Introduction

Tumor necrosis factor-like ligand 1A (TL1A) is a pleiotropic cytokine involved in immune-mediated pathways leading to inflammation and fibrosis. TEV-48574 is a human IgG1 monoclonal antibody that selectively inhibits TL1A binding to the death receptor 3 (DR3) with greater potency compared to the decoy receptor 3 (DcR3) which could preserve the natural homeostatic mechanism.¹ TEV-48574 has previously been shown to reduce fibrosis, inflammation, and mortality in animal models of asthma and IBD.¹ TEV-48574 is in clinical development as a potential treatment for ulcerative colitis and Crohn’s disease.

Aims & Methods

The objectives of the study were to characterize the pharmacokinetic properties of TEV-48574 and evaluate target engagement through analysis of free TL1A concentrations post-dose. Biologic-naïve male cynomolgus monkeys (n = 4) were each administered a single 5 mg/kg dose of TEV-48574 by subcutaneous (sc) injection. Serum samples were collected pre-dose and at selected time points up to last day of the study, Day 42. Serum samples were analyzed using ELISA to determine TEV-48574 concentrations and the presence of monkey anti-TEV-48574 antibodies (ADAs). Pharmacokinetic parameters were determined using non-compartmental methods, and free TL1A levels were measured using a ligand binding assay.

Results

Absorption following sc TEV-48574 administration was consistent, median T_max was 1 day with arange from 0.25 to 3 days, mean ± SD C_max was 42.2 ± 10.8 µg/mL. Mean t½ was 5.55 ± 4.10 days and AUC_0-∞ was 473 ± 134 day*µg/mL. ADAs were confirmed on day 14 in serum sample for 1 monkey and on Days 21 and 35 for serum samples from all 4 animals. Administration of TEV-48574 resulted in suppressed free TL1A levels immediately post-dosing. Free TL1A remained below the limit of quantitation until Day 21 and below pre-dose baseline values until Day 42.

Conclusion

TEV-48574 demonstrated an acceptable pharmacokinetic profile with maximum serum concentrations observed within 1 day post-dose of a single sc injection of 5 mg/kg TEV-48574 in 4 male cynomolgus monkeys. Target engagement was shown by a rapid and sustained TEV-48574-mediated suppression of free TL1A in serum, supporting further development of TEV-48574 in patients with ulcerative colitis and Crohn's disease.

References

1. Clarke AW, Poulton L, Shim D, et al. An anti-TL1A antibody for the treatment of asthma and inflammatory bowel disease. MABs.2018;10(4):664–677.

Disclosure

All authors are employees of Teva Global Research and Development. TEV-48574 is being developed in a partnership between Teva and Sanofi.

Introduction

A deeper understanding of the pathogenesis of UC has led to the emergence of new therapeutic strategies. One of them consists of targeted exposure with biological drugs to certain molecules that regulate the interaction between leukocytes and endothelial cells in the inflammatory zone (mainly leukocyte integrins and endothelial cell adhesion molecules of the immunoglobulin superfamily).

Aims & Methods

Purpose of the study: To study the content of adhesion molecules ICAM-1, ICAM-2 and L-selectin in the peripheral blood of patients with ulcerative colitis (UC) and the effect of vedolizumab (Intivio) on their levels.
Materials and methods: We examined 12 patients with moderate and severe forms of UC and the ineffectiveness of previous standard therapy. The severity of the UC attack was calculated according to the Mayo index. Antivio® 300 mg was administered to patients intravenously according to the attached instructions. The content of adhesion molecules in the peripheral blood was studied before and 6 weeks after the first injection of vedilizumab. The control group consisted of 15 healthy volunteers. The content of ICAM-1, ICAM-2 and L-selectin in blood serum was determined by multilayer ELISA analysis (Bender med.Systems, Austria). Statistical processing of the obtained results was carried out using SPSS 13.0 software.

Results

It was found that the initial levels of ICAM-1 (461.9±28.4 ng/ml), ICAM-2 (323.3±18.4 ng/ml) and sL-selectin (1650±12.25 U/ml) ) in the peripheral blood of patients with UC were increased (P<0.05 with control), the Mayo index was 9 points. After four infusions of Vedolizumab (week 14), the levels of soluble molecules decreased in 4 patients, with a predominant decrease in sL-selectin (201±9.32 ng/ml, 197±8.54 pg/ml and 1008±15.3 U/ml respectively). The Mayo index was 5 points. In 8 patients, by the 6th week of treatment, the levels of the studied adhesive molecules did not change, although the Mayo index decreased by 3 points.

Conclusion

The initial level of ICAM-1, ICAM-2 and sL-selectin in the peripheral blood of patients with severe forms of UC is increased. The dynamics of the synthesis of adhesive molecules by immunocompetent cells under the influence of the fourth administration of Vedolizumab may predict the possibility of continuing the administration of the drug.

Introduction

Fibrostenosis represents one of the major clinical complications of Crohn’s Disease (CD). However, the molecular mechanisms underlying intestinal fibrogenesis remain poorly understood and anti-fibrotic therapy has not yet been developed. Growing evidence supports that oxidative stress and the epithelial-mesenchymal transition (EMT) process contribute to the development and progression of fibrosis.

Aims & Methods

Based on these evidences, we assessed the role of lipids in fibrogenesis and whether mitochondria dysfunction can support fibrosis formation.
Spatial metabolomics analysis and adipophilin (ADFP) staining were performed on surgical specimens from fibrotic ileum and the surrounding region (healthy) derived from CD patients. Fibroblasts isolated from fibrotic and healthy ileum and human induced pluripotent stem cell-derived intestinal organoids (iHOs) were treated for 1-3 weeks with lipid mix (2%) and analyzed by RNA sequencing. Pathways significantly modulated were validated by RT-PCR, WB, FACS analysis, and proliferative, migratory and contraction assays, and mitochondrial functions by Seahorse analyzer.

Results

Spatial metabolomics revealed a significant accumulation of lipids characterized by very long-chain fatty acids in the fibrotic area compared to surrounding healthy regions, which was further confirmed by ADFP staining. RNA-seq analysis showed overlapping dysregulated pathways between healthy fibroblasts stimulated with lipids and fibrotic fibroblasts, in particular genes related to cell cycle, cytoskeletal reorganization, migration, contractility and cell metabolism (oxidative stress) which were further confirmed by functional assays. Among the genes related to oxidative stress, lipid stimulation significantly decreased NFE2L2 and promoted an increase in CPT1A, gene encoding for a fatty oxidation mediator.
Moreover, lipid-stimulated fibroblasts showed a reduction in mitochondrial respiration, particularly basal and maximal respiration, and spare respiratory capacity by Seahorse analysis. On the other hand, long exposure of iHOs to lipids promoted the EMT process through the upregulation of TWIST, ZEB, and VIM.

Conclusion

Lipid stimulation induced myofibroblast activation through oxidative stress and alteration of mitochondrial metabolism, and increased the expression of EMT transcription factors in intestinal epithelial cells (iHOs) that may support fibroblast-mediated pro-fibrotic activity. These data indicate that regulators of fatty acid oxidation involved in the fibrotic process may represent new potential targets for the treatment of fibrostenotic CD patients.

Introduction

Histopathological analysis of mucosal biopsies in ulcerative colitis (UC) is currently performed by pathologists on digital whole slide images (WSIs) or under the microscope; but established grading scales are not routinely employed and are subject to well-described intra- and inter-observer variations. Previously, we demonstrated that our Artificial Intelligence (AI) Tool can assign a Nancy Index (NI) [1] to a biopsy case with accuracy comparable to an expert pathologist [2]. Here we introduce the novel concepts of “smart tiling” and HeatMaps for comprehensive AI-powered assessment of WSIs and deploy these to describe a sample of WSIs.

Aims & Methods

We refer to a high-power location in a WSI as a ‘tile’, a fixed size region of interest of 1024 by 1024 pixels, with 0.5 microns per pixel in WSI with 20-fold magnification. Our previously validated AI Tool identifies tissue types, cell types (neutrophils, lymphocytes, plasmacytes), cell density, crypts, and ulcerations, and calculates an NI with high degree of agreement [2]. In this analysis, we ‘mapped’ the WSIs on a tile-by-tile basis and using the NIs, created a HeatMap of grades from NI 0 to 4. The NI for the WSI was selected on the basis of the most frequently appearing NI. We included fixed size tiles that contained more than 15% of tissue in them and excluded the rest. In this feasibility study, we processed 11 WSIs received from 2 different scanners, which resulted in a 1175 tile database.

Results

The average number of tiles per WSI was 107, with a range from 30 tiles (WSI with NI=0) to 203 tiles (WSI with NI=4). Every WSI contained multiple tiles with a variety of NIs. WSIs scored as NI= 3 or 4 contained on average 53 tiles of NI=4, 36 with NI=3, 16 with NI=2, and 8 with NI =1 and 8 with NI=0. WSIs scored as NI= 0-2 contained on average 16 tiles of NI=4, 5 with NI=3, 34 with NI=2, and 10 with NI =1 and 18 with NI=0. The average neutrophil or eosinophil / lymphocyte / plasmacyte counts per tile were: in WSIs with NI=0 15/22/52, in WSIs with NI=2 22/35/88, in WSI with NI=3 57/53/125, in WSI with NI=4 73/31/85. The average sum of neutrophils divided by the number of tiles in WSIs with NI=0 0.83, in WSIs with NI=2 1.92, in WSI with NI=3 20.3, in WSI with NI=4 25.6.

Conclusion

This is the first description of novel concepts for histopathological analysis of mucosal biopsies in UC with smart tiling and HeatMaps. We identified significant heterogeneity and variation among tiles and within WSIs in both degree of inflammation by the AI-determined NI, but also in cell types. These novel findings and automatic assessments provide new insight into the pathophysiology of UC and may allow for more reliable clinical assessments in our patients.

References

1. Marchal-Bressenot, A et al. Development and validation of the Nancy histological index for UC. Inflammatory Bowel Disease (2014). https://doi.org/10.1136/gutjnl-2015-310187
2. Peyrin-Biroulet, L et al. An artificial intelligence‐driven scoring system to measure histological disease activity in ulcerative colitis. United European Gastroenterology Journal (2024) https://doi.org/10.1002/ueg2.12562
3. Tanevski et al. Learning tissue representation by identification of persistent local patterns in spatial omics data. bioRxiv (2024). https://doi.org/10.1101/2024.03.06.58369

Footnote: David T Rubin and Viktor H Koelzer share joint first authorship. Laurent Peyrin-Biroulet and Olga Kubassova share joint last authorship.

Disclosure

DTR has received grant support from Takeda; and has served as a consultant for Abbvie, Altrubio, Apex, Avalo Therapeutics, Bristol-Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen Pharmaceuticals, Lilly, Pfizer, Samsung Neurologica, and Takeda. He serves on the Board of Trustees for the Crohn’s & Colitis Foundation and is on the Board of Directors for Cornerstones Health.
VHK has been a speaker for Indica Labs; has received research support/grants from Image Analysis Group and Roche; and other support from Sharing Progress in Cancer Care (invited chair).
WX has no disclosures.
BH, SA, and MF are employees of Takeda. CPdC, JH, and OK are employees of Image Analysis Group.
LPB has received consulting fees from AbbVie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki, Eli Lilly, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, H.A.C. Pharma, Image Analysis Group, InDex, Inotrem, Janssen, Medac, Merck Sharp and Dohme, Mopac, Morphic, Norgine, Novartis, OM Pharma, Ono Pharmaceutical, OSE Immunotherapeutics, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi , Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, and Ysopia; grants from Celltrion, Fresenius Kabi, and Takeda; lecture fees from AbbVie, Amgen, Arena, Biogen, Celltrion, Eli Lilly, Ferring, Galapagos, Genentech, Gilead, Janssen, Medac, Merck Sharp and Dohme, Pfizer, Sandoz, Takeda, Tillotts, Viatris, Vifor, and Ysopia; travel support from AbbVie, Amgen, Celltrion, Connect Biopharm, Eli Lilly, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Medac, Merck Sharp and Dohme, Pfizer, Sandoz, Takeda, Thermo Fisher, and Tillotts.
Funding: This study was sponsored by Takeda.
Acknowledgements: Medical writing support was provided by Paul Hassan, PhD, of Excel Scientific Solutions, and was funded by Takeda.

Introduction

Precision medicine aims to expand upon the summary average treatment effects reported in clinical trials by providing more refined, individualised estimates of treatment effects. The phase IIb TUSCANY-2 study (NCT04090411), which examined the efficacy and safety of afimkibart (RO7790121/RG6631; previously PF-06480605/RVT-3101), an anti-TL1A antibody, in patients (pts) with moderate to severe ulcerative colitis (UC), previously reported clinically meaningful treatment effects at UEGW 2024.¹ Here, we report post hoc analyses of the relationship between baseline clinical characteristics and Week 14 efficacy in pts enrolled in TUSCANY-2.

Aims & Methods

Pts were randomised to receive subcutaneous afimkibart 50mg, 150mg, 450mg or matched placebo (PBO) monthly during induction. In this post hoc analysis, all afimkibart doses were pooled, and the endpoint of interest was clinical remission by modified Mayo score (mMS; defined as stool frequency subscore=0 or 1; rectal bleeding subscore=0; and endoscopic subscore [ES]=0 or 1) at Week 14. Our investigation of more patient-specific treatment effects was guided by the Predictive Approaches to Treatment effect Heterogeneity (PATH) statement.² We developed a regularised logistic regression model to predict the probability of Week 14 remission and to help examine heterogeneity of treatment effects based on the following baseline characteristics: mMS, C-reactive protein (CRP), serum albumin, Robart’s Histopathology Index (RHI), number of failed advanced therapy classes, corticosteroid use, disease extent, disease duration, age and sex. Baseline faecal calprotectin (FCP) was investigated separately due to the extent of missing data.

Results

The proportion of pts achieving clinical remission by mMS at Week 14 in the afimkibart pooled dose arm was 32.5% (65/200; 90% confidence interval [CI]: 27.3 to 38.1) compared with 13.3% (6/45; 90% CI: 7.1 to 23.8) of pts in the PBO arm (treatment delta: 19.2%; 90% CI: 7.6 to 27.9). Based on calibrated predictions from the multivariate model, all of the individual TUSCANY-2 pts (both treated with PBO and afimkibart) had anywhere between a 2–76% probability of Week 14 remission at baseline. The clinical characteristics included in the model explained ~10% of the variability in the observed outcomes. There was no evidence that the clinical characteristics were associated with heterogeneous treatment effects on the relative scale (odds ratios appeared to be constant; p-value >0.5). On the clinically meaningful absolute scale, the treatment delta in the top 50% of pts with a higher baseline probability of remission (27–76%) was 28.5% (90% CI: 8 to 42; 45.2% in afimkibart pooled dose arm vs 16.7%, in PBO arm), compared with a treatment delta of 7.6% (90% CI: –7 to 18; 18.8% in afimkibart pooled dose arm vs 11.1%, in PBO arm) in pts with a lower baseline probability of remission (2–27%). Lower baseline CRP, lower RHI and higher serum albumin contributed to a greater probability of remission and absolute benefit from treatment with afimkibart.

Conclusion

Pts with inflammatory bowel disease (IBD) have diverse baseline characteristics that are associated with variability of treatment outcomes, yet clinicians rely on reported averages from clinical trials to make individual treatment decisions. This analysis demonstrates how precision medicine approaches, that account for diverse characteristics, may improve interpretation of positive IBD clinical trial results. Integrating genetic and novel biomarkers alongside clinical features could help to better predict individual outcomes for pts with IBD.

References

1. Danese S, et al. Presented at UEGW 2024 (Oral presentation OP079).
2. Kent D, et al. The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement. Ann Intern Med 2020;172:35–45.

Disclosure

This study was sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of the authors, was provided by Victoria Dagwell, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.
LP-B reports consulting or advisory role/board from AbbVie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Inc., Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion, Par' Immune, Pfizer, Prometheus, Protagonist, F. Hoffmann-La Roche Ltd, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx and Ysopia; speakers’ bureau from AbbVie, Alfasigma, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Inc., Gilead, Janssen, Kern Pharma, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots and Viatris. JRA reports consulting or advisory role/board from Janssen, Pfizer, AbbVie, Vedanta, Genentech, Inc., Seres Therapeutics, Ferring, GSK, Merck, Bristol Myers Squibb, Roivant, Celltrion, TRXBio and Shattuck Labs; speakers’ bureau from AbbVie and Janssen. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, F. Hoffmann-La Roche Ltd, Sandoz, Sublimity, Takeda, Teladoc Health, TiGenix, UCB, Vial and Vifor; lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer and Takeda. PSD reports employment at Northwestern University; consulting or advisory role/board from AbbVie, Adiso, Alimentiv, Celltrion, Genentech/Roche, Geneoscopy, Janssen, Shattuck and Takeda; research funding from Takeda and Bristol Myers Squibb. AB reports employment and stockholder from Pfizer. DEC reports employment and stock ownership from Pfizer. EP reports employment, stock or other ownership interests and patents, royalties, other intellectual property from Pfizer. SN reports employment and stock or other ownership interests from Pfizer. MSV reports employment and shareholder from Pfizer. KH reports no conflict of interest. LU reports employment at Genentech, Inc. CS reports employment, stock or other ownership interests from Genentech/Roche. DB reports employment at F. Hoffmann-La Roche Ltd. KL reports employment and stock or other ownership interests from Genentech, Inc. BES reports honoraria for consulting from AbbVie, Adiso, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen, AstraZeneca, Biolojic Design, Biora, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Enveda, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic, MRM Health, Nexus, Nimbus Discovery, Odyssey, OSE Immunotherapeutics, Palisade Bio, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist, Q32 Bio, Rasayana, Recludix, Reistone, Sanofi, Sorriso, Spyre, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union and Ventyx; consulting/speaking fees from Abivax; consulting/speaking fees/other support from Lilly; research grants/consulting/speaking fees/other support from Bristol Myers Squibb, Lilly, Janssen, Pfizer and Takeda; research grants/consulting fees from Janssen; stock/stock options from Ventyx.

Introduction

Short Bowel Syndrome (SBS) is a rare complex disease causing chronic intestinal failure (CIF) for which Parenteral Support (PS) is the reference treatment. Teduglutide (TED), a GLP-2 analogue, is available and reimbursed in France since 2015 for the treatment of SBS-CIF patients. The cost of this drug is very high and there is few data about the number of potential candidates in real life. The aim of the study was to analyze in a real-life setting the implementation of TED in a cohort of SBS-CIF patients as well as the treatment outcomes.

Aims & Methods

This work was a monocentric retrospective study conducted in an expert center of Home PS. We enrolled all patients with SBS-CIF followed in the center between 2015 and 2020. Two sub-populations were defined for this study: the prevalent population, composed of the patients who were already followed in the center before 2015, and the incident population, composed of the new patients who initiated follow-up in the center between 2015 and 2020. Treated and non-treated patients were compared using Wilcoxon-mann-withney or pearson chi2 tests. TED retention rate was calculated using Kaplan-Meier survival estimate.

Results

331 SBS-CIF patients were included in the study (156 prevalent and 175 incident patients). In total, 56 patients initiated a treatment with TED (16.9% of the cohort). 27.9% of prevalent patients initiated treatment, with an annual average rate of 4.3%, against 8.0% of incident patients, with an annual average rate of 2.5%. Treatment with TED allowed a median decrease of 60% (IQR 40-100) of PS volume in our cohort. The reduction of PS was significantly higher in the incident population than in the prevalent population (p=0.02). The long-term retention rate of treatment was 82% after 2 years, 67% after 3 years and 64% after 5 years. Among the non-treated patients, 50 patients (18.2%) were declared non suitable because of non-medical reasons (doubt about compliance, patient refusal, cognitive disorders).

Conclusion

In the prevalent population of SBS patients, more than a quarter of patients were treated with TED, against 8% of incident population. The treatment retention rate is higher than 80% after two years, which can be explained by the careful selection of patients that is important to examine. Furthermore, this real-life study confirms the efficacy of TED in the long term and reports a better response to TED in the incident population, suggesting a benefit of early treatment compared to late treatment.

Disclosure

Research support from Takeda

Introduction

Long-term real-life data on vedolizumab (VDZ) are scarce. In this study, we aim to evaluate the long-term outcomes of patients (pts) with inflammatory bowel disease (IBD) who received VDZ.

Aims & Methods

The LONG-LIVE is the long-term extension (LTE) of the LIVE study, including IBD pts who had started VDZ from 04 to 06/2017 at 47 Italian centres affiliated with IG-IBD, prospectively followed-up to 06/2019. For this study, data on therapy withdrawal, clinical and endoscopic activity, need for surgery/hospitalizations, deaths, and serious adverse events (SAEs) were retrospectively extracted from 07/2019 up to the last available follow-up (fup).

Results

Seven hundred eighty-two (70% of the original cohort) pts were enrolled in the LTE (394 CD, 388 UC), 316 (40%) of whom had already definitively discontinued VDZ; 43% were female, mean age was 53±16 years, mean disease duration was 17±9 years, 76% of patients were bioexposed to anti-TNFα therapy. Among the remaining 466 still receiving VDZ, 204 (44%) subsequently suspended VDZ permanently and 9 (2%) temporarily: mean VDZ therapy duration was 113±92 weeks and 311±60 weeks among those who suspended and those who continued VDZ, respectively. Mean therapy duration was 177±124 weeks (172±124 weeks for CD and 182±125 weeks for UC, with no significant differences); longer mean persistence was observed in bionaive vs bioexposed CD pts (197±123 vs 182±122 weeks, p<0.05), while no such difference was observed in UC pts (193.1±126 vs 190±122. week, p=ns). Among CD pts who continued VDZ throughout the entire LTE, 74% and 54% were in clinical and endoscopic remission, respectively, at the last fup; among UC pts who continued VDZ throughout the entire LTE, 79% and 50% were in clinical and endoscopic remission, respectively, at the last fup. During the LTE, CD pts had a higher risk of IBD-related hospitalizations (Hazard Ration, HR, 1.37, 95% Confidence Interval, CI, 1.04-1.72, p=0.027). Specifically, 153 (20%) pts (83 CD, 70 UC) were hospitalized to receive IBD-related surgery after a mean time of 136±87 weeks from VDZ start (for CD vs UC comparison, HR 1.17, 95% CI 0.85-1.60, p=ns); 85 (11%, 54 CD, 31 UC) pts underwent IBD-related hospitalization for non-surgical reasons (CD vs UC, HR 1.71, 95% CI 1.21-2.62, p=0.015). New or recurrent cancers were reported in 17 pts (the most common localization being 4 breast cancers and 3 gastrointestinal cancers): mean interval between first VDZ administration and cancer diagnosis was 214 (±95) weeks; 20 non-oncological SAEs were recorded in pts receiving VDZ, the most common being infections (n=7), mostly pneumonia (n=4). Finally, 15 deaths were reported (of which 9 occurred in patients still receiving VDZ); the most common causes of death were infections (n=5), cardiovascular diseases (n=5) and cancer (n=3).

Conclusion

About one-third of pts were still receiving VDZ after a fup of more than 6 years, with the majority of them being in clinical remission and more than 50% also having quiescent endoscopic activity at the last observation; bionaive CD patients had longer persistence compared to bioexposed ones. During the LTE, CD pts had higher rates of IBD-related hospitalizations; most hospitalizations were due to the necessity of surgery. SAEs were observed in a minority of patients and predominantly consisted of infections; the rates of cancer diagnosis are seemingly in line with those of the general population. Overall, our study strengthens the notion that vedolizumab is associated with a long-term real-life durability in terms of both effectiveness and safety.

Disclosure

Daniela Pugliese received speaker fees and/or advisory board from AbbVie, Galapagos, MSD, Takeda and Janssen, Pfizer. Giuseppe Privitera received consultancy fees from Alphasigma and Janssen. Alessandro Armuzzi: consulting and/or advisory board fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mitsubishi-Tanabe, Novartis, Pfizer, Roche, Sandoz, Samsung Bioepis, Takeda; and research grants from MSD, Pfizer, Takeda and Biogen.