Introduction

Mirikizumab is an interleukin (IL)-23 inhibitor approved for the treatment of ulcerative colitis (UC); however, real-world data are limited.

Aims & Methods

The Dutch Initiative on Crohn and Colitis (ICC) Registry is a prospective multicentre study collecting real-world data on advanced therapeutic agents in inflammatory bowel disease (IBD). Patients included in the current study had a confirmed diagnosis of UC and received at least one intravenous induction dose of mirkizumab before the 28^th of February 2025. Patients who did not use at least two therapies with different mechanisms of action (i.e. difficult-to-treat UC) or with colectomy were excluded. The primary endpoint was clinical remission at week (W) 12, defined as Simple Clinical Colitis Activity Index (SCCAI) ≤ 2. Secondary outcomes at W12 included corticosteroid-free (CSF) clinical remission (i.e. clinical remission without the use of systemic corticosteroids on the day of the visit), biochemical remission (faecal calprotectin (FC) level ≤ 250μg/g) and endoscopic remission (Mayo endoscopic subscore = 0). In addition, drug survival and adverse events were assessed.

Results

In total, 22 patients were included; 13 (59.1%) were male. Most patients (n = 12; 54.5%) were diagnosed with pancolitis. Patients had a median disease duration of 9.5 years (IQR 18.0). Twelve patients (54.5%) had used at least four different advanced therapies; 19 (86.4%) patients have previously used ustekinumab (IL-12/23 inhibitor). At treatment initiation, all patients showed active disease, either clinically, biochemically or endoscopically. Median SCCAI was 7.0 (IQR 6); median FC was 1696.5μg/g (IQR 2079). As the study is still ongoing, data at W12 were available for 19 (86.4%) patients. Clinical data were available for 14 patients; 35.7% (5/14) of them were in clinical remission. These five patients were also in CSF clinical remission. Similar rates were observed between ustekinumab-experienced and ustekinumab-naïve patients, although the naïve subgroup was rather small (3/14). Biochemical data were available for 12 patients; median FC was 1434.5μg/g (IQR 824). Only one (8.3%) patient was in biochemical remission at W12; this patient was ustekinumab-naïve. Another patient, with only endoscopic data, was in endoscopic remission. Two patients discontinued mirikizumab before W12: one patient stopped mirikizumab after the intravenous injection because of fever; the other patient showed no response. Four other patients discontinued mirikizumab after W12; none of them were in clinical or biochemical remission at W12. Reasons for treatment discontinuation were primary non-response (5/6) and adverse event (1/6). Four adverse events were reported in four patients: nausea and skin problems, both classified as possibly related to the treatment, a gastrointestinal infection requiring antibiotics and fever during the infusion.

Conclusion

We found that 7/16 patients with difficult-to-treat UC were in either clinical, biochemical or endoscopic remission at W12. Moreover, all patients in clinical remission at W12 were not using other medications. Mirikizumab was well tolerated, although the follow-up period was relatively short. The ICC Registry is ongoing, and results with higher patient numbers with longer exposure to mirikizumab will be analysed to further characterise the real-world effectiveness and safety for patients with difficult-to-treat UC.

Disclosure

LMMV - none MRN - none ACdV - advisory boards for Takeda, Janssen, Bristol Myers Squibb, Abbvie, Pfizer, and Galapagos; research grants from Takeda, Janssen, and Pfizer WAvD - none MCV - speaker fees from Janssen-Cilag, Galapagos, and Ferring B.V. IM - advisory board/lecture fee from Abbvie, dr. Falk, and Janssen-Cilag FDMvS - adviser and/or speaker for Takeda, Galapagos, Dr. Falk, Lilly, and Janssen-Cilag; received an unrestricted grant from Takeda JMJ -consultant/speaker for AbbVie, Lilly, Takeda, and Janssen; consultant for MSD AGLB - none ML - consultancy/lecture fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, and Tillotts Pharma; grants from Alfasigma, the Netherlands Federation of University Medical Centres, TKI, and ZonMW AEvdMDJ - speaker fee from AbbVie, Alfasigma, Ferring, Janssen Pharmaceuticals, Takeda, Tramedico, and Vedanta; grants from Norgine, Cablon, Alfasigma, and ZonMW MJP - speaker fee from BMS, Janssen Cilag, and Takeda; non-restricted research grants from Horizon 2020, ZONMW (Dutch national research fund), MLDS, Takeda, Johnson and Johnson, Abbvie, and Galapagos ZM - speaker fee from Friso – Friesland Campina, Galapagos, Eli Lilly, and Takeda (paid to host institution); advisory board fees from Johnson & Johnson, Eli Lilly, Pfizer (paid to host institution); grants from ZonMw, Niels Stensen Fellowship, MLDS, Top consortium for Knowledge and Innovation (TKI), and Galapagos MD - speaking fee from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, and Dr. Falk; advisory board fees from Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda; grant/research support from Pfizer, Bristol Meyers Squibb, Galapagos Alfasigma, and Janssen

Introduction

Janus kinase inhibitors (JAKi) exhibit distinct performance characteristics versus monoclonal antibody (mABs) biological agents in the management of ulcerative colitis (UC). There is a lack of direct comparative effectiveness data of JAKi small molecules versus mABs in the real world.

Aims & Methods

In the absence of direct head-to-head comparisons, we determined the persistence of tofacitinib (TOF) versus vedolizumab and tumour necrosis factor inhibitor (TNFi) mABs in advanced therapy (AT)-naïve and AT-exposed real-world UC subjects from a population-based prospective registry.

The Persistence Australian National IBD Cohort (PANIC5) registry collected AT prescribing data for the entire Australian population up until Dec 2021. In Australia, all advanced therapies for IBD are prescribed without a hierarchical order in subjects with moderate-severe UC refractory to conventional therapies, irrespective of occupation and insurance status. Treatment is provided indefinitely in those that enter into clinical remission. Non-persistence was defined as failure to continue AT prescriptions for >6-months. Propensity score matching (PSM) statistically controlled for baseline selection biases. Kaplan-Meier survival curves were generated for AT persistence and compared using the log-rank test. Cox proportional hazards regression models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI). P<0.05 was deemed statistically significant (SPSS, USA).

Results

A total of 9,671 consecutive UC patients were recruited (53% male, 23,348 patient-years of follow up). The cohort comprised 14,772 treatment lines: 6,044 infliximab (IFX), 1,981 adalimumab (ADA), 5,467 vedolizumab (VED), 750 golimumab (GOL) and 530 tofacitinib (TOF). TOF exhibited superior persistence versus IFX (HR: 1.88, 95%CI: 1.34-2.63, P<0.001), ADA (HR: 2.10, 95%CI: 1.49-2.94, P<0.001) and GOL (HR: 2.20, 95%CI: 1.55-3.11, P<0.001) but not versus VED (HR: 1.28, 95%CI: 0.92-1.80, P=0.14). Following PSM, TOF was not significantly higher in persistence compared to mABs among AT-naïve subjects (all P>0.05). However, TOF showed superior persistence compared to all mABs among AT-exposed (all P<0.001). The persistence of TOF (P=0.77) did not significantly decline moving from AT-naive- to AT-exposed treatment status, unlike for TNFi (-8 months) and VED (-19 months, both P<0.001). PSM-multivariate Cox regression showed predictors of higher persistence to be use of TOF, AT-naïve status, use of immunomodulator. Rankings of persistence of ATs are presented for AT-naïve- and AT-exposed UC subjects (Table).

Conclusion

This is the first real-world study comparing treatment effectiveness using a national universal insurance persistence dataset. It found that tofacitinib had significantly greater persistence than biological agents in patients with ulcerative colitis who had previously received advanced therapy. Unlike monoclonal antibodies, tofacitinib did not show a decline in persistence after exposure to advanced therapy. Given these findings, JAK inhibitors like tofacitinib should be strongly considered for patients switching advanced therapies in ulcerative colitis.

Disclosure

RL advisory board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grants: Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, MRFF

Introduction

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex conditions characterized by significant clinical, immunological, molecular, genetic, and microbiological heterogeneity. Current therapeutic strategies, particularly biologics and Janus kinase (JAK) inhibitors, are effective for inducing clinical remission and controlling inflammation. However, one-third of patients fail to respond to these treatments, highlighting the need for predictive biomarkers to better tailor therapy and improve outcomes.

Aims & Methods

In this study, we conducted a multi-omic approach, integrating transcriptomics, proteomics, metabolomics, and metagenomics to identify biomarkers of treatment response in IBD. A cohort of 57 active CD and 70 active UC patients was analyzed before and after 14 weeks of treatment with anti-TNF, ustekinumab, vedolizumab, or tofacitinib. Response was evaluated using endoscopic criteria, categorizing patients as responders or non-responders. Biological samples [serum, urine, serum extracellular vesicles (EVs), intestinal biopsies, and stool] were analysed using RNA sequencing, liquid chromatography-mass spectrometry, nuclear magnetic resonance, and 16S rRNA gene sequencing to assess molecular and microbial profiles.

Results

Our results identified multiple mRNAs, proteins and metabolites associated with treatment response. Gene expression analysis in intestinal tissue showed significant differences between UC patients responders and non-responders to vedolizumab. Proteomic analysis of serum EVs and intestinal tissue samples revealed differentially expressed proteins between different study groups. Metabolomic analysis identified deregulation of 24 serum lipoproteins from CD responders to ustekinumab compared to non-responders. Pathway analysis highlighted significant enrichment in ketone and butyrate metabolism, mitochondrial electron transport chain activity, carnitine synthesis, and fatty acid oxidation pathways. Metagenomic analysis revealed microbial differences in UC patients responders to anti-TNF therapy compared to non-responders.

Conclusion

This multi-omics analysis uncovers promising biomarkers that could serve as predictive indicators of therapeutic response to biologics and JAK inhibitors. Nevertheless, further studies are crucial to confirm these findings and evaluate their clinical relevance in identifying patients most likely to respond to tailored therapeutic interventions. One of the challenges is integrating results from different omics approaches to create a more holistic understanding of the disease, potentially opening doors for more precise/early detection through multipanel biomarkers.

Introduction

Mirikizumab is an anti-IL-23p19 monoclonal antibody, a key mediator in the pathogenesis of inflammatory bowel diseases. We evaluated the induction efficacy and safety of mirikizumab in the LUCENT-1 (NCT03518086) Chinese subpopulation.

Aims & Methods

In this Phase 3, multi-center, randomized, parallel-arm, double-blind, placebo-controlled trial, conventional-failed or biologic/tofacitinib-failed Chinese adult patients (N=184) with moderately to severely active ulcerative colitis (UC, Modified Mayo Score 4-9, endoscopic subscore ≧2) were randomized in a 3:1 ratio to 300 mg mirikizumab (intravenous) or placebo every 4 weeks for 12 weeks. Randomization was stratified by biologic/tofacitinib failure status, baseline corticosteroid use and baseline disease activity (Modified Mayo Score). The primary objective was to test the hypothesis that mirikizumab was superior to placebo in inducing clinical remission at Week 12 (W12). Key secondary endpoints included alternate clinical remission, clinical response, clinical response in biologic-failed patients, symptomatic remission, endoscopic remission, histologic-endoscopic mucosal and bowel-movement urgency improvement. Analyses in Chinese subpopulation were descriptive. Missing data was imputed as non-responders for the categorical endpoints. Bowel urgency change from baseline data was reported based on Mixed Model Repeated Measured.

Results

Baseline characteristics were balanced across groups. A greater proportion of mirikizumab-treated patients achieved clinical remission (18.6% vs. 7.0%; Δ=11.5 [95%CI: 1.7, 21.3]) and alternate clinical remission at W12 (21.4% vs. 7.0%; Δ=14.3 [95%CI: 4.4, 24.2]). Mirikizumab also improved key secondary endpoints at W12. The frequencies of treatment-emergent adverse events were similar between groups (mirikizumab [60.0%] vs. placebo [62.8%]). There were fewer serious adverse events (10 [7.1%] vs. 7 [16.3%]) and discontinuations due to adverse events (2 [1.4%] vs. 3 [7.0%]) in mirikizumab-treated patients compared to placebo. There was 1 adenocarcinoma of colon (mirikizumab group) and no deaths during the treatment period.

Conclusion

Efficacy and safety profiles were consistent with LUCENT-1 overall population, supporting benefits of mirikizumab treatment in the Chinese UC patients.

Disclosure

No conflict of interest to disclose