Introduction

The therapeutic goal in inflammatory bowel disease (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), is the control of the inflammatory process through drugs (biologic and JAK-inhibitor therapies) that generally have a high cost and may have side effects. Unfortunately, only one-third of patients respond to these treatments and there are no markers that accurately predict this response.

Aims & Methods

The aim of this study was to identify potential serum metabolic biomarkers predictive of response to different drugs for IBD at baseline (before treatment), which could facilitate the selection of the most appropriate therapy for each patient. For this purpose, a prospective and multicenter study was conducted including CD and UC patients who initiate biologic (anti-TNF, ustekinumab or vedolizumab) or JAK-inhibitor (tofacitinib) therapies. Patients were assessed at 14 weeks to determine if they had achieved endoscopic response, based on the SES-CD and on the endoscopic sub score of the Partial Mayo Score. The analysis of the serum metabolome and deconvolution of the serum lipoprotein profile into 110 fractions were conducted using nuclear magnetic resonance for quantitative differential analysis comparing baseline serum samples of responders compared with non-responders.

Results

A total of 150 patients were included (30 CD anti-TNF, 30 UC anti-TNF, 30 CD ustekinumab, 30 UC vedolizumab, and 30 UC tofacitinib). Table 1 shows a summary of the most relevant results obtained during the metabolomic analysis, which revealed metabolites and lipoproteins (common or drug-specific) with significantly altered levels (p<0.05) in the baseline serum samples of subsequent responders compared to non-responders. Moreover, based on ROC curves, potential biomarkers with good sensitivity and specificity for distinguishing between responders and non-responders before treatment were identified. Finally, our analysis identified alanine, aspartate, glutamate, arginine and butanoate metabolism, and the citrate cycle, as the main baseline altered metabolic pathways that could be associated with the response to IBD treatment.

Table 1. Summary of identified potential metabolic biomarkers predictive of endoscopic response to IBD treatment.

Study group	Number of Biomarkers*		Best AUC values**
	Metabolites	Lipoproteins
CD anti-TNF	2	3	0.83; 0.81; 0.78; 0.75; 0.74
UC anti-TNF	1	7	0.88; 0.84; 0.83; 0.77; 0.76; 0.73
CD ustekinumab	4	24	0.96; 0.95; 0.94; 0.91; 0.90; 0.89; 0.87; 0.80
UC vedolizumab	5	8	0.90; 0.79; 0.78
UC tofacitinib	3	8	0.98; 0.96; 0.91; 0.88; 0.87; 0.85

​*Biomarkers with significantly altered levels (p<0.05) in the baseline serum of responders vs non-responders patients. **AUC corresponding to the biomarkers with the best sensitivity and specificity for distinguishing between responders and non-responders patients before treatment. AUC: Area Under the Curve calculated using the Metabolanalyst software in univariate analysis; CD: Crohn's disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis.

Conclusion

The present study represents an effort towards personalized medicine in targeted therapy selection in IBD patients, which is an important unmet need. Although it needs further validation, we were able to identify a number of serum metabolites and lipoproteins with the potential of predicting response to biologic and JAK-inhibitor therapies.

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

The efficacy and safety of risankizumab (RZB), an anti-interleukin 23p19 monoclonal antibody, as induction and maintenance therapy for adults with moderately to severely active ulcerative colitis (UC) was recently reported.^1,2 Influences of baseline disease characteristics on clinical outcomes are important to consider when optimizing UC treatment. Herein we analyze the efficacy of RZB stratified by baseline UC disease characteristics.

Aims & Methods

In the 12-week phase 3 INSPIRE induction study (NCT03398148) patients with moderately to severely active UC were randomized 2:1 to receive intravenous (IV) RZB 1200 mg or placebo (PBO) at weeks 0, 4, and 8. Patients with clinical response to RZB IV induction at week 12 or 24 in the phase 2b/3 induction studies were randomized 1:1:1 to receive subcutaneous (SC) RZB 180 mg, RZB 360 mg, or PBO (RZB withdrawal) every 8 weeks in the 52-week phase 3 COMMAND maintenance study (NCT03398135). This post hoc analysis evaluates clinical response, clinical remission, endoscopic remission, endoscopic improvement, and histological-endoscopic mucosal improvement (HEMI) at week 12 and 52 in subgroups stratified by baseline disease characteristics (Adapted Mayo score, pancolitis, high‑sensitivity C‑reactive protein [hs‑CRP], Mayo endoscopic subscore [ES], and disease duration).

Results

The induction analysis included 650 and 325 patients who received RZB 1200 mg IV and PBO IV, respectively. The maintenance analysis included 179, 186, and 183 patients who received RZB 180 mg SC, RZB 360 mg SC, and PBO (RZB withdrawal) SC, respectively. At induction week 12, the proportions of patients receiving RZB 1200 mg IV who achieved clinical response were numerically higher for the following baseline characteristic subgroups: pancolitis absence (70.5%) vs pancolitis presence (58.4%), Mayo ES of 2 (75.5%) vs Mayo ES of 3 (59.0%), and hs-CRP ≤ 5 mg/mL (68.9%) vs hs-CRP > 5 mg/mL (57.3%); the proportions of patients receiving RZB 1200 mg IV who achieved clinical remission at induction week 12 were also numerically higher for subgroups with pancolitis absence (25.3%) vs pancolitis presence (15.6%), Mayo ES of 2 (31.7%) vs Mayo ES of 3 (14.9%), and hs-CRP ≤ 5 mg/mL (23.7%) vs hs-CRP > 5 mg/mL (14.5%; Table). Differences in outcomes were not observed between subgroups stratified by Adapted Mayo score or disease duration. At week 52 of the maintenance study, there was no impact of baseline disease characteristics on achievement of clinical response and clinical remission with RZB (Table).

Conclusion

RZB induction and maintenance therapy improved clinical outcomes, regardless of baseline disease characteristics. Numerically higher RZB induction efficacy was observed for patients with no baseline pancolitis, Mayo ES of 2, and hs‑CRP ≤ 5 mg/L. These trends are consistent with prior observations that patients with milder UC disease phenotypes tend to be more responsive to therapy.

Table. Clinical Response and Clinical Remission by Baseline Disease Characteristics
Subgroup Patients, % (95% CI)	Induction Week 12			Maintenance Week 52
		Clinical Response	Clinical Remission		Clinical Response	Clinical Remission
AMS ≤ 7 > 7	PBO RZB 1200 mg IV PBO RZB 1200 mg IV	31.1 (24.5, 37.6) 63.8 (59.4, 70.7) 42.2 (33.9, 50.6) 65.1 (59.4, 70.7)	8.0 (4.1, 11.9) 22.6 (18.4, 26.8) 3.7 (0.5, 6.9) 17.2 (12.7, 21.7)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	57.6 (47.5, 67.7) 66.7 (57.5, 75.8) 63.3 (54.3, 72.4) 42.6 (35.9, 56.4) 70.1 (59.9, 80.4) 61.0 (50.1, 71.9)	29.3 (20.0, 38.7) 41.1 (31.5, 50.6) 36.7 (27.6, 45.7) 20.9 (12.5, 29.2) 39.0 (28.1, 49.9) 39.0 (28.1, 49.9)
Pancolitis Yes No	PBO RZB 1200 mg IV PBO RZB 1200 mg IV	32.8 (25.8, 39.7) 58.4 (53.1, 63.7) 39.1 (31.3, 46.9) 70.5 (65.4, 75.5)	6.5 (2.8, 10.1) 15.6 (11.7, 19.5) 6.0 (2.2, 9.7) 25.3 (20.5, 30.1)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	44.9 (35.1, 54.7) 64.9 (55.2, 74.5) 62.8 (53.0, 72.5) 60.0 (49.3, 70.4) 71.8 (62.2, 81.3) 61.9 (52.0, 71.9)	19.4 (11.6, 27.2) 40.4 (30.5, 50.3) 36.2 (26.5, 45.9) 31.8 (21.9, 41.7) 39.9 (29.4, 50.3) 39.1 (29.2, 49.1)
hs-CRP, mg/L ≤ 5 > 5	PBO RZB 1200 mg IV PBO RZB 1200 mg IV	39.0 (31.8, 46.2) 68.9 (64.3, 73.5) 30.5 (22.9, 38.1) 57.3 (51.1, 63.5)	7.5 (3.6, 11.4) 23.7 (19.4, 27.9) 4.3 (0.9, 7.6) 14.5 (10.1, 18.8)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	58.5 (48.6, 68.5) 62.2 (52.2, 72.2) 67.5 (59.0, 76.0) 47.1 (36.4, 57.7) 73.6 (64.3, 82.8) 53.7 (41.8, 65.7)	28.7 (19.6, 37.9) 42.2 (32.0, 52.4) 41.9 (32.9, 50.8) 22.4 (13.5, 31.2) 37.8 (27.6, 48.0) 31.3 (20.2, 42.5)
Mayo ES 2 3	PBO RZB 1200 mg IV PBO RZB 1200 mg IV	38.3 (28.5, 48.1) 75.5 (69.6, 81.3) 34.6 (28.5, 40.8) 59.0 (54.4, 63.6)	8.5 (2.9, 14.2) 31.7 (25.4, 38.4) 5.3 (2.4, 8.2) 14.9 (11.6, 18.3)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	59.6 (46.3, 73.0) 80.9 (69.6, 92.1) 66.7 (55.0, 78.3) 48.9 (40.3, 57.4) 63.6 (55.4, 71.8) 60.1 (51.5, 68.8)	32.7 (19.9, 45.4) 57.4 (43.3, 71.6) 39.7 (27.6, 51.8) 22.1 (15.0, 29.2) 34.0 (25.9, 42.1) 36.6 (28.1, 45.1)
Duration, years < 2 2–5 5–10 > 10	PBO RZB 1200 mg IV PBO RZB 1200 mg IV PBO RZB 1200 mg IV PBO RZB 1200 mg IV	42.9 (29.9, 55.8) 66.0 (57.0, 75.1) 32.5 (22.0, 42.9) 63.4 (56.5, 70.4) 32.3 (23.1, 41.5) 64.9 (58.0, 71.8) 37.6 (27.8, 47.5) 63.4 (56.2, 70.6)	5.4 (0, 11.3) 25.5 (17.2, 33.8) 9.4 (2.8, 16.0) 19.9 (14.2, 25.6) 2.0 (0, 4.8) 21.5 (15.6, 27.4) 8.6 (2.9, 14.3) 16.3 (10.8, 21.8)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	60.9 (40.9, 80.8) 70.4 (53.1, 87.6) 75.0 (53.8, 96.2) 35.3 (22.2, 48.4) 59.1 (44.6, 73.6) 66.6 (54.0, 79.2) 60.0 (47.6, 72.4) 76.5 (64.8, 88.1) 50.0 (34.9, 65.1) 55.1 (41.2, 69.0) 66.7 (54.4, 78.9) 63.5 (52.5, 74.5)	26.1 (8.1, 44.0) 55.2 (36.3, 74.1) 37.5 (13.8, 61.2) 17.6 (7.2, 28.1) 38.6 (24.2, 53.0) 40.7 (27.6, 53.8) 36.7 (24.5, 48.9) 51.0 (37.3, 64.7) 31.0 (17.0, 44.9) 18.4 (7.5, 29.2) 24.6 (13.4, 35.7) 39.2 (28.1, 50.3)
AMS, Adapted Mayo score; ES, endoscopic subscore; hs-CRP, high-sensitivity C-reactive protein; IV, intravenous; PBO, placebo; RBS, rectal bleeding subscore; RZB, risankizumab; SC, subcutaneous; SFS, stool frequency subscore. Data are reported using nonresponder imputation while incorporating multiple imputation to handle missing data due to COVID-19 or the geo‑political conflict in Ukraine and surrounding impacted regions. Clinical response is defined as a decrease in AMS that is ≥ 2 points and ≥ 30% from baseline plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1. Clinical remission is defined as SFS ≤ 1 (and not greater than baseline), RBS = 0, and endoscopic subscore ≤ 1 without evidence of friability.

References

1. Louis E, et al. United Eur Gastroenterol J . 2023;11(S8):26–28. Abstract OP021.
2. Louis E, et al. J Crohns Colitis. 2024;18(S1):i10–12. Abstract OP06.

Disclosure

CH has served as a consultant, advisor, and/or has received education funds from AbbVie, Bausch Health, BMS, the Helmsley Charitable Trust, Janssen, Pfizer, Roivant, and Takeda.
MDL has received consulting fees and/or research grants from AbbVie, BMS, Intercept, Janssen, Lilly, Pfizer, Prometheus, Takeda, and Target RWE.
SRF has served as a consultant or advisor for AbbVie, Janssen, MSD, Takeda, Tillots, and Vitoria.
TF has received research grants and/or speaking honoraria from AbbVie, Ajinomoto, Alfresa, BI, BMS, Celgene, Celltrion, Daiichi Sankyo, EA Pharma, Eisai, Gilead, Janssen, Kissei, Kyorin, Kyowa Hakko Kirin, Lilly, Mebix, Mitsubishi Tanabe, Mochida, Nichiiko, Nippon Kayaku, Pfizer, Sanofi, Taiho, Takeda, and Zeria.
ZR has no disclosures to report.
JK, PL, SC, LC, RV, and PMH are employees of AbbVie and may hold AbbVie stock and/or stock options.
FA-A has served as a consultant and/or has received grants and speaker fees from AbbVie, Celltrion, Kern, MSD, and Takeda.
RA has served as a consultant or advisor for AbbVie, AstraZeneca, BI, Biogen, BMS, CED-Service GmbH, Celltrion, Falk Foundation, Galapagos, Gilead, InDex, Janssen-Cilag, Lilly, MSD, Roche, and Takeda.
Funding
AbbVie funded this study and participated in the study design, research, data collection, analysis, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and the authors thank all trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Morgan A Gingerich, PhD, of JB Ashtin, and funded by AbbVie, and Karen Chien, PhD, of AbbVie.

Introduction

Obefazimod is an investigational, oral, once-daily (od), small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obefazimod demonstrated efficacy and safety in patients with UC at week-8 in a placebo-controlled, Phase 2b induction trial and in the subsequent open-label maintenance (OLM) study [2]. Here we present results for effects of obefazimod induction on histologic and combined histologic and endoscopic outcomes at week 8.

Aims & Methods

Patients with a modified Mayo score of 5-9 and a centrally read Mayo endoscopy subscore ≥2 at induction baseline were randomized 1:1:1:1 to receive either obefazimod 25mg, 50mg or 100mg od or placebo. Rectal or sigmoidal biopsies were collected during endoscopy at baseline and week 8 to evaluate treatment effect on histopathology scores utilizing the Geboes Index. Histologic improvement (Geboes histologic score ≤3.1), and histo-endoscopic mucosal improvement (Geboes histologic score ≤3.1 + Mayo endoscopy subscore of 0 or 1 with no friability; HEMI) were evaluated at week 8.

Results

Of the 252 patients randomized (with a mean age of 41.2 years; 41.3% female; mean UC disease duration of 8.05 years), 188 received obefazimod treatment, and 64 were administered a placebo. Baseline demographics, disease characteristics and histologic activity were consistent across treatment groups. The proportion of patients with histologic improvement at week 8 was 43% among obefazimod-treated patients (all doses) and 31% among those receiving placebo (Table 1). The proportion of patients with endoscopic improvement at week 8 was 35% among obefazimod-treated patients (all doses) and 13% among those receiving placebo. The proportion of obefazimod-treated patients who achieved HEMI at week 8 was greater than placebo-treated patients (27% vs 13%, respectively). Consistently positive histological outcomes were observed when evaluating all three obefazimod induction doses individually compared to placebo (Table 1).

Table 1: Histologic and combined histologic and endoscopic outcomes at week 8

1: Histological improvement: Neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system (ie, Geboes histologic score ≤3.1); 2: Endoscopic improvement: endoscopic sub-score ≤1; 3: Histo-endoscopic mucosal improvement: A combination of histologic improvement (ie, Geboes histologic score ≤ 3.1) and endoscopic improvement (Mayo endoscopy subscore of 0 or 1 with no friability).

Conclusion

In this Phase 2b induction trial, patients with moderately to severely active UC treated with obefazimod experienced clinically meaningful improvements in histologic and combined histologic and endoscopic outcomes at week 8.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.

Disclosure

Bruce E Sands has served as a consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio, and stock options from Ventyx Biosciences.
Séverine Vermeire has received grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; SV has received consulting and/or speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.
Laurent Peyrin-Biroulet has received grants from Celltrion, Fresenius Kabi, Takeda; LPB has served as a consultant or received speaker’s fees from Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, Connect Biopharm , Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilea, Gossamer Bio, GSK, Hac Pharm, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopa, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vifor, Vectivbio, Ventyx, Ysopia.
Silvio Danese has served as consultant or received speaker’s fees from AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
Parambir Dulai received speaker’s fees from Abbvie, Abivax, Adiso, Bristol Meyer Squibb, Geneoscopy, GSK, Janssen, Lilly, Pfizer, Takeda.
Herbert Tilg has served as a consultant or received speaker’s fees from Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).

Introduction

Vedolizumab (VDZ) is a monoclonal antibody approved for use in both Crohn’s Disease (CD) and Ulcerative Colitis (UC). Some patients treated with VDZ have suboptimal disease response to induction and 8-weekly maintenance dosing. Dose intensification (DI) by shortening the dosing interval is a strategy used to improve response to treatment. This study aims to identify factors associated with DI in an Asian cohort of IBD patients.

Aims & Methods

This was a retrospective cohort study performed in a single tertiary center in Singapore. Patients who received VDZ between Sept 2016 to Sept 2022 were identified from a prospectively maintained registry. Patient demographics, disease phenotype, treatment history and biochemical parameters were retrieved. Factors predictive of requiring DI were analysed. Statistical analysis was performed using SPSS v23.0.

Results

A total of 69 IBD patients who received VDZ were identified. Mean age was 57.1 years (SD=20.1). Males made up 63.1% of the cohort, with 3 patients (4.6%) being active smokers. Thirty-nine patients (60.0%) had prior exposure to immunomodulators, 32 patients (49.2%) had prior anti-tumour necrosis factor-alpha inhibitor exposure, 5 patients (7.7%) had prior ustekinumab exposure. None of the patients had prior exposure to small molecules.
A total of 4 patients (6.2%) had prior exposure to 2 biologic agents, 30 patients (45.2%) had prior exposure to 1 biologic agent, and 31 patients (47.7%) were biologic-naïve. Disease duration prior to VDZ use was 8.4 years (SD=8.0). VDZ treatment duration was 24.4 months (SD=19.2).
A total of 25 patients (10 CD, 15 UC) underwent DI. Time from induction to DI was 384.4 days (SD=301.2). Gender, active smoking status, age of diagnosis, previous treatment or biologic exposure, higher pre-induction C-reactive protein and stool calprotectin did not predict for need for DI. (Figure 1)
Four patients achieved clinical remission post induction but subsequently required DI. Fourteen patients underwent DI to Q6W dosing and 11 patients received Q4W dosing. Patient demographics are shown in Figure 2a.
Outcomes of DI at 52-weeks post DI is shown in Figure 2b. Eight patients (32.0%) achieved treatment endpoints of corticosteroid-free remission (n=2), biochemical remission (n=2) and endoscopic remission (n=4). Mean duration on VDZ with DI in CD was 9.9months (SD=9.1), and 35.9months (SD=19.9) in UC.
Ten patients were switched to another biologic. Five (2 UC, 3 CD) patients required surgery despite DI. One patient had recurrent Clostridium difficile infections while on VDZ. There were no other complications or hospitalizations associated with DI.

Conclusion

This is the first VDZ DI study in Asia. One third of patients who receive VDZ required DI, of which a third achieved remission by week 52. Some Asian patients with IBD may require DI to achieve remission.

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.