Introduction
Mirikizumab (miri), a p19-directed IL-23 antibody, has been shown to be effective in patients with moderately-to-severely active ulcerative colitis (UC) in Phase 3 trials (LUCENT-1 NCT03518086; LUCENT-2 NCT03524092).1 The relationship between symptomatic, endoscopic, and clinical remission and levels of the inflammatory biomarker faecal calprotectin (fCAL) was studied for miri-treated patients enrolled in the trials.
Aims & Methods
This post hoc analysis evaluated patients treated with intravenous (IV) miri 300mg every 4 weeks (Q4W) until week (W)12 in induction (n=868) followed by subcutaneous miri (n=365) Q4W up to W52 (miri induction responders at W12 who were rerandomized for the maintenance period) or placebo. The improvement in fCAL at W12 and W52 between miri and placebo were compared using Cochran Mantel Haenszel, adjusting for randomization stratification factors. Missing data were imputed as nonresponse. The relationship between achieving symptomatic, endoscopic, or clinical remission (defined in Table) and fCAL levels at W4, W12 and W52 was assessed using receiver operating characteristic (ROC) approaches. Predictability was measured by area under the ROC curve (AUC), and AUC≤0.5 indicates no predictability. Optimal fCAL threshold was obtained based on Youden Index.
Results
Greater proportions of miri-treated patients compared to placebo achieved fCAL≤250 ug/g at W4, W12, and W52. A total of 19.0% vs. 12.5%, 34.3% vs. 20.1%, 50.7% vs 19.3% patients achieved fCAL≤250 ug/g at W4, W12, and W52 miri vs. placebo, respectively. Greater proportions of patients achieving symptomatic, endoscopic, and clinical remission reached the predefined threshold of fCAL≤250 ug/g or the optimum fCAL threshold obtained from the ROC (see Table footnote) in this study compared with those not achieving the endpoints (Table). W4 fCAL levels had 70.5% predictability for W12 endoscopic remission and 64.9% for clinical remission, but lower predictability for symptomatic remission (59.1%). W12 fCAL levels had 83.0% predictability for W12 endoscopic remission, 78.5% for clinical remission, and 67.4% for symptomatic remission. W52 fCAL levels had higher predictability for W52 endoscopic (76.6%) and clinical remission (72.7%) than for symptomatic remission (62.3%).
Table. Faecal Calprotectin Normalization at Week 12 in LUCENT-1 and Week 52 in LUCENT-2 per achievement of efficacy outcomes
| | Symptomatic Remission | Endoscopic Remission | Clinical Remission |
| Week 4 | | Achieving (N=360) | Not Achieving (N=406) | Achieving (N=290) | Not Achieving (N=478) | Achieving (N=193) | Not Achieving (N=571) |
| fCAL ≤ 250 ug/g | 109 (30.3) | 79 (19.5)╪ | 122 (42.1) | 65 (13.6) ╪ | 77 (39.9) | 110 (19.3)╪ |
| Optimum fCAL threshold | 193 (53.6) | 159
(39.2)╪ | 158 (54.5) | 106 (22.2)╪ | 103 (53.4) | 168 (29.4)╪ |
| Week 12 | | Achieving (N=364) | Not Achieving (N=398) | Achieving (N=293) | Not Achieving (N=472) | Achieving (N=199) | Not Achieving (N=562) |
| fCAL ≤ 250 ug/g | 200 (55.0) | 116 (29.2)╪ | 216 (73.7) | 100 (21.2)╪ | 151 (75.9) | 164 (29.2)╪ |
| Optimum fCAL threshold | 237 (65.1) | 149 (37.4)╪ | 216 (73.7) | 93 (19.7)╪ | 151 (75.9) | 157 (27.9)╪ |
| Week 52 | | Achieving (N=230) | Not Achieving (N=44) | Achieving (N=188) | Not Achieving (N=93) | Achieving (N=166) | Not Achieving (N=107) |
| fCAL ≤250 ug/g | 161 (70.0) | 22 (50.0)* | 151 (80.3) | 38 (40.9)╪ | 133 (80.1) | 49 (45.8)╪ |
| Optimum fCAL threshold | 161 (70.0) | 21 (47.7)* | 134 (71.3) | 24 (25.8)╪ | 129 (77.7) | 42 (39.3)╪ |
ES=Endoscopic Subscore; fCAL=Faecal Calprotectin; RB = Rectal Bleeding; SF=Stool Frequency.
Data shown as n(%). *p<0.05 and
╪p<0.001 from Fisher's exact test. Symptomatic remission: SF=0 or 1 with a ≥1-point decrease from baseline, RB=0. Endoscopic remission: ES=0 or 1 (excluding friability). Clinical remission: SF=0 or 1 with a ≥1-point decrease from baseline, RB=0, and ES=0 or 1 (excluding friability). Optimal fCAL for symptomatic/endoscopic/clinical remission: ≤585/≤390/≤415 ug/g at Week 4; ≤365/≤230/≤230 ug/g at Week 12; ≤230/≤150/≤205 ug/g at Week 52.
Conclusion
These results support the use of fCAL as an early predictor of clinical outcomes and as a non-invasive biomarker for predicting clinical outcomes.
References
1. D’Haens G, et al. NEJM 2023;388(26):2444-2455. DOI: 10.1056/NEJMoa2207940
Disclosure
SV has received research support from AbbVie, Johnson & Johnson, Pfizer, Galapagos, and Takeda; lecture fees from AbbVie, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Ferring, Galapagos, Genentech-Roche, Gilead, Janssen, Johnson & Johnson, Lilly, Materia Prima, Merck Sharp & Dohme, Pfizer, Takeda, Tillotts Pharma, and Zealand Pharma; and consulting fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma Merck, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma, and Zealand Pharma.
ML has served as a Consultant for AbbVie, Pfizer, Takeda, Lilly, Bristol-Meyers Squibb, Target RWE, and Prometheus and has received research support from Pfizer, Takeda, and Janssen.
PD has consulted for Abbvie, Abivax, Adiso, Bristol Myers Squibb, GSK, Janssen, Lilly, Pfizer, and Takeda; grant support from Bristol-Myers Squibb, Janssen, Pfizer, and Takeda; Licensing royalties from PreciDiag.
CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer.
F C-D, RM, and BZ are employees and minor shareholders of Eli Lilly and Company.
JP is an employee of Syneos Health.
ST has served as a paid consultant to AbbVie, Allergan, Amgen, Asahi, Bioclinica, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, ChemoCentryx, Cosmo, Enterome, Equillium, Ferring, GSK, Genentech, Genzyme, Giuliani SpA, Immunocore, Immunometabolism, Janssen, Lilly, MSD, Merck, Mestag, Neovacs, Novo Nordisk, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Roche, Satisfai Health, Sensyne Health, Shire, Sigmoid Pharma, Sorriso, Takeda, Topivert, UCB, VHsquared, Vifor, and Zeria; he has received grants and/or has grants pending from AbbVie, ECCO, Helmsley Trust, IOIBD, Janssen, Lilly, Norman Collisson Foundation, Pfizer, UCB, UKIERI, and Vifor; he has received honoraria from AbbVie, Amgen, Biogen, Ferring, Lilly, Pfizer, and Takeda; and he has had travel/accommodation expenses covered or reimbursed by AbbVie, Amgen, Biogen, Ferring, Lilly, Johnson & Johnson, Pfizer, and Takeda.
RP reports personal fees from Abbott, AbbVie, Alimentiv [formerly Robarts], Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, HC3 Communications, Janssen, Meducom, Merck, Mylan, Oppilan, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Receptos, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus Health, and UCB.