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

Irritable bowel syndrome is one of the most common Disorders of gut-brain interaction, with diarrhea being the predominant subtype. At present, there are limited drugs for effective management of irritable bowel syndrome.
Compound glutamine entersoluble capsules are composed of traditional chinese medicine formulas Sijunzi Tang and L-glutamine. The Sijunzi Tang, which has been used in traditional complementary and alternative integrated medicine, has been used for the treatment of irritable bowel syndrome for many years. However, there is a lack of evidence from modern evidence-based medicine, its clinical efficacy and safety need to be confirmed. L-glutamine has the function of repairing damaged intestinal mucosa.

Aims & Methods

This study performed a multicenter randomized double-blind placebo-controlled withdrawal trial to explore the effectiveness and safety of compound glutamine entersoluble capsules in the treatment of diarrhea predominant irritable bowel syndrome.
The selected participants received the investigational drug for four weeks during the first single arm stage. The responding participants were randomly assigned to the compound glutamine entersoluble capsules and placebo groups in a 1:1 ratio for another 4 weeks.
The primary efficacy endpoint of the study was the response rate of both the improvement in abdominal pain and bowel movements after treatment in randomized controlled trial subjects (50% of the treatment course met the requirement of at least 30% improvement in abdominal pain severity (NRS pain score) and a reduction of at least 50% in bowel movement days for Bristol 6 or 7 types).

Results

A total of 558 subjects in 22 centers, of which 493 subjects were successfully screened and entered the placebo introduction period. During the placebo introduction period, there were a total of 493 subjects, of which 481 subjects were successfully rescreened and entered the single arm period. 437 subjects entered the randomized controlled trial period and were randomly divided into a treatment group of 217 subjects and a placebo group of 220 subjects.
For the primary efficacy endpoint, the number of response cases in the experimental group and placebo group were 114 (54.55%) and 89 (41.20%), respectively (P=0.0059). For secondary efficacy endpoints: (1) The number of improvements in NRS pain scores in the experimental group and placebo group were 138 (66.03%) and 107 (49.54%), respectively (P=0.0006); (2) The number of improved bowel movements in the experimental group and placebo group were 157 (75.12%) and 118 (54.63%), respectively (P<0.0001); (3) The median (quartile) relative baseline change of IBS-SSS scale in the experimental group was -47.00 (-97.00, -14.00) points; The median (quartile) relative baseline change in the placebo group was -17.00 (-63.00, 16.00) points, and there was a statistically significant difference between the two groups (P<0.0001); (4) The median (quartile) relative baseline change of IBS-QOL in the experimental group was -11.46 (-43.01, 0.00) points; The median (quartile) relative baseline change in the placebo group was -3.57 (-39.43,0.00) points (P=0.0007).
During the randomized controlled trial period, the incidence of all adverse events in the 217 subjects in the trial group was 18.89%, the placebo group was 22.27%, the incidence of TEAEs related to the drug in the trial group was 2.30%, and the placebo group was 3.18%.

Conclusion

Compound glutamine entersoluble capsule can effectively improve the clinical symptoms of diarrhea predominant irritable bowel syndrome with a satisfactory safety.

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.

Introduction

Current IBD therapy regimens are still frequently inefficient, can exert severe side effects, and loss of treatment response is common. Thus, the development of novel therapeutic approaches is an unmet clinical need – especially for patients featuring a primary non-response, refractory disease and/or severe side effects. Here we assessed novel small molecule inhibitors targeting a4b7 integrin or IRAK4 regarding their efficacy to relieve colitis in a model of spontaneous intestinal inflammation either as a stand-alone treatment or in combination.

Aims & Methods

IL-10 knockout (IL-10KO) mice, which develop spontaneous immune-driven intestinal inflammation resembling human IBD, were used for all studies. Mice with established disease were fed for three weeks ad libitum with control chow or chow containing the inhibitors at two previously defined concentrations: a higher concentration intended to induce optimal treatment response or a lower, sub-optimal concentration that did not induce therapeutic effect as stand-alone therapy.

Results

When administered as stand-alone treatment at the higher dose, a4b7 and IRAK4 inhibitors both significantly reduced colitis severity (reduced endoscopic and histological colitis scores [p<0.001 and p<0.01], reduced disease activity index scores [p<0.001]). This effect was accompanied by a normalization of immune cell populations in the colonic lamina propria. Particularly, we found reduced numbers of granulocytes, Th1, Th17, and cytotoxic T cell sin a4b7 and IRAK4 treated mice. Furthermore, mRNA and protein levels of inflammatory cytokines (IFNg, IL17, TNFa and IL-1b) were normalized in intestinal tissue of a4b7 and IRAK4 inhibitor-treated mice (p<0.01, each). When administered in lower concentrations, however, the a4b7 and IRAK4 inhibitors were not able to reduce disease activity as a stand-alone treatment. Of note, a combination of the low doses of the a4b7 inhibitor and the IRAK4 inhibitor significantly reduced the disease severity as evidenced by reduced endoscopic and histologic colitis scores [p<0.001, each], reduced disease activity scores [p<0.01] and a normalization of immune cell infiltrates (reduced levels of granulocytes [p<0.001], Th1 cells [p<0.001], Th17 cells [p<0.001] and less IFNg+ CD8 T cells [p<0.001]). Furthermore, while low doses of anti-IL12/23 p40 antibody were not able to reduce disease severity as a stand-alone treatment, combination of low-dose anti-IL12/23 p40 with the low dose of the a4b7 inhibitor resulted in amelioration of colitis (normalized endoscopic [p<0.001] and histologic [p<0.01] colitis scores, reduced infiltration of granulocytes, Th1, Th17 and IFNg+ CD8 T cells [p<0.01, each], normalization of IFNg, TNFa and IL-1b protein and mRNA levels in the intestine).

Conclusion

Our results demonstrate that small molecule inhibitors for a4b7 and IRAK4 were efficient in reducing colitis in a model of spontaneous immune-cell driven intestinal inflammation. Combination of the a4b7 inhibitor with low doses of the IRAK4 inhibitor or sub-optimal doses of an anti-IL12/IL23 antibody was effective to relieve the disease in the IL-10-KO model. This indicates that combination treatment of a4b7 inhibition with other immune-modulatory drugs, such as IL12/23 neutralization or IRAK4 inhibition might be a promising approach for patients that do not respond to single therapies. Furthermore, our results indicate that combination therapy is able to induce significant disease-relieving effects when the drugs are administered in low concentrations what could minimize side effects without interfering with treatment response.

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

During and following the COVID-19 pandemic, there has been a major expansion of self-administered subcutaneous biologics for the management of inflammatory bowel disease. These agents are more difficult to monitor since patients do not need to attend the Biologics infusion unit and there is no audit trail to confirm administration of the drug at the scheduled time points.

Aims & Methods

Following a successful NHS D&I bid for funding, a pilot proof of concept project to assess the feasibility and uptake of a digital technology (Health Beacon Digital Sharps Box®) to record and monitor subcutaneous injectable pen use was implemented in 50 consecutive IBD patients who were being treated with subcutaneous infliximab (Remsima®), Adalimumab (Amgevita®) or Vedolizumab (Entyvio®), on a 2-weekly schedule. The Health Beacon ICMS is comprised of a Smart Sharps Bin, pre-programmed with a patient’s individual treatment schedule. The bin electronically captures each time a used injection is disposed of, to create a time-stamped record as a proxy for medication adherence. This is accompanied by Health Beacon’s Companion App and Care Team support. Patients were also sent electronic dose reminders if they failed to dispose of a scheduled injection within certain time periods. Adherence data from the HealthBeacon ICMS, as well as patient satisfaction, transmission reports of data to

Results

Of 50 patients invited to join the programme, 45 registered patients had complete record of 6 months follow up; 4 patients deactivated recruitment and 1 left the programme. 21 patients were on Vedolizumab, 18 on Adalimumab and 8 on Infliximab, all 2-weekly SC injection. 45% patients were in the 36-50year age group, with the remaining spread between 18-75 years. M: F=21:24. Of 418 scheduled drops, 360 were made, with overall adherence being 86%. On time adherence was 76%. The study showed that up to 24% pts on SC Biologics at home delay their scheduled drug administration. Patient satisfaction was high. Reasons for delay in administration included forgetting, being away from home and being busy. Reminders were acknowledged.

Conclusion

This is the first study to our knowledge exploring adherence to subcutaneous biologics at home for IBD. It showed that a digital injection monitoring and support system is useful and acceptable to track adherence. Of the patients involved in the study there is an overall adherence of 90%, with up to 24% patients delaying their scheduled administration. Further studies are needed to analyse patient behaviour and impact on disease course.

Disclosure

Anjan Dhar has been paid an honorarium as a Speaker for presenting this abstract the a Health Beacon Meeting