Introduction

Ozanimod was efficacious and well tolerated for up to 52 weeks in patients with moderately to severely active ulcerative colitis (UC) in the phase 3 True North study (NCT02435992).Type IV collagen, a major component of the intestinal basement membrane, is thought to be involved in the pathogenesis of UC.

Aims & Methods

This analysis assessed the effect of ozanimod on type IV collagen biomarkers and their association with ozanimod efficacy in True North. Patients in Cohort 1 were randomized to ozanimod (n=429) or placebo (n=216) and patients in Cohort 2 received open-label ozanimod (n=367) through Week 10. Ozanimod patients with clinical response at Week 10 were rerandomized to ozanimod (ozanimod/ozanimod, n=230) or placebo (ozanimod/placebo, n=227) through Week 52; placebo patients with clinical response at Week 10 continued placebo through Week 52 (n=69). Levels of biomarkers for type IV collagen formation (type IV collagen propeptide [PRO-C4]), degradation (granzyme B-degraded [C4G] and matrix metalloproteinase-degraded [C4M] type IV collagen), and turnover (PRO-C4/C4M ratio) were assessed at baseline, Week 10, and Week 52. Baseline and Week 10 disease activity scores, including rectal bleeding, stool frequency, Physician Global Assessment (PGA), and endoscopy subscores, and partial and total Mayo scores, were correlated to biomarker levels. Associations between type IV collagen biomarkers and disease activity were assessed using Spearman’s rho correlation.

Results

At Week 10, significant decreases in PRO-C4, C4G, and C4M and significant increases in PRO-C4/C4M were seen with ozanimod vs placebo (Table). C4M decreases and PRO-C4/C4M increases with ozanimod at Week 10 were significantly greater in patients with vs without Week 10 clinical response. Baseline C4M was significantly positively correlated and PRO-C4/C4M was significantly negatively correlated with all baseline disease activity scores except rectal bleeding. In ozanimod-treated patients, changes in PRO-C4 and C4M at Week 10 were significantly positively correlated with changes in all disease activity scores at Week 10 except rectal bleeding and PGA for PRO-C4, while changes in C4G and PRO-C4/C4M at Week 10 were significantly negatively correlated with changes in all disease activity scores at Week 10. Decreases in PRO-C4 and C4G continued through Week 52 and were significantly greater in ozanimod/ozanimod than ozanimod/placebo patients; decreases in C4M and increases in PRO-C4/C4M continued at Week 52 at similar levels in ozanimod/ozanimod and ozanimod/placebo patients (Table).

Conclusion

Ozanimod decreased type IV collagen degradation and increased turnover, which are effects associated with disease activity. The T-cell activity marker C4G showed the strongest, but delayed, decrease at Week 52, which is aligned with the mechanism of action of ozanimod. These findings support ozanimod involvement in modulating key molecules in intestinal epithelial barrier function, extracellular matrix remodeling, and T-cell activity in UC.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Anny Wu, PharmD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.
GD: served as an advisor for AbbVie, Agomab, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cytoki, Eli Lilly, Exeliom Biosciences, Galapagos, GlaxoSmithKline, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Takeda, Tillotts, and Ventyx; received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.
RM, CW, YH, JZ, AP, and SH: employees and/or shareholders of Bristol Myers Squibb.
BES: received consulting fees from AbbVie, Alimentiv, Amgen, Arena, Artugen, AstraZeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Enthera, Equillium, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, and Ventyx Biosciences; received consulting and speaker fees from Abivax; received consulting and speaker fees and other support from Eli Lilly; received research grants, consulting and speaker fees, and other support from Bristol Myers Squibb, Janssen, Pfizer, and Takeda; received research grants and consulting fees from Theravance Biopharma; received stock options from Ventyx Biosciences.
JHM: employed at Nordic Bioscience A/S, a company involved in the discovery and development of biochemical biomarkers.

Introduction

Etrasimod is an oral, once-daily (QD), selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). S1P₁ receptor modulation is believed to reversibly sequester lymphocytes¹; its impact on UC intestinal tissue is unknown.

Aims & Methods

We characterised the impact of etrasimod in inflamed colonic biopsy tissue using ribonucleic acid sequencing (RNA-seq) to examine transcriptional-level impacts on disease, in terms of mucosal barrier inflammatory pathways and immune cell populations. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (pts) aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg QD or placebo (PBO). Etrasimod treatment effects were characterised by RNA-seq at Week 12 vs baseline (both trials), and in responders achieving clinical remission vs nonresponders. CytoPro (CytoReason) was used for colon-specific cell type deconvolution analysis and single sample Geneset Enrichment Analysis was used for pathway analysis.

Results

At baseline in ELEVATE UC 52/ELEVATE UC 12, colon biopsy samples were available for 245/166 pts receiving etrasimod and 114/84 pts receiving PBO. There were significant reductions in T cell subsets (CD4+, CD8+, helper [Th]1 and Th17), plasma/mature B cell subsets and innate immune cell subsets (monocytes, macrophages, dendritic cells and natural killer cells) in the colon of pts receiving etrasimod (false discovery rate [FDR] < 0.05]); significant changes were not seen among pts receiving PBO. There were also reductions in inflammatory fibroblasts and increases in epithelial cells in the colon of pts receiving etrasimod but not PBO. The change in immune cell populations for responders vs nonresponders at Week 12 was similar to that for etrasimod Week 12 vs baseline. At Week 12, several inflammatory pathways were reduced in responders vs nonresponders to etrasimod; IL-17 signalling was among the most affected (both trials). Nonimmune pathways related to mucosal healing were significantly increased in Week 12 responders.

Conclusion

Decreases in activated immune cell subset and inflammatory signalling pathway changes in responders to etrasimod suggest reductions in local inflammation may contribute to remission and mucosal healing. RNA-seq with cell type deconvolution and pathway analysis contributes to the understanding of etrasimod’s mechanism of action.

References

1. Scott FL et al. Br J Pharmacol 2016; 173: 1778–1792.

Disclosure

BS has received lecture fees from AbbVie, CED Service GmbH, Chiesi, Dr. Falk, Forga Software, Galapagos, IBD Passport, Janssen, Materia Prima, Pfizer Inc and Lilly; consultancy fees from AbbVie, Arena Pharma, Boehringer Ingelheim, BMS, Celgene, CT-Scout, Endpoint Health, Galpagos, Gilead Sciences, Janssen, Landos, Lilly, Pfizer Inc, PredictImmune and PsiCro. RDR is an employee of and holds stock options with Pfizer Inc. CMC, XG and JCW are employees and shareholders of Pfizer Inc. MTA has received consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celsius, Eli Lilly, Gilead, Janssen, Microba Life Sciences, Pfizer, Prometheus, Prometheus Bioscience, Takeda and UCB Biopharma. SV has received lecture/speaker fees from AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda and Tillotts; consultancy/advisory fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena , AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG and Zealand Pharma; grant/research support from AbbVie, MSD, Pfizer Inc, Galapagos, Janssen and Takeda. ID has received consultancy fees, research grants or honoraria from Abbott, AbbVie, Altman, Arena, Athos, Cambridge Healthcare, Celgene/BMS, Celltrion, Falk Pharma, DSM, Ferring, Food Industries Organisation, Galapagos, Genentech/Roche, Gilead, GSK, Hospital for Sick Children, Integra Holdings, Iterative Scopes, Janssen, Mediahuset, Medscape, Neopharm, Nestle, Peer voice, Pfizer, Rafa Laboratories, Sangamo, Sublimity, Takeda, Wilbio. KMR has received grant/research support from Bristol Myers Squibb. HKK has received consultancy fees from Kinevant Sciences and is an employee/shareholder for Uniquity Bio. MG is an employee and shareholder of Pfizer AG. SD has received lecture/speaker fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer and Takeda; consultancy/advisory fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor; holds directorship/ownership for Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele.

Introduction

Ulcerative colitis (UC) is a chronic intestinal inflammatory disease mainly involving the mucosa and submucosa. The pathogenesis of UC has not been clearly elucidated and there are limitations of existing treatment measures. Dietary factors have been implicated closely related to the pathogenesis and clinical outcome of UC. Our team in the early clinical trials observed that UC patients had aggravation or recurrence of their disease after taking in lamb. However, the relationship between them is unclear. Does lamb aggravate the intestinal inflammation of UC patients? What is the mechanism if lamb has a negative impact on intestinal inflammation? It is urgent for us to study further.

Aims & Methods

We aimed to clarify the effect of lamb on intestinal inflammation in UC mice and to reveal the mechanism, so as to provide scientific basis for clinical dietary guidance for UC patients.
Mice were given 2.5% DSS (w/v) solution for 5 days and deionized water for 7 days for 1 cycle, repeated 3 cycles to establish the chronic UC model. Take the start of giving DSS solution as day1, corresponding measures of lamb suspensions at a dose of 0.25, 0.50, 1.00 g/mL or sterile water were administered for 31 days. Then the general condition and the severity of colitis were monitored. Colon tissues were obtained to assess the degree of pathological damage by HE staining and detect the levels of key factors of intestinal barrier by RT-qPCR. Spleen tissues were collected to detect the levels of M1/M2 macrophages and related factors by flow cytometry and RT-qPCR.

Results

Our results showed that lamb aggravated intestinal inflammation of UC mice, as indicated by higher weight loss and DAI, shorter colon and more severe pathological damage. Also, the colonic mechanical barrier-associated factors including ZO-1, Claudin-1, Occludin, E-cadherin mRNA and colonic mucosal barrier associated-factors such as Muc1, Muc2, Muc3 mRNA showed significant decrease in lamb-treated colitis mice. Moreover, colitis mice with lamb treatment showed significant increased M1 macrophages and reduced M2 macrophages in the spleen, leading to an increased the ratio of M1/M2 macrophage. Meanwhile, the M1 macrophage-associated inflammatory factors gene TNF-α, IL-6 mRNA increased and M2 macrophage-associated inflammatory factors gene IL-10, TGF-β mRNA decreased significantly in lamb-treated colitis mice.

Conclusion

Our results show that lamb aggravates the intestinal inflammation and damages the mucosal barrier of colitis mice, whose mechanism is related to the promotion of macrophages to M1 cells and inhibition M2 cells differentiation, thereby aggravating the imbalance of M1/M2 macrophages.

Introduction

Mucosa protective effects can be mediated by physical as well as by anti-inflammatory mechanisms of action. For the root extract of marshmallow (Althaea officinalis L., REAo), known to cure mild irritation of stomach/gut mucosa [1], only a physical action had been considered. Recent studies have shown that it also induces regeneration of irritated mucosa [2,3]. Mucosal wound healing depends on the recruitment of several cell types, e.g., endothelial cells, fibroblasts, and macrophages (MΦ). Reactive oxygen species (ROS)-induced damage is associated with mucosal infiltration of activated leukocytes, such as MΦ, which produce excessive ROS and pro-inflammatory cytokines that may overwhelm the antioxidant and immune defenses of the cells and exacerbate mucosal inflammation. Additionally, fibroblasts exhibit a metabolic adaptation to control inflammation-related oxidative stress.

Aims & Methods

We aimed to investigate whether REAo has, on top of its physical effects, also anti-inflammatory/-oxidative properties in human dermal fibroblasts (NHDF), human umbilical vein endothelial cells (HUVEC), and human acute monocytic leukemia (THP-1) differentiated MΦ, critical cellular components of the gastrointestinal and oral mucosa.

The cells were pre-treated with REAo or its final formulation STW 42, containing REAo and selected excipients, followed by incubation with H₂O (pro-oxidative) or lipopolysaccharide (LPS, pro-inflammatory). Intracellular ROS were quantified with DCFDA. The releases of IL-6 and TNF-α were determined by ELISA. THP-1 cells were differentiated into MΦ with 0.1 μg/ml phorbol-12-myristate-13-acetatefor 3–5 days.

Results

Pre-treatment (24 h) of HUVEC, NHDF or THP-1-MΦ with STW 42 or REAo (100-1000 μg/ml) significantly inhibited the H₂O-induced intracellular ROS production by 30.0% to 58.7%. Whereas 24h(HUVEC, NHDF) or 48 h (THP-1-MΦ) pre-treatment with STW 42 or REAo (100-1000 μg/ml) inhibited the LPS-activated IL6 release by 25.0-67.0%. Additionally, 48 h pre-treatment of THP-1-MΦ with 50-500 μg/ml STW 42 or REAo significantly inhibited LPS-induced TNF-α release by 21.5% (50 μg/ml) to 52.0% (500 μg/ml), in comparison with LPS-treated MΦ. The observed effects of STW 42 or REAo were similar to 25-100 μM Diclofenac, which was used as an anti-inflammatory control.

Conclusion

These anti-inflammatory and antioxidant properties may support the benefit of STW 42 and its constituent REAo in patients with mucosal irritation with subsequent irritative cough or gastric complaints due to its protective/reparative effects on the mucosa.

References

1. HMPC of EMA 2016. European Union herbal monograph on Althaea officinalis L., radix. EMA/HMPC/436679/2015
2. Deters A, Zippel J, Hellenbrand N, Pappai D, Possemeyer C, Hensel A. 2010. Aqueous extracts and polysaccharides from Marshmallow roots (Althea officinalis L.): Cellular internalisation and stimulation of cell physiology of human epithelial cells in vitro. J Ethnopharmacol. 127: 62-9. doi: 10.1016/j.jep.2009.09.050.
3. Bonaterra GA, Schmitt J, Schneider K, Schwarzbach H, Aziz-Kalbhenn H, Kelber O, Müller J, Kinscherf R. Phytohustil^® and root extract of Althaea officinalis L. exert anti-inflammatory and anti-oxidative properties and improve the migratory capacity of endothelial cells in vitro. Front Pharmacol. 2022 Dec 8;13:948248.
   

Disclosure

JS and NS have nothing to disclose. GAB and RK received project support from Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany. OK, HAK and KB are employees of Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany.

Introduction

The LIR!C trial demonstrated that laparoscopic ileocaecal resection (ICR) is a cost-effective alternative to infliximab therapy (IFX) in patients with uncomplicated ileocaecal Crohn’s disease (CD), with comparable quality of life outcomes. The aim of this study was to assess the 10-year follow-up of patients enrolled in the LIR!C trial.

Aims & Methods

This retrospective follow-up study included patients from the original LIR!C trial, a multicentre randomized controlled trial comparing ICR to IFX treatment in patients with ileal CD. Long term follow-up data were collected between February 3 and April 14, 2025. Data extraction was focused on initiation or switch of IBD treatments (corticosteroids, immunomodulators and/or advanced medical therapies) and (re)-resections. The follow-up period ranged from trial enrolment to the last visit with the gastroenterologist or surgeon. Primary outcomes were: (1) proportion of patients in clinical remission without therapy switch (no medical therapy or re-resection in the ICR group, and continuation or the cessation of IFX in case of remission in the IFX group), and (2) therapy-free remission, defined as clinical remission without IBD medication and (re)resections.

Results

Follow-up data were available from 60 ICR patients and 57 IFX patients (87% of 134 patients originally included). The median follow-up time was 12 years (IQR 9-14). The clinical remission rate without therapy switch was 40% in the ICR group compared to 26.3% in the IFX group (p=0.117). Of the 60 ICR patients, 24 (40%) had no additional therapy, 13 (21.7%) received an immunomodulator, 18 (30%) biological therapy and 5 (8.3%) underwent a second resection after biological treatment. In the IFX group, 33 (57.9%) required an ICR of whom 25 (75.8%) had previously received second-line biological treatment. Additionally, 7/57 patients (12.3%) were therapy free, 8 (14%) continued IFX treatment, 6 (10.5%) received other biological treatment, and 3 (5.3%) switched to an immunomodulator. Therapy-free remission was significantly higher in the ICR group when compared to the IFX group (40% vs 12%, p < 0.001).

Conclusion

After 10 years of follow-up, the clinical remission rate without therapy switch was comparable between both groups, highlighting the long-term durability of both treatment approaches. The majority of IFX patients needed ICR within 10 years of follow-up. 40% of the ICR group did not require any additional therapy further supporting ICR as first-line treatment option in ileal CD.

References

Ponsioen, C. Y., de Groof, E. J., Eshuis, E. J., Gardenbroek, T. J., Bossuyt, P. M. M., Hart, A., Warusavitarne, J., Buskens, C. J., van Bodegraven, A. A., Brink, M. A., Consten, E. C. J., van Wagensveld, B. A., Rijk, M. C. M., Crolla, R. M. P. H., Noomen, C. G., Houdijk, A. P. J., Mallant, R. C., Boom, M., Marsman, W. A., Stockmann, H. B., … LIR!C study group (2017). Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial. The lancet. Gastroenterology & hepatology, 2(11), 785–792. https://doi.org/10.1016/S2468-1253(17)30248-0

Disclosure

GD'H served as a consultant for AbbVie, Alimentiv, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Exeliom Biosciences, Johnson & Johnson, Pfizer, and Takeda; and has received speakers bureau fees from AbbVie, Eli Lilly, Pfizer, Bristol Myers Squibb, and Takeda.