Introduction

Fistulating peri-anal Crohn’s disease can affect approximately 20% of patients and have a major impact on quality of life. Despite being an important area of unmet clinical need, there is a paucity of evidence for most medical treatments and a lack of dedicated clinical trials for perianal Crohn’s disease. Current studies also report a high level of heterogeneity for outcomes with both treatments and placebo - making interpretation of the available data challenging for both clinical practice and design of clinical trials. Use of Bayesian methodology offers an attractive solution to help address some of these challenges. We sought to conduct a Bayesian prior elicitation exercise to determine the efficacy of licensed medical therapies for fistulating perianal Crohn’s disease.

Aims & Methods

A formal Bayesian prior elicitation meeting was convened. This was composed of a group of 11 gastroenterologists and 5 statisticians. Consensus priors were developed leveraging both published data and expertise of the gastroenterologists, to determine one-year fistula remission rates for seven options of licensed medical treatments based on five different mechanisms of action (anti-TNF, anti-integrin, anti-IL12/23, anti-IL-23, and JAK inhibitor). Consensus priors on the efficacy of each of seven treatment options was determined relative to an elicited consensus prior for placebo control. The log-odds ratio for efficacy for each of the seven therapy options versus placebo control was also established.

Results

Consensus priors were obtained for seven medical treatments for likelihood of fistula remission at one year. The prior mean, together with a 90% prior credible interval, of the one-year fistula remission rate was 0.22 (0.05, 0.46) for placebo, 0.58 (0.09, 0.96) for intravenous infliximab, 0.39 (0.06, 0.82) for adalimumab, 0.53 (0.09, 0.93) for subcutaneous infliximab, 0.24 (0.03, 0.60) for intravenous vedolizumab, 0.44 (0.05, 0.90) for upadacitinib, 0.34 (0.04, 0.77) for ustekinumab, and 0.36 (0.04, 0.82) for risankizumab. When assessing treatment effect on the log-odds ratio scale, oral upadacitinib and subcutaneous infliximab had the strongest “priors”, with the highest probability for likely efficacy, alongside intravenous infliximab.

Conclusion

We have conducted, to the best of our knowledge, the first formal Bayesian prior elicitation exercise for efficacy of medical therapies in perianal Crohn’s disease. These priors developed for the efficacy of licensed medical therapies can be internationally validated and potentially taken forward for planning of dedicated clinical trials. Importantly, these results could be used to enhance the design and analysis of clinical trials for fistulating perianal Crohn’s disease. Notable potential benefits from these findings include: improved estimation of treatment efficacy, reduction in the required sample sizes, and with minimisation or even avoidance of placebo control arms for future dedicated fistulating perianal Crohn’s disease clinical trials.

Disclosure

NMN declares educational/travel grants and/or speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, J&J, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma AG. RC reports personal fees from AbbVie, Galapagos, Lilly outside the submitted work, and grants from Celltrion, Ferring, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Bristol Myers Squibb outside the submitted work. SD reports personal fees from AbbVie, Ferring, Janssen, Takeda outside the submitted work; and grants from AbbVie, Dr Falk, Janssen, outside the submitted work; and fees from advisory board membership of AbbVie outside the submitted work. HG has received speaker fees from: Janssen, Ferring, Takeda, and AbbVie, and consultancy fees from. AbbVie, Galapagos. KBK reports serving as a speaker, a consultant, and/or an advisory board member for Abbvie, Falk, Galapagos, Janssen, and Takeda. JOL reports personal fees from AbbVie, Atlantic Healthcare, Bristol Meyer Squibb, Celgene, Celltrion, Engytix, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Norgine, Pfizer, Shire, and Takeda outside the submitted work; and grants from AbbVie, Ferring, Gilead, Takeda, and Shire outside the submitted work. GWM declares consultancy fees/grant funding from AbbVie, AstraZeneca and Janssen; all outside the submitted work. KVP reports personal fees from AbbVie, DrFalk, Galapagos, Janssen, PredictImmune, Pfizer, Takeda outside the submitted work; and grants from AbbVie, Celltrion, Dr Falk, Ferring, Janssen, Takeda, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Galapagos, Janssen, Pfizer outside the submitted work. SS reports consulting fees from Takeda, AbbVie, Merck, Ferring, Pharmacosmos, Warner Chilcott, J&J Innovative Medicine, Dr Falk Pharma, Biohit, TriGenix, Celgene, and Tillots Pharma outside the submitted work; payment or honoraria from AbbVie, Takeda, Celltrion, Pfizer, Biogen, AbbVie, J&J Innovative Medicine, Merck, Warner Chilcott, Dr Falk Pharma, outside the submitted work; and is co-director of research for the South Asian IBD Alliance. TR has received research/educational grants and/or speaker/consultation fees from Abbvie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Takeda, UCB, and XAP Therapeutics. SS reports person fees from Abbvie, Celltrion, Dr. Falk, Ipsen, Janssen, Takeda outside the submitted work. ALH has received consultancy fees from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; has received honoraria from AbbVie, Bristol Myers Squibb, Celltrion, Galapogos, Johnson & Johnson, Takeda, Pfizer, Lilly; and has received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; all outside of the submitted work. MP reports personal fees from Janssen and Takeda outside the submitted work; and grants from AstraZeneca, Galapagos, Gilead, Pfizer outside the submitted work. All other authors declare no conflicts of interest.

Introduction

Fatigue is a debilitating, multifactorial symptom experienced by many patients with Crohn’s disease (CD).¹ Mirikizumab (MIRI), an anti-interleukin-23p19 antibody, demonstrated significant improvement in fatigue in patients with moderately to severely active CD in the Phase 2 AMAG² and Phase 3 VIVID-1³ studies.

Aims & Methods

This analysis examines the association of changes in clinical, endoscopic (endo) and selected patient-reported outcomes with changes in fatigue in MIRI-treated patients in the VIVID-1 study. Co primary and gated secondary outcomes, including comparisons with ustekinumab, have been presented elsewhere^4,5Adult patients (N=1065) with moderately to severely active CD were randomized 6:3:2 to MIRI, ustekinumab or placebo. MIRI was given every 4 weeks (W) as 900 mg intravenous at W0, W4, and W8, then 300 mg subcutaneous from W12 to W52. Fatigue was assessed via the validated Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire (scale from 0-52, higher scores indicating less fatigue⁶ andat least 6-point increase identified as a clinically meaningful within-patient change). Achievement of ≥6-point increase in FACIT-F at W52 was reported among those with and without clinical remission by Crohn’s Disease Activity Index (CDAI), endo response, endo remission, and Urgency Numeric Rating Scale (NRS) ≤2 at W52. For stool frequency (SF), abdominal pain (AP), fecal calprotectin (FCP), and C-reactive protein (CRP), the association of the change from baseline (CFB) at W52 vs. the CFB in FACIT-F at W52 was assessed by the Pearson correlation coefficient.

Results

At W52, 50.9% (268/527) of MIRI-treated patients achieved FACIT-F ≥6-point increase from baseline. Greater proportions of patients who achieved clinical and endo outcomes had ≥6-point increase in FACIT-F (p<0.05) vs. those who did not achieve the outcome (Table). There was weak/moderate correlation between CFB at W52 in AP, SF and log-transformed FCP and CRP, and the CFB in FACIT-F at W52 (Table).

Table: W52 FACIT-F, A: ≥6-pt Increase From BL by Outcomes at W52 and B: CFB Correlation With CFB at W52 in Outcomes

A. W52 FACIT-F ≥6-point Increase From BL by Outcome at W52a, NRI	Outcome Achieved n/N (%) (95% CI)b	Outcome NOT Achieved n/N (%) (95% CI)b	Risk Difference (95% CI)b	p-Valuec
Clinical remission by CDAId	185/280 (66.1) (60.5-71.6)	83/247 (33.6) (27.7-39.5)	32.5 (24.4-40.6)	<0.0001
Endo responsee	154/256 (60.2) (54.2-66.2)	114/271 (42.1) (36.2-47.9)	18.1 (9.7-26.5)	<0.0001
Endo remissionf	59/96 (61.5) (51.7-71.2)	209/431 (48.5) (43.8-53.2)	13.0 (2.1-23.8)	0.0216
Urgency NRS ≤2g	127/188 (67.6) (60.9-74.2)	127/311 (40.8) (35.4-46.3)	26.7 (18.1-35.4)	<0.0001
B. CFB in FACIT-F vs. CFB in Outcomes at W52	N	Pearson Correlation Coefficient	95% CIh	p-Value
CFB in AP score	574	-0.379	-0.447 to -0.306	<0.0001
CFB in SF score	572	-0.306	-0.378 to -0.230	<0.0001
CFB in log-transformed FCP	461	-0.112	-0.201 to -0.020	0.0166
CFB in log-transformed CRP	576	-0.208	-0.285 to -0.128	<0.0001

^aMIRI-treated patients with baseline (BL) FACIT-F score ≤46 points; ^bConfidence interval (CI) constructed using asymptotic method without continuity correction; ^cChi Square test; ^dCDAI <150; ^eSimple Endoscopic Score for CD (SES-CD) Total Score ≥50% improvement from BL; ^fSES-CD Total Score ≤4, ≥2-point reduction from BL and no subscore >1; ^gIn those with BL Urgency NRS ≥3; ^hPearson correlation with Fisher’s z-transformation. A negative correlation indicates an improvement in outcome is associated with an improvement in FACIT-F. Correlation strength defined as: >0.5=strong, 0.3 to ≤0.5=moderate, 0.1 to <0.3=weak, <0.1=insubstantial⁷
NRI=nonresponder imputation.

Conclusion

In patients with moderately to severely active CD treated with MIRI, improvements in clinical, endoscopic, and selected patient-reported outcomes were associated with clinically meaningful improvements in fatigue at W52.

References

1. D’Silva A, et al. Clin Gastroenterol Hepatol. 2022;20:995-1009.
2. Regueiro MD, et al. Am J Gastroenterol. 2023;118:S816.
3. Travis S, et al. J Crohn's Colitis.2024;18:i21–i23.
4. Ferrante M, et al. J Crohn's Colitis. 2024;18:S1 i7–i9.
5. Jairath V, et al. J Crohn's Colitis. 2024;18:i62–i64.
6. Tinsley A, et al. Aliment Pharmacol Ther. 2011;34:1328-36.
7. Cohen J. Statistical Power Analysis for the Behavioural Sciences, 1988, Routledge.

Disclosure

P. Bossuyt has received financial support for research from: AbbVie, Amgen, Janssen, Pfizer, and Viatris; lecture fees from: AbbVie, Bristol Myers Squibb, CAG, Celltrion, Eli Lilly and Company, EPGS, Galapagos NV, Globalport, Janssen, Materia Prima, Pentax, Scope, and Takeda; and advisory board fees from: AbbVie, Bristol Myers Squibb, Celltrion, CIRC, Dr. Falk Pharma Benelux, Eli Lilly and Company, Galapagos NV, Janssen, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros; M. Regueiro has served as an advisor and/or consultant for: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Genentech, Gilead Sciences, Janssen, Organon, Pfizer, Prometheus Therapeutics and Diagnostics, Salix Pharmaceuticals, Takeda, and UCB Pharma; M. Fischer has received consulting fees from: AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Ferring Pharmaceuticals, Janssen, Pfizer, Rebiotix, Scioto Biosciences, and Seres Therapeutics; K. Traxler, G. Yu, M. Protic, K. Tsilkos, and A. Vadhariya are employees and shareholders of: Eli Lilly and Company; T. Hisamatsu has received lecture fees from: AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda; has received honoraria as an advisory board member or consultant for: AbbVie, Brystol Myers Squibb, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Pfizer, and Takeda; and has received pharmaceutical/research grants from: AbbVie, Boston Scientific, Daiichi Sankyo, EA Pharma, Kissei Pharmaceutical, JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nichi-lko Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; P. Juillerat has received fees for lectures and consulting/advisory board from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Ferring Pharmaceuticals, Gilead Sciences, Janssen, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Sandoz, Takeda, Tillotts Pharma AG, and UCB Pharma

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).