical remission only at both W12 and W52 (p<0.01). The combined improvement of achieving both clinical remission and BU remission was significantly associated with higher reduction in activity impairment at W12 (-36.1% vs -27.3%; p=0.0147) and overall work impairment at W52 (-39.9% vs -29.8%; p=0.0394). Patients who achieved both clinical response or clinical remission and BU CMI or BU remission did not show a significant difference in absenteeism compared to those who achieved clinical response or remission alone.
TABLE 1. Association of Clinical Remission/Response with achievement of Bowel Urgency Remission/CMI on Change from Baseline of WPAI:UC Domain Scores in Patients with UC at W12 and W52 of Continuous Treatment
| Activity Impairment (Change from BL at W12), p-value*
| Absenteeism (Change from BL at W12), p-value*
| Presenteeism (Change from BL at W12), p-value*
| Overall Work Impairment (Change from BL at W12), p-value*
| Activity Impairment (Change from BL at W52), p-value*
| Absenteeism (Change from BL at W52), p-value*
| Presenteeism (Change from BL at W52), p-value*
| Overall Work Impairment (Change from BL at W52), p-value*
|
|---|
| Clinical Response + BU CMI1 | -32.15(24.47)
| -10.94(30.46)
| -28.66(22.85)
| -29.77(25.37)
| -41.21(25.10)
| -12.40(27.30)
| -36.82(24.18)
| -38.25(26.25)
|
| Clinical Response - BU CMI2 | -17.11(26.39),
<.0001 | -9.45(22.11), 0.634 | -14.43(24.64), <.0001 | -17.19(26.48), <.0001 | -27.26(27.35), <.0001 | -10.85(26.03), 0.7116 | -19.62(24.09), <.0001 | -21.18(28.03),
<.0001 |
| Clinical Response + BU Remission3 | -34.52(24.63)
| -10.31(27.38)
| -29.72(22.76)
| -31.05(24.91)
| -41.94(25.59)
| -11.64(24.31)
| -36.96(23.91)
| -39.55(25.44)
|
| Clinical Response - BU Remission4 | -23.30(26.13),
<.0001 | -10.46(27.98), 0.9635 | -20.33(24.74), 0.0012 | -22.23(26.75), 0.0048 | -33.81(26.42), 0.0034 | -12.35(29.33), 0.8462 | -27.82 (25.83), 0.0096 | -28.15(28.76),
0.0031 |
| Clinical Remission + BU CMI5 | -35.03(23.87)
| -14.17(27.32)
| -31.83(22.93)
| -34.37(25.77)
| -44.05(24.25)
| -14.54(28.78)
| -37.47(24.09)
| -39.76(25.70)
|
| Clinical Remission - BU CMI6 | -18.64(29.80),
<.0001 | -6.30(17.37), 0.1334 | -15.00(29.68), 0.0015 | -17.28(30.59), 0.0031 | -31.71(23.12), 0.0035 | -10.49(28.23), 0.5077 | -20.77(21.34), 0.0016 | -21.41(26.58),
0.0016 |
| Clinical Remission + BU Remission7 | -36.07(23.09)
| -12.72(27.29)
| -32.50(21.41)
| -34.91(24.60)
| -43.10(25.38)
| -12.13(24.79)
| -37.37(24.79)
| -39.91(26.14)
|
| Clinical Remission -BU Remission8 | -27.30(28.01), 0.0147 | -12.00(24.22), 0.8744 | -24.23(28.01), 0.0772 | -26.75(29.76), 0.109 | -39.66(23.12), 0.3134 | -15.94(33.46), 0.4496 | -28.78(23.15), 0.0545 | -29.80(27.03),
0.0394 |
Note: data is represented as mean (SD).
N-values (W12: Activity Impairment, Absenteeism, Presenteeism, Overall Work Impairment; W52: Activity Impairment, Absenteeism, Presenteeism, Overall Work Impairment):
1: W12: 396, 220, 220, 220; W52: 272, 160, 160, 160.
2: W12: 225, 122, 122, 122; W52: 84, 56, 56, 56.
3: W12: 188, 114, 114, 114; W52: 180, 106, 106, 106.
4: W12: 433, 228, 228, 228; W52: 176, 110, 110, 110.
5: W12: 167, 100, 100, 100; W52: 173, 106, 106, 106.
6: W12: 59, 31, 31, 31; W52: 41, 28, 28, 28.
7: W12: 89, 56, 56, 56; W52: 126, 79, 79, 79.
8: W12: 137, 75, 75, 75; W52: 88, 55, 55, 55.
BL = Baseline; BU = Bowel Urgency; CMI= Clinical Meaningful Improvement; SD: standard deviation; W12: week 12; W52: week 52. Clinical remission: stool frequency subscore = 0 or 1 with a ≥1-point decrease from baseline; rectal bleeding (RB) subscore = 0; and endoscopic subscore = 0 or 1. Clinical response: ≥2-point and ≥30% decrease in the modified Mayo Score from baseline, and RB = 0 or 1, or ≥1-point decrease from baseline.
*Evaluated using ANOVA (Analysis of variance) model including BU CMI (yes/no) or BU remission (yes/no). P-values less than 0.05 are bolded.
|
Conclusion
Among patients with UC from miri phase 3 trials, the addition of BU (CMI or remission) to the achievement of clinical response or remission was associated with reduction of WPAI:UC scores: activity impairment, presenteeism, and overall work impairment.
References
- D’Haens, G., et al. "OP26 Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study." J Crohns Colitis 16. Supplement_1(2022):i028-i029.
- Dubinsky, M.C., et al. "867e: Efficacy and safety of mirikizumab as maintenance therapy in patients with moderately to severely active ulcerative colitis: results from the phase 3 LUCENT-2 study." Gastroenterology 162.7(2022):S-1393.
- Dubinsky, M.C., et al. “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.” Crohns Colitis 360, 5(1), (2023): otac044.
- Sands B.E., et al. “Relative association of bowel urgency clinically meaningful improvement and bowel urgency remission versus stool frequency remission and rectal bleeding remission with improvement in Work Productivity and Activity Scores in patients with moderately-to-severely active Ulcerative Colitis: An analysis from LUCENT-1 and LUCENT-2 phase 3 clinical trials.” J Crohns Colitis 17, Supplement_1(2023):i775–i777.
- Reilly Associates WPAI Scoring. Accessed March 28, 2022. http://www.reillyassociates.net/WPAI_Scoring.html
- Dubinsky, M.C., et al. "P138 Psychometric validation and interpretation of a patient-reported outcomes instrument to assess bowel urgency among adults with moderate to severe Ulcerative Colitis." J Crohns Colitis 16. Supplement_1(2022):i220-i222.
Disclosure
David T. Rubin receives grants or contracts from Takeda, and discloses consultancy fees with Abbvie, Altrubio, Allergan, Inc., American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Ltd., Bristol-Myers Squibb, Celgene Corp/Syneos, Cornerstones Health, Inc. (non-profit), GalenPharma/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, LLC, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Eli Lilly and Company, Materia Prima, Pfizer, Prometheus Biosciences, Reistone, Takeda and Techlab, Inc. Jianmin Wu, Bomina Park, Simin K Baygani, Nathan Morris, Theresa Hunter Gibble are employees of Eli Lilly and Company. Stefan Schreiber receives consultancy and/or personal fees from AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Galapagos/Gilead, HIKMA, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Prometheus, Takeda, and Theravance.