Introduction

Etrasimod is an investigational, once-daily (QD), oral, selective sphingosine 1-phosphate (S1P)_1,4,5 receptor modulator in development to treat immune-mediated inflammatory disorders. CULTIVATE (NCT04173273) is a seamless phase 2/3 trial comprising 5 substudies designed to evaluate the efficacy, safety and tolerability of etrasimod in patients with moderately to severely active Crohn’s disease (CD).

Aims & Methods

Here, we report the induction data from the first substudy (Substudy A). Substudy A was a phase 2, randomised, double-blind study using a 14‑week induction period followed by a 52-week extension period. Adults (18–80 years) with moderately to severely active CD and an inadequate response, loss of response or intolerance to ≥1 conventional or advanced treatments for CD were randomised 1:1 to etrasimod 2 or 3 mg QD. Patients were stratified by baseline biologic failure status and oral corticosteroid use. The primary efficacy endpoint was achievement of endoscopic response (defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD score) at Week 14. Secondary/exploratory endpoints included achievement of endoscopic remission, clinical remission (CDAI <150) and IBDQ remission (IBDQ ≥170), at Week 14. Outcomes were analysed in the full analysis set (all randomised patients treated with ≥1 dose of etrasimod) using non-responder imputation or observed data.

Results

Of 83 patients randomised to either etrasimod 2 or 3 mg QD, 32/42 (76.2%) and 36/41 (87.8%) completed Week 14, respectively. Overall, 21.4% and 9.8% of patients receiving etrasimod 2 and 3 mg QD, respectively, achieved the primary endpoint of endoscopic response, 14.3% and 7.3% achieved endoscopic remission, 31.0% and 43.9% achieved clinical remission, and 33.3% and 40.0% achieved IBDQ remission at Week 14. Most TEAEs were mild or moderate. The incidence of serious TEAEs (4.8% and 2.4%) and TEAEs leading to discontinuation (4.8% and 7.3%) was low with etrasimod 2 and 3 mg QD, respectively (Table). Two patients randomized to etrasimod 3 mg QD experienced second-degree atrioventricular block type I TEAEs (one patient during 2-mg titration).

Conclusion

Data from this substudy of patients with moderately to severely active CD suggest endoscopic and clinical improvement with both etrasimod 2 and 3 mg QD. However, the small sample size and lack of a placebo arm limit the ability to draw conclusions about efficacy, including comparison between the etrasimod 2 and 3 mg groups. Both doses were well tolerated, and safety was consistent with other etrasimod clinical programmes. Data from the extension phase of Substudy A and the placebo-controlled, dose-ranging phase 2b Substudy 1 are forthcoming.

Disclosure

GD’H: advisor: AbbVie, AstraZeneca, Alimentiv, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson & Johnson, Takeda, Pfizer, Polpharma, Prometheus, Tillotts, Ventyx; speaker: AbbVie, Boehringer Ingelheim, Celltrion, Johnson & Johnson, Takeda, Pfizer, Tillotts.
MCD: grant/research: Janssen; consultancy: AbbVie, Arena, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, Trellus Health, UCB; shares/royalties: Trellus; directorship/ownership interests: Trellus.
LPB: grant/research: Takeda, Fresenius Kabi, Celltrion; consultancy: AbbVie, Alimentiv, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol-Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, HAC, IAG Image Analysis, Index, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; speaker: Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Eli Lilly, Gilead, Viatris, Medac, Sanofi; stock: CTMA.
SD: consultancy/advisory: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, Vifor; speaker: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda; directorship/ownership interests: Gastroenterology and Endoscopy.
BES: grant/research: Arena, Janssen. Lecture fees/Speakers Bureau: BMS, Janssen, Lilly, Pfizer, Takeda; consultancy/advisory: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer-Ingelheim, BMS, Celltrion, Fresenius Kabi, Genentech, GSK, Janssen, Lilly, Merck, Pfizer, Prometheus Biosciences, Sun Pharma Global, Takeda Pharmaceuticals International, Teva Branded Pharmaceutical Products R&D; stock: Ventyx Biosciences; non-financial support: Janssen, Lilly, Pfizer, Takeda.
DCW: grant/research: AbbVie, Arena, Bristol Myers Squibb, Janssen, Pfizer, Takeda, Ventyx; speaker: AbbVie, Bristol Myers, Squibb, Janssen, Pfizer, Takeda; consultancy: AbbVie, Arena, Bristol Myers Squibb, Janssen, Pfizer, Takeda.
AJY: consultancy: Pfizer, Arena, Takeda, Bristol-Myers Squibb; speaker: Bristol-Myers Squibb.
MVC: grant support: Pfizer, Janssen, Novartis, Bristol-Myers Squibb; consultancy fees: AbbVie, Arena, Bristol-Myers Squibb, Medtronic, Pfizer, Prometheus, Eli Lilly, Janssen, Takeda; speaker fees: AbbVie, Janssen, Medtronic, Pfizer, Bristol-Myers Squibb, Takeda.
DD: employee of Pfizer Inc at the time of the abstract.
IM, HT, GG, CS: employees & shareholders of Pfizer Inc.
CL, FC: employees of Pfizer Inc at the time of this analysis.
JZ: employee & shareholder of Arena Pharmaceuticals.
AMcD: employee & shareholder of Pfizer Ltd.
SS: speaker: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk, Fresenius, Janssen, MSD, Pfizer, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention, Takeda, Theravance.
BGF: consultant/advisory board: AbbVie, AbolerIS, AgomAB, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital, Atomwise, BIOJAMP, Biora, Boehringer Ingelheim, Boxer, Celsius, Celgene/Bristol-Myers Squibb, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, FirstWord, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge, HotSpot, InDex, Imhotex, Immunic, JAK, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K., Lenczner Slaght, LifeSci, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Diagnostics, Play to Know AG, Progenity, Protagonist, PTM, Q32, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts, Ventyx, VHSquared, Viatris, Ysios, YSOPIA, Zealand; speaker: AbbVie, Janssen, Takeda; Alimentiv Senior Scientific Director, provides central reading services; not a company employee, no equity stake; shareholder: Gossamer.
SV: grant/research: AbbVie, MSD, Pfizer, Galapagos, Takeda; consultancy/advisory: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, Zealand; speaker: AbbVie, Dr. Falk, Ferring, Hospira, MSD, Takeda, Tillotts.

Introduction

Autoimmune atrophic gastritis (AAG) leads to significant changes in the gastric mucosa, including hypo-achlorhydria and increased gastrin (G) levels, providing proliferative stimuli on the gastric mucosa (1-5).

Aims & Methods

The aim of our study is to evaluate the occurrence and characteristics of gastric polyps in AAG patients across six tertiary centers in Italy. We conducted a multicentric, cross-sectional study from January to June 2023, prospectively enrolling consecutive patients diagnosed with AAG, from January 2000 to June 2023, who underwent at least one endoscopy. Data on demographics, clinical history, biochemical profiles, serological data, and endoscopic and histopathological findings were collected.

Results

Among 612 AAG patients (73.9% female, median age 66) followed up for a median of 4 (IQR 2-7.5) years, 222 (36.3%) had at least one gastric polyp. Non-endocrine polyps (214) were found in 162 patients, including 151 (70.5%) inflammatory, 29 (13.6%) adenomatous, 18 (8.4%) fundic gland polyps, 13 (6.1%) adenocarcinomas, and one MALT lymphoma. Additionally, 108 patients (48.6% of the population with polyps and 17.6% of the overall AAG patients) presented with gastric neuroendocrine neoplasms (gNENs), 48 of whom also had non-endocrine polyps. The median polyp size was 4 (IQR 2-7) mm. Older age, smoking prevalence, and higher levels of G and chromogranin A (CgA) were associated with polyp presence. No significant differences in OLGA/OLGIM stages or H. pylori status were noted between patients with and without polyps.

Conclusion

This study represents the largest multicentric cohort of AAG patients, highlighting the significant presence of gastric polyps, including gNENs and various non-endocrine types including a not negligible proportion of patients who showed gastric adenocarcinoma. These results emphasize the importance of proactive endoscopic monitoring and comprehensive histopathological evaluation in patients with AAG, to effectively identify and manage these different gastric lesions.

References

1. Zhang H, Jin Z, Cui R, Ding S, Huang Y, Zhou L. Autoimmune metaplastic atrophic gastritis in chinese: a study of 320 patients at a large tertiary medical center. Scand J Gastroenterol. 2017;52(2):150-6.
2. Krasinskas AM, Abraham SC, Metz DC, Furth EE. Oxyntic mucosa pseudopolyps: a presentation of atrophic autoimmune gastritis. Am J Surg Pathol. 2003;27(2):236-41.
3. Kishino M, Nonaka K. Endoscopic Features of Autoimmune Gastritis: Focus on Typical Images and Early Images. J Clin Med. 2022;11(12).
4. Park JY, Cornish TC, Lam-Himlin D, Shi C, Montgomery E. Gastric lesions in patients with autoimmune metaplastic atrophic gastritis (AMAG) in a tertiary care setting. Am J Surg Pathol. 2010;34(11):1591-8.
5. Massironi S, Elvevi A, Gallo C, Laffusa A, Tortorella A, Invernizzi P. Exploring the spectrum of incidental gastric polyps in autoimmune gastritis. Dig Liver Dis. 2023.

Introduction

Fecal microbiota transplantation (FMT) is a highly effective treatment for recurrent Clostridioides difficile infection (CDI), but its safety is jeopardized by the potential risk of transmitting microbial pathogens. Stool biobanks have established to provide both a widespread and equitable access to FMT and high safety, quality, and traceable workflows. To guarantee the safety of each donor stool batch, international guidelines recommend either a quarantine or a direct stool testing with a rapid molecular assay for gut pathogens. While reports of the quarantine-based approach are emerging, data on the direct testing-based approach are still limited

Aims & Methods

Our aim is to report outcomes of a donor screening program for FMT including a direct stool testing-based approach based on a rapid molecular assay for gut pathogens.We prospectively evaluated all candidates enrolled in our FMT donor program since the introduction of a direct stool testing with a rapid molecular assay for gut pathogens, in 2019. Following international guidelines, donor screening consisted of a five-step framework, including: 1) collection of clinical history; 2) blood and stool testing; 3) a further questionnaire the day of each donation; 4) nasopharyngeal swab and stool RT-PCR assay for SARS-CoV-2 the day of each donation (after March 2020); 5) a direct stool testing with a rapid molecular assay for gut pathogens and cultures for MDRO evaluation. Specifically, the RT-PCR Allplex™ Gastrointestinal Panel Assay (Seegene, Korea) was used for a comprehensive identification of common gastrointestinal pathogens. The QIAamp Fast DNA Stool Mini Kit (QIAGEN, Hilden, Germany) was used for nucleic acid extraction. We evaluated rates of donations per year, rates and reasons of candidates’ exclusion at each step of the donor screening, as well as the rate of unsuitable fecal donations and the intestinal pathogens that caused their rejection. Finally, we recorded the number of total fecal aliquots provided by eligible donors, and related safety outcomes at 12 weeks after their use within FMT.

Results

From January 2019 to December 2022, 227 candidates were assessed for eligibility. Of them, 122 were excluded at different steps of the screening process. Finally, we enrolled 69 eligible donors (37 females, 53,6%; mean age 37, 30% of the total pool). Thirty-seven fecal aliquots were collected in 2019 (13 donors), 39 in 2020 (20 donors); 51 in 2021 (24 donors), and 104 in 2022 (43 donors). Overall, we collected 231 fecal donations, of which 136 (58.8%) were considered eligible and stored at -80°C for FMT. Eight donations were discarded for insufficient amount of feces (<50 g - 3%), and 87 (37.6%) for positivity to intestinal pathogens, including Enteropathogenic E. coli (EPEC) (n=31 samples – 13.4%), ESBL (extended-spectrum beta-lactamase) E. coli (n=15 samples, 6.5%), Blastocystis hominis (n=17 samples, 7.3%).Notably, we found a seasonal variation among pathogen positivity, as most pathogens were observed in Autumn (from September to December: n=48/87, 55.8%).All donations have been used, and no serious adverse events or infections have been observed at 12 weeks after FMT.

Conclusion

Our screening of donor feces based on direct stool testing guarantees high safety of FMT, although with high rates of donor exclusion, with the need of a well-established framework to guarantee a continuous availability of eligible donors to avoid shortages of fecal aliquots.

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.

Introduction

Epstein-Barr virus (EBV) associated gastric cancer (GC) has been reported to be about 5-16% of all gastric cancers with good prognosis compared to EBV-negative GC. The aim of this study was to evaluate the clinicopathological characteristics of EBV-positive GC including survival analysis in the prospective observational cohort study in a tertiary hospital in South Korea.

Aims & Methods

Total 4,586 patients who underwent EBV in situ hybridization (EBV-ISH) testing among 14,613 patients diagnosed with GC were prospectively enrolled at Seoul National University Bundang Hospital from 2003 to 2023. Data including age, sex, smoking, cancer type and stage, tumor size and location, histologic type, molecular features (p53 expression and MSI), and survival information including causes of death were collected and analyzed.

Results

EBV-positive cancer group showed significant differences compared to EBV-negative cancer group. That is, they showed higher proportion of males (p<0.001), predominant presence in the proximal stomach (p<0.001), higher proportion of undifferentiated cancer (p<0.001), and lower cancer stage (p=0.004) (Table). In Cox multivariate analyses, age (HR 1.022, p<0.001), tumor size (HR 1.118, p<0.001) along with cancer stage (stage 2 HR 5.843, p<0.001; stage3 HR 15.570, p<0.001; stage4 HR 50.075, p<0.001, respectively) were significant risk factors for GC-specific mortality, while EBV positivity was inversely correlated (HR 0.537, p=0.023). In the survival analyses, EBV-positive cancer group showed statistically significant survival advantages over EBV-negative cancer group in both overall (p=0.016) and gastric cancer-specific survival (p=0.005)

Conclusion

EBV-positive GC group was associated with male sex, proximal location, poorly differentiated histology and lower cancer stage, and showed significantly better prognosis than EBV-negative gastric cancer. EBV might play a role in the gastric carcinogenesis to make less metastasis resulting in better survival.

Introduction

Fibrosis constitute an important complication of CD. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have been shown to participate in the molecular interactions of both inflammation and fibrosis. Lower levels of miR-378a-3p have been reported associated to murine liver fibrosis [1] and we analyze here the relevance of miR-378a-3p on intestinal fibrosis.

Aims & Methods

B57BL/6 mice were intravenously injected with 2,5mg/kg of negative control (NC) or mm-miR-378a-3p mimic, twice a week and received vehicle or Dextran Sulfate Sodium (DSS) for 2 cycles (7 days drinking DSS 2% in water solution followed by 10 days drinking water). Body weight and DAI score was obtained every day and the colon was collected after sacrifice. Sirius and hematoxylin-eosin dyes were employed to determine the fibrosis and structural state in 5µm slides of intestinal tissue. Gene expression and miRNA profiles were analyzed by RT-qPCR. Human small intestinal fibroblasts (HSIF; P10760, Innoprot, Spain) were transfected with 20nM of NC or hsa-miR-378a-3p mimic during 24h.

Results

No significant changes in body weight, DAI score, and colon length were detected between mice receiving NC and those receiving mimic, all along the two DSS cycles. Colon of mice treated with DSS, exhibited a significant diminution in the mRNA expression of mm-miR-378a-3p compared with naïve samples. In DSS-treated mice, the iv administration of the mimic compared with the NC: a) significantly increased levels of miR-378a-3p in the colon; b) increased the number of neutrophils, and heightened changes in the glandular epithelia and architectural distortion C) decreased the number of lymphoid follicles; d) slightly increased collagen deposition, as analyzed by sirius red and e) significantly increased the mRNA expression of Tgfb1, Il1b, and Mmp2. Treatment of human intestinal fibroblasts with hsa-miR-378a-3p mimic did not significant modify the mRNA expression of markers of fibrosis but it significantly increased the mRNA expression of two antiapoptotic molecules BCL2 and MCL1.

Conclusion

Levels of mm-miR-378a-3p are diminished in a murine model of intestinal fibrosis; The exogenous administration of miR-378a-3p, increased the acute inflammatory response and the expression of fibrosis markers in murine fibrotic colon and the expression of antiapoptotic molecules in human intestinal fibroblasts.

References

1. Hyun, J.; Wang, S.; Kim, J.; Rao, K.M.; Park, S.Y.; Chung, I.; Ha, C.S.; Kim, S.W.; Yun, Y.H.; Jung, Y. MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression. Nat Commun 2016, 7, 10993, doi:10.1038/ncomms10993.

Introduction

Pancreatic duct (PD) stones frequently occur in chronic calcifying pancreatitis (CCP) and are a main factor contributing to pain onset and exacerbation as well as impaired quality of life (QOL). In these patients endoscopic intervention with removal of obstructing pancreatic duct (PD) calculi and regaining pancreatic duct drainage should be performed. In this regard, digital single operator video pancreatoscopy (d-SOVP) is still under investigation for the treatment of PD stones but seems to be an emerging alternative to standard endoscopic procedures with reported success rates between 43%-100%, based on small retrospective studies. However, while reported short term success rates seem very promising, there is still poor evidence for long-term clinical success and benefit for patients` quality of life.

Aims & Methods

Aims: To investigate the role of d-SOVP guided PD-stone lithotripsy in patients with CCP on clinical success and QOL in a long-term follow-up (FU).
Methods: Patients with CCP undergoing d-SOVP (SpyGlass DS) guided lithotripsy of PD stones with initial technical and clinical success were recruited in this retrospective analysis. Persistence of technical success (ductal clearance) and clinical success (defined as pain reduction >50 % in numerical rating scale (NRS)) as well as postinterventional QOL were evaluated by database analysis and a systematic questionnaire (based on SF-12) regarding pain intensity and incidence, painkiller intake and impact on QOL every 6 months obtained in the respective outpatient clinic. Data are presented as mean±SD.

Results

A total of 32 patients was evaluated during long-term FU of 40.8±8.3 months (range 32 – 57 months). 81% of patients (26/32) reported a significant and lasting decrease in pain and symptom burden with mean decrease of NRS from 6.1±0.55 (preinterventionally) to 1.6±0.35 at last reported visit of FU, p<0.01. In 4 patients (12.5%) subsequent pancreatic duct stenting was required due to persistent PD strictures, no recurrent intraductal stones were observed. 3 patients (9.4%) reported persistent pain, with 2 of these being eligible for partial pancreatectomy. QOL criteria significantly improved in 81% of patients defined by major improvements of their general health status and everyday life performance. Two patients were lost to follow-up, 3 patients (9.4%) died during follow up.

Conclusion

D-SOVP guided lithotripsy is safe and effective, achieving high rates of initial technical and clinical success rates as defined by complete ductal clearance and QOL. Beneficial effects on symptom control and QOL persist in the majority of CCP patients after approximately 41 months of FU. Therefore, we suggest d-SOVP to become the intervention of choice in these complex patients. Nevertheless, further prospective trials are warranted to prove these results.

Disclosure

Mark Ellrichmann, Horst Neuhaus, Torsten Beyna and Christian Gerges received lecture from Boston Scientific.

Introduction

Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial aetiology, which is still not completely understood. OCTN1, an organic cation transporter could have a role in modulating the inflammatory response, whose genetic polymorphisms were associated to increased risk of inflammatory bowel diseases. Up to now, limited information exists on its role in predicting/modulating response to therapies.

Aims & Methods

The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and immune composition to Infliximab therapy in murine colitis. Dextran sodium sulphate model of colitis on C57BL/6 mice and ocnt1 gene knockout mice was used to assess clinical efficacy of infliximab administered intravenously. Stool, colon and mesenteric lymph node samples were collected to assess differences in gut microbiota composition, histology for Rachmilewitz score and T cell populations respectively.

Results

Octn1^-/-influences microbiota profile and is associated with a worse dysbiosis in colitis mice. Infliximab treatment attenuates colitis-associated dysbiosis with increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1^-/- mice have a higher baseline percentage of Treg, Tmemory, Th2 and Th17.

Conclusion

Our data support murine model to study OCTN1 genetic asset in inflammatory bowel diseases. This could be the first step to consider this membrane transporter as a biomarker in inflammatory conditions and as a predictor of response to therapies.