Introduction

Mirikizumab is a humanized immunoglobulin G4 monoclonal antibody against the p19 subunit of interleukin-23, a key inflammatory mediator in ulcerative colitis (UC). Here we report efficacy and safety in pediatric patients with moderate to severe UC from the Phase 2 SHINE-1 study (NCT04004611) following 52 weeks of mirikizumab treatment.

Aims & Methods

Patients aged 2 to <18 years with active UC who had an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies, or had corticosteroid-dependent colitis, were included in the study. Patients weighing >40 kg received an induction dose of 300 mg via intravenous infusion; patients weighing ≤40 kg received 5 or 10 mg/kg via intravenous infusion at weeks 0, 4, and 8. At week 12, patients were assessed for clinical response using the Modified Mayo Score. Responders entered the maintenance period and received subcutaneous doses of mirikizumab at 200 mg (>40 kg), 100 mg (>20 kg to ≤40 kg), or 50 mg (≤20 kg) once every 4 weeks, with the last patient visit at week 52.

Results

All patients (N=26) completed induction through week 12, and 73.1% (N=19) completed through week 52. At week 12, 69.2% (18/26) were Modified Mayo Score responders; at week 52, 55.6% (10/18) of responders were in clinical and endoscopic remission. Clinical response, remission, and endoscopic remission rates were consistent with LUCENT Phase 3 UC adult studies.
The safety profile of mirikizumab was consistent with the safety profile in LUCENT adults. Three serious adverse events (11.5%) were reported: non-infective appendicitis, UC flare, and pseudarthrosis. The UC flare resulted in study discontinuation.

Conclusion

Mirikizumab demonstrated an acceptable safety profile, and similar clinical response, clinical remission, and endoscopic remission compared to LUCENT adults. These results are the foundation of the pivotal Phase 3 pediatric SHINE-2 study.

Disclosure

J. L. Kaplan has nothing to disclose; D. Turner received consulting fees from: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring Pharmaceuticals, Janssen, Pfizer, Prometheus Biosciences, Takeda, Galapagos, and Sorriso Pharmaceuticals; and research funding from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda; A. Bousvaros has received research support from: AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, BUHLMANN Diagnostics, Eli Lilly and Company, Janssen, Procise Diagnostics, and Takeda; was a consultant for: Best Doctors, Eli Lilly and Company, Fresenius Kabi, and Takeda; and has received honoraria and royalties from: Boston University and UptoDate; M. Dubinsky has received honoraria as a consultant for: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma; has been contracted for research by: AbbVie, Janssen, Pfizer, and Prometheus Biosciences; has stock interest in: Trellus Health; and has received licensing fees from: Takeda; W. J. Komocsar, A. Larkin, J. Johns, X. Zhang, W. Crandall, V. Arora, and K. Todd are employees and shareholders of: Eli Lilly and Company; J. S. Hyams is on an advisory board for: AbbVie, Eli Lilly and Company, Janssen, and Pfizer; and has been a consultant to: Boehringer Ingelheim, Bristol Myers Squibb, and Takeda.

Introduction

Microscopic colitis (MC) refers to two pathologies – Collagenous colitis (CC) and Lymphocytic colitis (LC) that cause chronic watery diarrhoea, urgency, incontinence leading to significantly decreased quality of life¹. It is thought that MC develops due to a pathological immune response to intestinal luminal antigens in genetically predisposed individuals, with microbiota playing an important role^{2, 3}. However, the pathogenesis of MC is still unclear.

Aims & Methods

The aim of this study was to identify and characterize changes in bacterial composition of MC patients in terminal ileum and different colonic segments and determine its relation to the clinical course of disease. Biopsies from terminal ileum and six segments of the colon were collected during diagnostic colonoscopies. DNA extraction was performed using AllPrep DNA/RNA Micro Kit (Qiagen) following the manufacturer’s instructions. To determine bacterial composition, sequencing of the 16S rRNA variable region V3-V4 was conducted using the 27F and 338R polymerase chain reaction primers and sequenced on a MiSeq (2×250 bp; Illumina, Hayward, CA). Bioinformatic analysis was performed using DADA2, and taxonomic classification was carried out with the RDP classifier.

Results

Biopsy samples from 20 active CC patients, 20 active LC patients, and 50 controls demonstrated distinct microbial profiles across different intestinal segments, as revealed by beta-diversity and differential compositional analyses. Compared with controls, CC patients had consistent alterations in three bacterial families throughout the entire colon, with Erysipelatoclostridiaceae and Coriobacteriaceae decreased and Pasteurellaceae increased. Additionally, 35 families had segment-specific changes, and 25 families displayed altered abundance in the terminal ileum.
LC patients exhibited a consistent increase in Erisypelotrichaceae across the entire colon, with 38 other families showing segmental changes, and 12 families displaying altered abundance in the terminal ileum. Comparing LC and CC revealed a significantly different bacterial profile. LC showed lower abundance across many families, particularly in the right colon and terminal ileum. After sample collection, 15 CC patients and 12 LC patients received budesonide, with 3 CC and 2 LC patients having incomplete response. Beta diversity analysis revealed significant differences in the ascending colon and left side of the colon of CC patients based on response to budesonide. Patients with incomplete response to budesonide had an increased abundance of the genus Paucibacter. Similar tendencies were not observed in LC.
1 CC patient exhibited a quiescent disease course, 6 reached a sustained remission after treatment, 7 had a relapsing and 6 had a chronic active disease. Significant differences in beta diversity were observed in transverse, descending colon and rectum. Beta diversity of the descending colon had a medium correlation with disease behaviour. In the LC group 6 patients had a quiescent disease, 8 had a sustained remission after treatment, 3 exhibited a relapsing and 4 had a chronic active disease. No significant correlation between microbiota and disease behaviour was observed in LC.

Conclusion

This study showed significant differences in bacterial composition between CC, LC and controls in the terminal ileum and colon. In both CC and LC, bacterial alterations were not consistent throughout the entire colon but varied between different colonic segments. Microbiome differences based on response to budesonide and disease behaviour were observed in CC, but not LC.

References

1. Verhaegh BPM, Münch A, Guagnozzi D, et al. Course of Disease in Patients with Microscopic Colitis: A European Prospective Incident Cohort Study. J Crohns Colitis. 2021;15(7):1174-1183.
2. Miehlke S, Guagnozzi D, Zabana Y, et al. European guidelines on microscopic colitis: United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations. United European Gastroenterol J. Published online 2020.
3. Burke KE, D’Amato M, Ng SC, Pardi DS, Ludvigsson JF, Khalili H. Microscopic colitis. Nat Rev Dis Primers. 2021;7(1).

Introduction

Patients with moderately to severely active ulcerative colitis (UC) have debilitating symptoms that may incur substantial negative effects on health-related quality of life (HRQoL). According to the STRIDE-II consensus, restoration of HRQoL is a desirable long-term treatment goal for patients with active UC.¹ In this post-hoc analysis, we evaluated the extent to which patients treated with upadacitinib (UPA) achieved normalisation of HRQoL after induction and maintenance treatment.

Aims & Methods

Data from the multicentre, double-blind, Phase 3 trials, U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026), were analysed. During induction, patients were randomised 1:2 to oral placebo (PBO) or UPA 45 mg once daily (QD) for 8 weeks. Patients achieving a clinical response to UPA per Adapted Mayo score at Week 8 were re-randomised 1:1:1 to PBO, UPA 15 mg, or UPA 30 mg QD for 52 weeks of maintenance. The proportion of patients achieving normalisation of each individual HRQoL outcome, per literature-base normative value thresholds, was assessed at Weeks 8 and 52: FACIT-Fatigue score; IBDQ score; WPAI-UC (overall work impairment, work time missed, impairment while working, activity impairment); SF-36 PCS; SF-36 MCS; EQ-5D-5L VAS; and EQ-5D-5L index. A stringent composite score including these outcomes was also calculated to determine the proportion of patients who achieved normalisation of all individual HRQoL-related scores. Point estimates were calculated for all outcomes and treatment differences between UPA and PBO were compared using the Cochran-Mantel-Haenszel test.

Results

During induction, 660 patients were randomised to UPA 45 mg and 328 patients to PBO. In patients receiving UPA 45 mg vs PBO, more patients achieved normalisation of each individual HRQoL outcome at Week 8 of induction (p<0.001; Table 1). Improvements were also observed at Week 52 of maintenance in patients receiving UPA 15 mg (n=148) and 30 mg (n=154), with more patients achieving normalisation of each HRQoL outcome with both doses of UPA vs PBO (p<=0.01). More patients achieved normalisation of composite HRQoL scores at Weeks 8 (UPA 45 mg: 18.9%; PBO: 5.5%) and 52 (UPA 30 mg: 24.0%; UPA 15 mg: 22.3%; PBO: 8.7%) with all doses of UPA compared to PBO (p<=0.001).
Table 1. Proportion of patients with UC achieving normalisation of HRQoL outcomes after treatment

Conclusion

UPA is more efficacious than PBO at achieving normalisation of patients’ HRQoL, at induction and through Week 52 of maintenance. These results suggest that UPA may help patients with moderately to severely active UC achieve the long-term treatment goal of normalisation of HRQoL.

References

1. Turner D, et al. Gastroenterology. 2021;160:1570–83.

Disclosure

Joana Torres has received grant funding/speaker fees from and/or has participated in advisory boards for AbbVie, Galapagos, Janssen, and Pfizer.
Gareth Parkes received personal payments/honoraria/speaker fees and/or accepted travel grants or fellowships from AbbVie, Allergan, BMS, Celltrion, Ferring, Galapagos, Janssen, Napp, Takeda, and Tillotts; and is a Director and Shareholder in Ampersand Health.
Corey Siegel has served as a consultant, advisor, speaker for CME activities, and/or received grant funding from AbbVie, BMS, Celltrion, Fresenius, Janssen, Lilly, Napo, Pfizer, Prometheus, Prometheus Labs, Roivant, and Takeda.
Julian Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman; and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.
Edward V. Loftus Jr: served as a consultant for AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Calibr, Celgene, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota, Iterative Scopes, Janssen, Morphic Therapeutics, Ono Pharma, Pfizer, Protagonist, Scipher Medicine, Surrozen, Sun Pharma, Takeda, and UCB; and received research grants from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, and UCB.
Remo Panaccione served as a consultant for Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Spyre Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, UCB; and received speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and was an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.
Yuri Sanchez Gonzalez, Si Xuan, Valencia Remple, Justin Klaff, Cecile Holweg, and Dolly Sharmaare full-time employees of AbbVie and may hold AbbVie stock and/or stock options.
Funding statement: Financial support for the study was provided by AbbVie. AbbVie participated in interpretation of data, review, and approval of the abstract. All authors contributed to development of the abstract and maintained control over final content. No honoraria or payments were made for authorship. Medical writing services provided by Kay Hallam, MSc, of Fishawack Facilitate, Ltd, part of Avalere Health and funded by AbbVie.

Introduction

​​​​​Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks interleukin 23 (IL-23) and binds to CD64, a receptor on cells that produce IL-23¹. In patients with moderately to severely active Crohn’s disease (CD), the GALAXI-2 and GALAXI-3 Phase 3 studies established short- and long-term efficacy of GUS compared to placebo, and statistical superiority to ustekinumab (UST) in prespecified analyses of pooled data at Week (WK)48². We subsequently developed an endoscopic clustering method using Simple Endoscopic Score for Crohn's Disease (SES-CD) segmental scores in patients from GALAXI 2/3 which revealed higher endoscopic remission rates with GUS compared with UST at WK12 and WK48 in pts characterized by ileal disease and strictured right colon³. Here we report molecular differentiation of GUS compared with UST in isolated ileal disease based on serum pharmacodynamic (PD) markers and tissue transcriptomics in CD using pooled samples from the GALAXI studies.

Aims & Methods

Patients (pts) in GALAXI-2 (n=508) and GALAXI-3 (n=513) were randomized 2:2:2:1 to receive GUS 200mg IV q4w x3 → GUS 200mg SC q4w, GUS 200mg IV q4w x3→ GUS 100mg SC q8w, UST ⁓6mg/kg IV x1 → UST 90mg SC q8w or placebo IV q4w x3 (PBO). Serum biomarkers were measured in a subset of (n=50) pts per group at WK0, WK4 and WK12 using a proinflammatory panel and a high sensitivity IL-22 assay. Matched ileal and rectal biopsies were evaluated at WK0, WK12 and WK48 in a subset of 344 pts representative of the full study population. Transcriptional profiling was performed with bulk RNA sequencing (RNAseq) using transcriptional modules. Analysis of treatment effects was performed using molecularly inflamed samples (biopsy molecular inflammation score [bMIS]⁴ >0) from segments with SES-CD >0 at baseline. Serum proteins and transcriptional modules were evaluated for differential expression stratified by isolated ileal, isolated colonic and ileocolonic disease defined during screening.

Results

In pts with isolated ileal disease, GUS decreased serum protein levels of IL-22, IL-17A and IFNγ at WK12 while UST only reduced IFNγ. In ileal tissue, GUS significantly altered inflammatory modules at WK12 and WK48 including reductions in neutrophil, inflamed epithelium, IL-23/Th17 and inflammatory fibroblast biology compared with minimal changes observed with UST, which only significantly reduced neutrophil, plasma cell and macrophage modules at WK48. In contrast, in pts with isolated colonic or ileocolonic disease, both GUS and UST decreased IL-23-dependent serum proteins towards normal levels compared with an independent cohort of healthy control sera. In rectal tissue, both GUS and UST significantly altered key inflammatory transcriptional modules in rectal biopsies at WK12 and WK48. Overall, greater effects of GUS vs UST were observed in ileal tissue at WK12 and at WK48 in transcriptional modules associated with decreasing disease-related features and restoring epithelial health than UST.

Conclusion

GUS decreased IL-23-dependent serum proteins and improved tissue transcriptional profiles in pts with isolated ileal disease while UST only reduced serum IFNγ and had a minimal impact on IL-23-dependent transcriptional modules. These data suggest potential differences in IL-23 and IL-12 pathway enrichment in isolated ileal disease where inhibition of IL-23p19 subunit with GUS achieved greater molecular treatment effects early which were maintained through WK48 and associated with differential clinical outcomes in patients with isolated ileal disease.

References

1. Sachen K, Hammaker D, Sarabia I, et al. Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling. Frontiers in Immunology. 2025; doi:10.3389/fimmu.2025.1532852
2. Panaccione R, Danese S, Feagan BE, et al. Efficacy and safety of guselkumab therapy in patients with moderately to severely active Crohn’s disease: results of the GALAXI 2 & 3 phase 3 studies. Gastroenterology. 2024; 5 (Supplement): p1057b
3. Richards D, Seridi L, Sohn, K, et al. Guselkumab shows higher endoscopic remission rates than ustekinumab in patients characterized by isolated ileal and srtictured right colon Crohn’s disease: Post-hos analysis of GALAXI 2/3 Ph3 trials. DDW 2025 Abs #4253526; poster.
4. Argmann C, Hou R, Ungaro, R, et al. A biopsy and blood-based molecular biomarker of inflammation in inflammatory bowel disease. Gut. 2022; 0:1-17.

Disclosure

DR, KS, MZ, RP, BM, NAT, MV, DC and PB are current or former employees of Janssen and may hold stock in Johnson & Johnson.
WR has served as a speaker for AbbVie, Celltrion, Ferring, Janssen, Galapagos Medice, MSD, Roche, Pfizer, Sobi, Takeda, as a consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Janssen, Medahead, Microbiotica, Pfizer, Takeda; as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Pfizer, and has received research funding from AbbVie, Janssen, Sandoz, Sanofi, Takeda.