Introduction

Mirikizumab (miri), a humanized IgG4 monoclonal antibody that selectively binds to interleukin-23 subunit p19, is approved for the treatment of moderately to severely active ulcerative colitis and Crohn’s disease. In ulcerative colitis, maintenance treatment with 200 mg miri given as two 1-mL subcutaneous (SC) injections every 4 weeks was efficacious and safe in the phase 3 maintenance LUCENT-2 and long-term extension LUCENT-3 trials. As SC injections can be associated with pain/discomfort and thus poor patient experience, an investigational 2-mL single injection delivering the same miri dose has been developed.

Aims & Methods

This phase 1 study (NCT06475729) aimed to assess the pharmacokinetic (PK) bioequivalence and safety of miri solution administered as one 2-ml injection compared with the commercially available two 1-ml injections. Healthy participants were stratified into weight categories (<75 kg, 75–85 kg, and >85 kg) and randomized (1:1) to receive one dose of 200 mg of SC citrate-free miri as either one (200 mg/2 mL) or two injections (each of 100 mg/1 mL) delivered by an autoinjector. Participants were sub-randomized (1:1:1) by injection site (arm, thigh, and abdomen). Blood samples were collected at pre-defined intervals up to 10 weeks post-dosing. The primary endpoint was PK, assessed by the maximum observed concentration (C_max), area under the concentration–time curve (AUC) from time zero to infinity (AUC_0–∞), and AUC from time zero to the last timepoint with measurable concentration (AUC_0–t). PK parameters were estimated using non-compartmental analysis. The secondary endpoint was safety, assessed by the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) among participants exposed to miri. Evaluating the impact of injection site location on PK was an exploratory endpoint.

Results

A total of 244 participants (mean age: 42.4 years; 55.3% female) received one 200 mg/2 ml injection and 240 (mean age: 42.7 years; 53.3% male) received two 100 mg/1 ml injections. Baseline characteristics were similar in both groups. The three primary PK parameters all fell within the bioequivalence range (geometric least-squares mean [GM] ratio: 0.800–1.250; see table). Results were generally consistent across injection site locations with no significant differences between them. TEAEs were reported in 48 participants with one injection (19.7%) and 55 with two injections (22.9%). Most TEAEs were mild (62/74 events with one injection [83.8%] vs 85/100 with two injections [85.0%]). Injection-site reactions occurred in 5/244 [2.0%] of participants with one injection and 4/240 [1.7%] with two injections. No SAEs were reported in either group.

Conclusion

Miri 200 mg administered as one 2-ml SC injection was bioequivalent to two 1-ml injections, and most TEAEs were mild. In clinical practice, reducing the number of injections may improve patient experience and treatment adherence.

Disclosure

YO, CDP, AUK, KT, PP, XZ: Employees and shareholders of Eli Lilly and Company.
EVL Jr: Consulted for Abivax, AbbVie, Astellas, Avalo, Biocon, Bristol-Myers Squibb, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Janssen, Merck, Morphic, Ono Pharma, Takeda, and TR1X Bio; received research support from AbbVie, Genentech, Gilead, Janssen, Merck, and Takeda; shareholder of Exact Sciences and Moderna.
GDH: Adviser and/or speaker for Abbvie, Alimentiv, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Prometheus Laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx.
SBH: Received advisory board and/or consulting fees from Abbvie, Takeda, Janssen, Celltrion, Pfizer, GSK, Ferring, Novartis, Roche, Gilead, NeoPharm, Predicta Med, Galmed, Medial Earlysign, and Eli Lilly; stocks/options in Galmed, Evinature, PredictaMed and Alma Therapeutics; and research support from Abbvie, Takeda, Janssen, Celltrion, Pfizer, Medtronic & Galmed.

Introduction

Artificial intelligence (AI) is playing an increasingly prominent role in gastrointestinal endoscopy, particularly in enhancing real-time lesion detection during colonoscopy. This study evaluates the impact of an advanced AI-assisted detection system on the Adenoma Detection Rate (ADR), Adenomas per Colonoscopy (APC), and predictive performance, comparing outcomes across endoscopists with different levels of experience.

Aims & Methods

Three endoscopists participated in the study: two with limited experience (Physicians A and B) and one expert (Physician C). A total of 720 colonoscopies were analyzed, with 400 procedures performed using AI assistance and 320 without, evenly distributed among the three operators.
Patients included were between 40 and 75 years of age and underwent colonoscopy either as a screening examination or following a positive fecal occult blood test. Exclusion criteria comprised a history of inflammatory bowel disease (IBD), hereditary polyposis syndromes, major colorectal surgery, or inadequate bowel preparation. For each procedure, data were collected on ADR, APC, the predictive accuracy of the AI system, and retraction time (from cecum to anus).

Results

The use of AI resulted in a marked and consistent improvement in all primary performance indicators across all three endoscopists.
In terms of ADR, Physician A improved from 23.8% without AI to 29.7% with AI; Physician B from 26.9% to 31.6%; and Physician C from 34.7% to 36.6%. Similarly, the APC index increased from 0.52 to 0.63 for Physician A, from 0.55 to 0.65 for Physician B, and from 0.64 to 0.73 for Physician C.
The AI system demonstrated high predictive accuracy across all operators, with no false positives recorded for polyps ≥4 mm in size. Prediction rates were 87.9% for Physician A, 89% for Physician B, and 92% for Physician C, confirming the device’s reliability in supporting polyp identification during real-time examination. Retraction times were slightly prolonged with AI usage: 8.3 minutes vs 7.5 for Physician A, 8.7 vs 7.4 for Physician B, and 8.8 vs 8.0 for Physician C. However, these differences did not reach statistical significance, indicating that AI support did not meaningfully affect procedural efficiency.

Conclusion

The integration of AI into colonoscopy workflows significantly improved both ADR and APC, with the most substantial impact observed in less experienced endoscopists. Physicians A and B, who initially showed suboptimal detection metrics, achieved levels of quality comparable to those of the expert operator in the absence of AI, highlighting AI’s value as a tool for bridging the gap in operator performance. The high predictive reliability of the system—particularly for clinically relevant lesions—and the absence of false positives ≥4 mm further support its clinical utility. Although retraction times increased slightly with AI, this change was not statistically significant, suggesting that the diagnostic advantages were not offset by decreased procedural efficiency. Overall, AI proves to be a valuable and scalable solution to enhance adenoma detection, support clinical training, and promote uniform quality standards in colorectal cancer screening.

References

1.Antonelli, G., Gkolfakis, P., Tziatzios, G., Papanikolaou, I. S., Triantafyllou, K., & Hassan, C. (2020). Artificial intelligence-aided colonoscopy: Recent developments and future perspectives. World journal of gastroenterology, 26(47), 7436–7443.
2.Hassan, C., Balsamo, G., Lorenzetti, R., Zullo, A., & Antonelli, G. (2022). Artificial Intelligence Allows Leaving-In-Situ Colorectal Polyps. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 20(11), 2505–2513.e4
3.Houwen, B. B. S. L., Hassan, C., Coupé, V. M. H., Greuter, M. J. E., Hazewinkel, Y., Vleugels, J. L. A., Antonelli, G., Bustamante-Balén, M., Coron, E., Cortas, G. A., Dinis-Ribeiro, M., Dobru, D. E., East, J. E., Iacucci, M., Jover, R., Kuvaev, R., Neumann, H., Pellisé, M., Puig, I., Rutter, M. D., … Dekker, E. (2022). Definition of competence standards for optical diagnosis of diminutive colorectal polyps: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement. Endoscopy, 54(1), 88–99.

Introduction

Inspection accuracy on colonoscopy is problematic because of the colon’s complex structure and the need for skillful operators. In particular, lesions in the ascending colon (AC) may be difficult to detect because of its high folds. Additionally, it has recently been reported that post-colonoscopy colorectal cancer is often located in the proximal colon. There are only a few reports on the effectiveness of retroflex inspection after forward view inspection in the AC during colonoscopy. While endoscopes and colonoscopy using artificial intelligence or image enhancement systems to detect lesions have been developed, it is important to reconsider basic endoscopic techniques, such as retroflex inspection, during colonoscopy.

Aims & Methods

We performed a prospective study to investigate the usefulness of retroflex inspection after forward view inspection in the AC during colonoscopy. Between August 2022 and December 2024, a single endoscopist enrolled and performed screening colonoscopies for 335 consecutive patients aged ≥40 years. Patients with inflammatory bowel disease, gastrointestinal polyposis, post-colorectal surgery, or poor preparation (≤1 point in at least one of three areas on the Boston Bowel Preparation Scale) were excluded from this study. The AC was inspected in this sequence: forward direction (Inspection 1), retroflex direction (Inspection 2), and forward direction (Inspection 3). The primary endpoint was the adenoma detection rate (ADR) in the AC. Secondary endpoints were the adenoma miss rate (AMR) in the AC per colonoscopy in Inspection 1 and Inspections 1+2, percentage of cases in which lesions were detected in Inspection 2, average observation time in the AC for each inspection, success rate of retroflexion in the AC, average pain score (0 points: no pain, 5 points: most severe pain), and complication rate during Inspection 2.

Results

We evaluated 300 patients with a median age of 66 years. The ADR in the AC for Inspection 1 vs. 1+2 was 18.7% vs. 28.7%, respectively (odds ratio: 1.749; 95% CI: 1.174–2.622; p = 0.005); the values for Inspection 1+2 vs. 1+2+3 were 28.7% vs. 30.0%, respectively (odds ratio: 1.066; 95% CI: 0.739–1.540; p = 0.788) (Table 1). The average AMR in the AC per colonoscopy for Inspection 1 vs. 1+2 was 12.6% (95% CI: 9.0%–16.2%) vs. 2.6% (95% CI: 0.8%–3.8%) (p < 0.001) (Table 1). The percentage of cases in which lesions were detected in Inspection 2 was 13.8% (41/298; total number of lesions: 47). The average diameter of lesions discovered and resected endoscopically during Inspection 2 was 6.1 mm (range: 3–20 mm). The locations of these lesions were as follows: proximal AC: 27.7% (13/47); mid-AC: 38.3% (18/47); and distal AC: 34.0% (16/47). The average observation times in the AC (Inspection 1 vs. 2 vs. 3) were 80.7 (95% CI: 77.8–83.6) vs. 59.1 (95% CI: 56.9–61.3) vs. 82.1 (95% CI: 79.4–84.8) seconds, respectively. The success rate of retroflexion in the AC was 99.3% (298/300), and the average pain score and complication rate during Inspection 2 were 0.5 points (95% CI: 0.4–0.6 points) and 0%, respectively.

Conclusion

Retroflex inspection following forward inspection in the AC during colonoscopy detects additional adenomas and is minimally invasive and safe. This technique contributes to improving the accuracy of colonoscopy.

Introduction

Approximately 50% of patients with Ulcerative Colitis (UC) suffer from daily symptoms of faecal urgency, significantly impacting their quality of life¹. Treatment in quiescent disease is challenging and the first line treatment, loperamide, is often used with caution due to the side effect of constipation.
Enterosorbents such as Enterosgel provide a potential alternative treatment. Enterosgel is thought to work through the adsorption of small molecules in the gastrointestinal (GI) tract, with minimal or no systemic absorption and metabolism², without causing constipation. Enterosgel has shown clinical effectiveness in reducing urgency in patients with diarrhoea predominant irritable bowel syndrome (IBS-D), suggesting potential therapeutic value in patients with UC³, however the mechanism by which this may occur is unknown.

Aims & Methods

This study aimed to evaluate the in vitro adsorption capacity of Enterosgel for three key inflammatory mediators implicated in UC pathogenesis (IL-1β, MMP9 and TNF-α) to explore its potential as a therapeutic option in this patient group.
Three experimental paradigms were performed by diluting recombinant cytokines and enzymes in water-based Enterosgel solutions. After incubation, gel-free supernatants were harvested to analyse residual levels of metabolite via ELISA to identify the quantity of adsorption by Enterosgel. Conditions were conducted with different:

1. Incubation times (15,30,60,120 min)
2. Metabolite concentrations (5 concentrations ranging from 0 - 3000pg/mL)
3. Gel concentrations (0.056, 0.1125, 0.225g/mL)

Results

Enterosgel demonstrated measurable concentration-dependent adsorption of IL-1β, MMP9 and TNF-α with higher analyte input concentrations resulting in greater absolute adsorption. However for TNF-α adsorption saturated at 1000pg/mL, indicating that Enterosgel may not fully adsorb analytes at levels simulating extreme luminal inflammation. Charcoal consistently resulted in lower residual concentrations, although this did not reach statistical significance on permutation testing (p = 0.14).
In time dependent analysis, Enterosgel induced a rapid initial reduction in cytokine levels within 15 minutes, (IL-1β: 98.7%, MMP9: 99.4%, TNF-α: 95.8% adsorbed) with a plateau by 120 minutes (IL-1β: r²=0.74, MMP9: r²=0.64, TNF-α: r²=0.45). In contrast, charcoal demonstrated a near-linear monotonic decline with a slightly greater concentration adsorbed by 120 minutes (IL-1β: 99.9% vs. 99.8%; MMP9: 99.9% vs. 99.1%; TNF-α: 97.2 vs. 96.3%). Increasing gel concentrations improved adsorption efficiency; however, at the highest gel concentration small amounts of residual cytokines remained (IL-1β: 0.25%, MMP9: 0.28%, TNF-α: 3.5%). Doubling of gel concentration led to an average 30% decrease in residual cytokines.

Conclusion

Our findings suggest that Enterosgel demonstrates excellent adsorption of three key pro-inflammatory cytokines relevant to UC, with the greatest reduction at 1 hour and the highest gel concentration—though less than that achieved by charcoal. Evidence of saturation at high analyte levels suggests a limit to Enterosgel’s binding capacity under conditions simulating severe inflammation. These results highlight Enterosgel's clinical potential, however further validation with biological replicates and clinical studies assessing urgency in treated UC is required.

References

(1) Theresa Hunter Gibble, April N. Naegeli, Michael Grabner, Keith Isenberg, Mingyang Shan, et al. Identification of inadequate responders to advanced therapy among commercially-insured adult patients with Crohn’s disease and ulcerative colitis in the United States. 2023; 63 (23): 10.1186/s12876-023-02675-w.
(2) Howell CA, Mikhalovsky SV, Markaryan EN, Khovanov AV. Investigation of the adsorption capacity of the enterosorbent Enterosgel for a range of bacterial toxins, bile acids and pharmaceutical drugs. Scientific Reports. 2019; 9 (1): 10.1038/s41598-019-42176-z.
(3) Howell CA, Kemppinen A, Allgar V, Dodd M, Knowles CH, Mclaughlin J, et al. Double-blinded randomised placebo controlled trial of enterosgel (polymethylsiloxane polyhydrate) for the treatment of IBS with diarrhoea (IBS-D). BMJ; 2022.
(4) Shane O'Sullivan, John F Gilmer, Carols Medina. Matrix Metalloproteinases in Inflammatory Bowel Disease: An Update. Mediators of Inflammation. 2015; 2015 (1): 10.1155/2015/964131.
(5) Qingdong Guan JZ. Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease. Mediators of Inflammation. 2017; 2017 (1): 10.1155/2017/4810258.

Introduction

Crohn’s Disease (CD), a subtype of Inflammatory Bowel Disease (IBD), is believed to arise from complex interactions between gut microbes, environment, and genetics. A significant proportion of patients develop fistulae, but unclear aetiopathogenesis impacts treatment outcomes, quality of life, and healthcare costs. Chronic granulomatous disease (CGD) is a monogenic condition caused by pathogenic variants in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes which can present as CD-like colitis, abscesses, and immunodeficiency. Given CD’s genetic and phenotypic similarities with CGD, we hypothesised that NADPH oxidases may contribute to CD phenotypes, specifically in relation to fistulating disease behaviour.

Aims & Methods

This study explores the role of genetic variation in NADPH oxidases in CD patients (Southampton IBD cohort) using a per-patient, per-gene deleteriousness score (GenePy) to determine whether CD fistulating disease behaviour can be predicted and establish any potential epistatic interactions between genetic variation of subunits of the NAPDH oxidase complexes relevant to CD. Key NADPH oxidase protein-coding genes involved in CD were identified via literature review. Protein-protein interaction databases were used to collate a comprehensive network of potentially implicated genes. To determine subgroups of patients with differing genetic variation in the NAPDH oxidase genes we employed a principal component analysis (PCA), followed by hierarchical clustering of patients using GenePy scores, with optimal cluster numbers determined by silhouette scores. Cluster enrichment for fistulating disease was explored using Fisher’s exact test. To identify genes driving separation between CD patients we assessed differences in GenePy scores for the top PCA gene drivers between fistulating and non-fistulating subgroups using a Mann-Whitney U-test. Mutational profile characterisation include potential gene-gene interactions were evaluated via Spearman correlations. Multiple test correction was applied.

Results

Twenty-nine protein-coding genes were analysed. Clustering patients by GenePy scores for these genes after PCA resulted in distinct clusters, but no significant association between fistulating phenotype and cluster assignments was observed. However, significant differences between the GenePy scores of the top 5% of fistulating and non-fistulating groups were found for NOX3 (p = 0.016) and DUOX2 (p = 0.001), with fistulating patients having lower GenePy score for these genes, indicating these genes may drive a proportion of inflammatory CD behaviour.
Four gene pairs were significantly correlated (Table 1), indicating potential epistasis within NADPH oxidase complexes for patients with CD. High deleteriousness scores in multiple genes within a complex may indicate oligogenic contribution to a disease phenotype within individuals.

Conclusion

NADPH oxidase genes, and epistatic interactions between them, may modify the risk of fistulating CD and drive disease phenotype in a proportion of patients.

Disclosure

JJA is a scientific advisory board member for Orchard Therapeutics

Introduction

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening emergency that requires timely management. Intravenous corticosteroids are the first line therapy, but around 30% of patients fail to respond. Rescue therapy is effective in reducing short-term colectomy rates but its impact on disease course in the medium/long-term is not well characterized.

Aims & Methods

We aimed to assess if non-response to corticoids (and subsequent need for rescue therapy) in patients admitted with a first episode of ASUC is associated with worse disease-related outcomes in the long-term.
We conducted a retrospective study of all patients admitted with ASUC in the Gastroenterology department of a Portuguese tertiary center between 2018-2024. ASUC diagnosis was established according to Truelove and Witts’ criteria. Response to intravenous corticoids was defined as discharge without need for rescue therapy and/or colectomy. Patients with a previous admission for ASUC before the study period were excluded.
Patient files were reviewed and demographic, clinical, laboratory and endoscopic data was collected regarding the admission for ASUC and subsequent follow-up. Considered disease-related outcomes were need for switch of maintenance therapy, need for readmission and need for colectomy. Subanalyses were performed according to response to corticoid therapy. Statistical analysis was done using Stata version 12.1.

Results

A total of 35 patients hospitalized with a first episode of ASUC were included, 51.4% (n=18) male, median age at admission was 38 years [IQR 27-51]. Roughly half the patients had pancolitis at diagnosis (51.4%, n=18). Median disease duration was 9 months [IQR 0-26] and 22.9% (n=8) had previous exposure to biologic therapy. In 34.3% (n=12), ASUC was the initial presentation of UC. Median follow-up was 30 months [IQR 12-51].
Response to corticosteroid therapy was observed in 57.1% (20/35). All the steroid-refractory patients (15/35, 42,9%) responded to rescue therapy (Infliximab n=11; Tacrolimus n=3; Tofacitinib n=1) and avoided colectomy during the hospitalization.
Baseline characteristics were identical between steroid-responsive and steroid-refractory patients, except for a lower median age in corticoid refractory patients (29 years vs 48 years, p=0.02).
Survival analysis was performed and no differences between steroid-responsive and steroid-refractory patients were observed in need for switch of maintenance therapy [during first year (p=0,28) and during complete follow-up (p=0,54)] , need for readmission [during first year (p=0,55) and during complete follow-up (p=0,54)] or need for colectomy [during first year (p=0,09) and during complete follow-up (p=0,79)].

Conclusion

In our cohort of patients with a first episode of ASUC, with the current therapeutic paradigm, patients with steroid refractoriness had similar outcomes as corticosteroid responders. These results suggest that effective and timely therapy can change the natural history of ASUC.

References

1. Festa S, Scribano ML, Pugliese D, Bezzio C, Principi M, Ribaldone DG, Allocca M, Mocci G, Bodini G, Spagnuolo R, Vernia P, Mazzuoli S, Costa F, Barberio B, Cosintino R, Zerboni G, Aratari A, Armuzzi A, Papi C. Long-term outcomes of acute severe ulcerative colitis in the rescue therapy era: A multicentre cohort study. United European Gastroenterol J. 2021 May;9(4):507-516. doi: 10.1177/2050640620977405. Epub 2021 Feb 16. PMID: 33259773; PMCID: PMC8259429.
2. Zafer M, Zhang H, Dwadasi S, Goens D, Paknikar R, Dalal S, Cohen RD, Pekow J, Rubin DT, Sakuraba A, Micic D. A Clinical Predictive Model for One-year Colectomy in Adults Hospitalized for Severe Ulcerative Colitis. Crohns Colitis 360. 2021 Dec 21;4(1):otab082. doi: 10.1093/crocol/otab082. PMID: 36777555; PMCID: PMC9802419.