Introduction

Most clinical trials of systemic ulcerative colitis (UC) therapies exclude patients (pts) with isolated proctitis, who are considered a more treatment-refractory population, creating a need for clinical evidence. Etrasimod is an investigational, oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator in development for the treatment of moderately to severely active UC. The phase 3 etrasimod ELEVATE UC trials included pts with isolated proctitis (< 10 cm rectal involvement), provided they met all other eligibility criteria.¹

Aims & Methods

This post hoc analysis assessed predefined efficacy and safety outcomes in subgroups of pts with isolated proctitis and more extensive colitis (proctosigmoiditis/left-sided colitis/pancolitis). In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), pts (aged 16–80 years) with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg once daily or placebo. ELEVATE UC 52 comprised a 12-week (wk) induction period followed by a 40-wk maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12-wk induction period. Clinical endpoints were assessed in pts with isolated proctitis (data pooled from both trials) and in pts with more extensive colitis (individual trial data). Sustained and corticosteroid-free clinical remission were assessed at Wk 52 (ELEVATE UC 52 only). Bowel urgency Numeric Rating Scale (NRS) was assessed at Wks 12 and 52. Safety was assessed up to Wk 52.

Results

This analysis included 64 (pooled; Wk 12) and 36 (ELEVATE UC 52; Wk 52) pts with isolated proctitis, and 397 (ELEVATE UC 52; Wks 12 and 52) and 326 (ELEVATE UC 12; Wk 12) pts with more extensive colitis. Similar proportions of pts with isolated proctitis achieved the predefined efficacy endpoints vs those with more extensive colitis (Table). Pts with isolated proctitis receiving etrasimod had similar improvements in urgency NRS scores vs those with more extensive colitis (mean change from baseline: Wk 12, -2.8 vs -2.9 [both trials]; Wk 52, -5.0 vs -4.1). Safety in pts with isolated proctitis was generally similar to that in the overall trial population.¹

Conclusion

Etrasimod treatment had similar efficacy in pts with isolated proctitis and in those with more extensive colitis. Prospective confirmation in larger pt cohorts with isolated proctitis is necessary. Safety was consistent with the overall population.¹

References

1. Sandborn WJ et al. Lancet 2023: Epub ahead of print

Disclosure

LPB: research: Takeda, Fresenius Kabi, Celltrion; consultancy: AbbVie, Alimentiv, Alma, Amgen, Applied MolecularTransport, Arena, Biogen, BMS, Celltrion, CONNECTBiopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, HAC, IAG ImageAnalysis, Index, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; speaker: Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Eli Lilly, Gilead, Viatris, Medac, Sanofi; stock: CTMA.
MCD: research: Janssen; consultancy: AbbVie, Arena, BMS, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, Trellus Health, UCB; shares/royalties: Trellus; directorship/ownership interests: Trellus.
BES: research/grants: Arena, Janssen. Lecture/Speakers Bureau: BMS, Janssen, Lilly, Pfizer, Takeda. Consultancy: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer-Ingelheim, BMS, Celltrion, Fresenius Kabi, Genentech, GSK, Janssen, Lilly, Merck, Pfizer, Prometheus Biosciences, Sun Pharma Global, Takeda Pharmaceuticals International, Teva Branded Pharmaceutical Products R&D. Shareholder/Stock Options: Ventyx Biosciences. Other non-financial support: Janssen, Lilly, Pfizer, Takeda.
JP: personal: AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Galapagos, Genentech/Roche, GSK, Immunic, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Revolo, Takeda, Theravance, Wassermann; grants: AbbVie, Pfizer.
SS: speaker: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr. Falk, Fresenius, Janssen, MSD, Pfizer, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr. Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention, Takeda, Theravance.
WR: speaker: AbbVie, Celltrion, Dr. Falk, Ferring, Janssen, Galapagos, MSD, Roche, Pfizer, Pharmacosmos, Shire, Takeda, Therakos; consultant: AbbVie, Amgen, AOP Orphan, Arena, Astellas, AstraZeneca, Bioclinica, Boehringer Ingelheim, BMS, Calyx, Celgene, Celltrion, Eli Lilly, Dr. Falk, Ferring, Galapagos, Gatehouse, Genentech, Gilead, Grünenthal, ICON, Index, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Protagonist, Provention, Quell, Sandoz, Seres, Setpointmedical, Sigmoid, Sublimity, Takeda, Teva, Therakos, Theravance, Zealand; advisory board: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe, MSD, Pharmacosmos, Pfizer, Sandoz, Takeda; research: AbbVie, Janssen, MSD, Sandoz, Sanofi, Takeda.
BGF: consultant/advisory: AbbVie, AbolerIS, AgomAB, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital, Atomwise, BIOJAMP, Biora, Boehringer Ingelheim, Boxer, Celsius, BMS, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, FirstWord, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge, HotSpot, InDex, Imhotex, Immunic, JAK, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K., Lenczner Slaght, LifeSci, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Diagnostics, Play to Know AG, Progenity, Protagonist, PTM, Q32, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts, Ventyx, VHSquared, Viatris, Ysios, YSOPIA, Zealand; speaker: AbbVie, Janssen, Takeda; Alimentiv Senior Scientific Director, provides central reading services; not a company employee, no equity stake; shareholder: Gossamer.
SD: consultancy/advisory: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, J&J, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB Vifor; speaker: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda; directorship/ownership interests: Gastroenterology and Endoscopy.
AJY: consultancy: Pfizer, Arena, Takeda, BMS; speaker: BMS.
GD’H: advisor: AbbVie, AstraZeneca, Alimentiv, BMS, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, J&J, Takeda, Pfizer, Polpharma, Prometheus, Tillotts, Ventyx; speaker: AbbVie, Boehringer Ingelheim, Celltrion, J&J, Takeda, Pfizer, Tillotts.
MG, KW, JCW, IM, AMcD, LB, CJR: Pfizer employees & shareholders.
SV: research: AbbVie, MSD, Pfizer, Galapagos, Takeda; consultancy: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, J&J, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, Zealand; speaker: AbbVie, Dr. Falk, Ferring, Hospira, MSD, Takeda, Tillotts.

Introduction

Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease with increasing incidence and prevalence. Patients with EoE usually present with symptoms of dysphagia that impact their quality of life. In the 3-part, Phase 3 LIBERTY EoE TREET study (NCT03633617), dupilumab improved histologic, symptomatic, and endoscopic aspects of EoE up to 52 weeks.

Aims & Methods

The aim of this analysis was to assess the effect of dupilumab on symptoms of dysphagia in the 28-week extended treatment period of LIBERTY EoE TREET in patients who switched from placebo to dupilumab at 24 weeks. In Parts A and B, patients received dupilumab 300 mg or placebo weekly (qw) for 24 weeks. Patients who completed Parts A and B entered Part C - a 28-week extended treatment period in which all patients received dupilumab 300 mg qw; patients entering Part C remained blinded to their treatment in Parts A and B. Dysphagia Symptom Questionnaire (DSQ) score and number of days with dysphagia (assessed using the DSQ) were calculated over a 14-day period. Percent change in DSQ score and in number of days with dysphagia from Week 24 through Week 52 vs the Week 24 baseline were assessed for patients who switched from placebo to dupilumab 300 mg qw at Week 24 and or continued on dupilumab 300 mg.

Results

Mean (SD) DSQ score after 24 weeks of placebo was 24.7 (19.6) and 21.5 (18.4) in Parts A (n=37) and B (n=37), respectively. Significant improvements in DSQ score were observed within 4 weeks of the switch to dupilumab 300 mg qw (mean percent reduction: 31.5% and 29.9%). After 28 weeks (at Week 52), mean percent reduction in DSQ score was 63.6% and 59.7%. After 24 weeks of placebo, mean (SD) days with dysphagia was 6.6 (4.7) and 6.0 (4.7) in Parts A and B, respectively. At Week 52, there was a 63.2% and 46.8% mean reduction in the number of days with dysphagia.

Conclusion

In patients who initially received 24 weeks of placebo, weekly treatment with dupilumab 300 mg resulted in rapid (within 4 weeks) and sustained (up to 28 weeks) improvement in symptoms of dysphagia as assessed by the DSQ score. The magnitude of the improvement in dysphagia observed after switching from placebo to dupilumab was similar to that seen at 4 weeks in patients who originally initiated dupilumab in Parts A and B of the study.

Disclosure

Dellon ES. Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Dr. Falk Pharma, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio – consultant. Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda – research funding. Allakos, Aqilion, Holoclara, Invea – educational grants.
Chehade M. Adare Pharma Solutions/Ellodi, Allakos, AstraZeneca, BMS, Nexstone Immunology, Phathom, Recludix Pharma, Regeneron Pharmaceuticals Inc., Sanofi, and Shire/Takeda ‒ consultant. Adare Pharma Solutions/Ellodi, Allakos, AstraZeneca, Celgene/BMS, Danone, Regeneron Pharmaceuticals Inc., and Shire/Takeda ‒ research funding.
Bredenoord AJ. Alimentiv, Aqilion, AstraZeneca, Dr. Falk Pharma, Eupraxia, Laborie, Medtronic, Reckitt, Regeneron Pharmaceuticals Inc., and Sanofi ‒ consultant. Dr Falk Pharma, Norgine, Nutricia, Sanofi, SST, Regeneron Pharmaceuticals Inc., and Thelial ‒ research funding. Alimentiv, Aqilion, AstraZeneca, Dr Falk Pharma, Eupraxia, Laborie, Medtronic, Reckitt, Regeneron Pharmaceuticals Inc., and Sanofi ‒ speaker fees.
Spergel JM. Allakos, DBV Technologies, Novartis, Regeneron Pharmaceuticals Inc., and Shire/Takeda – consultant. DBV Technologies and Regeneron Pharmaceuticals Inc. ‒ research grant support.
Xia C, McCann E, Khodzhayev A, Radwan A. Regeneron Pharmaceuticals Inc. – employees and shareholders.
Tilton ST, Pela T, Jacob-Nara JA. Sanofi – employee, may hold stock and/or stock options in the company.

Introduction

Despite new therapeutic strategies, substantial proportion of patients with ulcerative colitis (UC) undergo colectomy at some point. Restorative proctocolectomy with ileal pouch ano anastomosis (IPAA) is regarded as intervention of choice in these patients. However, the disease conversion to Crohn´s disease (CD) is reported in up to one third of these patients who necessitate immune suppressive treatment after IPAA. Considering the life-long need for immune suppressive therapy in these patients, ileo-rectal anastomosis (IRA) would represent a good alternative to IPAA in this specific group of patients. Todate, no data are available to predict the UC-CD conversion. One of the possibility to reduce the risk of performing IPAA in patients developing CD in pouch is to use the modified two-stage proctocolectomy approach and identify patients who develop CD endoscopically between colectomy and the restoration of continuity.

Aims & Methods

The aim of the present study was to assess the UC-CD conversion rate identified prior IPAA via ileoscopy.
All patients with UC operated in one tertiary IBD center between 2016 and 2021 were identified in medical records. The main outcome was CD detected at ileoscopy between the first stage operation, i.e. total colectomy with terminal ileostomy and the restoration of continuity either via IPAA or IRA. The ileoscopy was performed between three to six months after colectomy. The secondary outcome was the rate of conversion to CD after IPAA or IRA.

Results

Sixty patients underwent total colectomy (mean age 41 years, range 22-77; 62% were men); seven patients were lost to follow-up, finally the data from 53 patients were analysed. The majority of these patients (36 - 68%) underwent colectomy for therapy resistent chronically active UC, 9 (17%) patients for acute severe UC, 2 patients had benign colonic stenosis, 5 had high-grade dysplasia or colorectal cancer detected at surveillance colonoscopy and one patient had extensive pseudopolyposis.
All resection specimen were reviewed and no histopathological features of CD were found. Three out of the 53 (6%) ileoscopically assessed patients prior IPAA or IRA were diagnosed with CD in prestomal terminal ileum. During the further follow-up, additional 4 patients developped CD, two after IPAA, one with definitive ileostomy in prestomal ileum and one in neoterminal ileum after IRA.
In total 7 out of 53 patients in this cohort developped CD (13%). Using the two stage approach with ileoscopy between colectomy and restoration of continuity, three out of these seven patients with CD convertion in this cohort were detected prior the decision on the type of second-stage operation.

Conclusion

The conversion from ulcerative colitis to Crohn`s disease occurs in a significant proportion of IBD patients after colectomy. Ileoscopy performed between the two stages of restorative proctolectomy is helpfull in detecting these patients and guiding the decision on the type of surgical intervention to restore continuity.

Disclosure

Nothing to disclose.

Introduction

Background
Lymphocyte trafficking to the inflamed gut is one of the hallmarks of Inflammatory Bowel Disease (IBD) pathology. Integrin a4b7 and its ligand MADCAM1 play an important role in targeting immune cells in the bloodstream to mucosal tissues and blocking this pathway using the anti-a4b7 monoclonal antibody Vedolizumab (VDZ) proved to be an effective treatment in IBD. However, VDZ is most efficient in treatment of Ulcerative Colitis (UC) and of colonic rather than ileal Crohn’s Disease (CD), for which the reasons have not been completely understood.

Aims & Methods

Aim:
To compare the expression of ITGA4, ITGB7 and MADCAM1 in gut tissue biopsies from small and large bowel with respect to the underlying severity of tissue inflammation.

Methods:
Differential gene expression analysis was conducted using bulk RNA Sequencing data generated from gut tissue biopsies of the large and small intestine of 611 CD and 315 UC patients enrolled in a multicentred longitudinal Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) obtained from the IBD Plexus program of the Crohn’s and Colitis Foundation. Gene expression levels of ITGA4, ITGB7 and MADCAM1 were compared across ileal, colonic and rectal segments of the intestine and data were then linked to available measures of local inflammation.

Results

Results:
ITGA4, ITGB7 and MADCAM1 were expressed at comparable levels in large vs small bowel biopsies. Expression of MADCAM1 was significantly increased in both ileal and colonic biopsies from patients with moderate to severe CD based on segmental or composite endoscopy score (SES-CD) across all bowel segments. Expression of both ITGA4 and ITGB7 was similarly increased in colonic biopsies of moderate/severe CD patients, whereas only minor changes were observed for both genes in ileal biopsies. Similar findings were obtained from UC patients, where expression of MADCAM1 was significantly increased in inflamed or ulcerated biopsies from both sigmoid colon and cecum as compared to normal appearing biopsies. Expression of ITGA4 and ITGB7 was only increased in inflamed/ulcerated biopsies of the sigmoid colon but not the cecum and correlated with the modified Mayo endoscopic score (MMES).

Conclusion

Conclusion:
Our analysis suggests that influx of leukocytes to inflamed tissue via ITGA4/ITGB7 and MADCAM1 interactions is more common in the distal colon compared to proximal colon or ileum. This provides a possible mechanistic explanation as to why VDZ is most effective in patients with colonic IBD. Further work is needed to understand the differential regulation of cell trafficking to different regions of the gut.