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

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.

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

The Health Outcome Observatory (H2O) project aims to standardize and facilitate the collection of patient-reported outcomes (PROs) as well as clinical outcomes by a Core Outcome Set (COS) defined for patients with inflammatory bowel disease (IBD).¹ The present study describes preliminary data on the PROMIS^®-10 questionnaire (Patient-Reported Outcomes Measurement Information System) – a generic health-related quality of life measure - in IBD patients.

Aims & Methods

This is a real-world interim analysis of IBD patients included in the H2O project at the Medical University of Vienna, Austria. The variables analyzed were part of the COS. PROMIS^®-10 was evaluated, including Global Physical Health and Global Mental Health scores. Higher scores indicate better health and a score between 40 and 59 was defined as normal range. A descriptive analysis and a correlation analysis, including sex, age, age at diagnosis, disease duration, IBD_Disk_managing_defecation_day and night, IBD_urge, PRO-2 for CD (number of liquid or very soft stools and abdominal pain score) and UC (rectal bleeding score and stool frequency score) were performed.

Results

691 patients (46% females) were included in the analysis. 460 were diagnosed with Crohn’s disease (CD), 220 with ulcerative colitis (UC), and 11 with IBD unclassified (IBDU). The PROMIS scores were similar in CD and UC. The mean PROMIS Global Physical Health score was 41.5 (SD 5.3) in CD and 41.9 (SD 4.5) in UC, respectively. The mean PROMIS Global Mental score was 46.9 (SD 8.8) in CD and 48.4 (SD 8.3) in UC. 223 patients had a PROMIS Global Physical Health score < 40, and no patient had a score > 59. 89 patients had a PROMIS Global Mental Health score < 40, and 32 patients had a score > 59. The PROMIS Global Physical Health score correlated with the Mental score (r=0.23; p<0.001), sex (male r=0.13; p=0.003), PRO-2 for CD number of liquid or very soft stools (r=-0.11; p=0.01) and abdominal pain score (r=0.14; p=0.002). The PROMIS Global Mental Health score correlated with sex (male r=0.13; p=0.004), the IBD_Disk_managing_defecation_day (r=-0.32; p<001) and night (r=-0.31; p<0.001), IBD_urge (r=-0.33; p<0.001), PRO-2 for CD number of liquid or very soft stools (r=-0.34; p<0.001) and abdominal pain score (r=-0.49; p<0.001), and PRO-2 for UC rectal bleeding score (r=-0.13; p=0.004) and stool frequency score (r=-0.35; p<0.001).

Conclusion

About one third of the patients had a PROMIS Global Physical Health score below the normal range. The majority of the IBD patients had a PROMIS Global Mental Health score within the normal range, which correlated with the severity of gastrointestinal symptoms, including urgency and incontinence.

References

¹Fierens L, Carney N, Novacek G, van der Woude CJ, Siegmund B, Casellas F, et al. A Core Outcome Set for Inflammatory Bowel Diseases: Development and Recommendations for Implementation in Clinical Practice Through an International Multi-stakeholder Consensus Process. J Crohns Colitis. 2024 Oct 15;18(10):1583-1595.

Disclosure

H2O has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 945345. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Trial Nation and JDRF. www.ihi.europa.eu DISCLAIMER: this poster reflects only the author’s view. Neither IMI, nor EFPIA, nor the European Commission, nor the JU are liable for any use that may be made of the information it contains.

Introduction

It is not clear whether the inverse relationship between colonoscopists’ adenoma detection rate (ADR) and post-colonoscopy colorectal cancer (PCCRC) is seamless or subject to “plateau” effect.

Aims & Methods

Aim of the study was to model the pattern of association between ADR and PCCRC. The present study is a systematic review and meta-analysis of studies published up to December 2024 providing the crude incidence rate of PCCRC according to various colonoscopists’ ADR categories. The primary outcome was calculated as the cumulative incidence of PCCRC at the lowest bound of each ADR category, starting from highest to lowest colonoscopists’ ADR. A restricted cubic spline multilevel metaregression analysis was applied to model the inverse association between ADR and cumulative PCCRC.

Results

After applying selection criteria, 7 studies published in 2020-2024, including 2,178,822 patients were included. All studies were conducted in organized CRC screening programs: 5 studies were set in primary colonoscopy screening, whereas 2 studies assessed FIT+ patients undergoing colonoscopy with two different cut-offs (20 µg Hgb/g and 47 µg Hgb/g feces). Four studies were European, and three studies were conducted in the US. Median patient age ranged from 57 to 65 years (see Table 1).
In primary colonoscopy setting (5 studies with 2,025,296 patients), adjusting for standardized follow-up and standardized CRC risk, cumulative incidence of CRC after colonoscopy showed a marked decrease for each 1-unit increase in ADR up to 27%, with a more gradual decline between 27% and 34%. In absolute numbers, assuming a 10-year follow-up period, CRC after colonoscopy ranged from 258/100,000 at 1% ADR, to 228/100,000 at 27% ADR, and 220/100,000 at 34% ADR, yielding a total decrease of 38 CRC after colonoscopy cases per 100,000 patients in 10 years. Beyond this threshold, according to model-based projections, CRC after colonoscopy would be 212/100,000 at 50% ADR, 207/100,000 at 60% ADR, and 197/100,000 at 80% ADR, yielding only an additional decrease of 8 (ADR 50%), 13 (ADR 60%), and 23 (ADR 80%) CRC after colonoscopy cases per 100,000 patients in 10 years, as compared to ADR 34%. Data remained consistent after excluding the study by Pilonis et al. [1], confirming that CRC after colonoscopy plateaus after 34% ADR. Heterogeneity was low (I²=0%) and the visual inspection of the funnel plot revealed some publication bias possibly leading to overestimate the inverse association between ADR and CRC after colonoscopy.
In the FIT-based setting (2 studies, 153,526 patients), quantitative synthesis was not performed owing to the low number of studies and different FIT thresholds (i.e., ≥20 and ≥47 µg Hb/g feces). Nonetheless, when examining the individual studies, there appears to be a more linear decline in post-colonoscopy CRC risk with increasing ADR.

Conclusion

In primary colonoscopy screening, achieving an ADR of at least 27% is essential. While increasing ADR beyond 27% continues to reduce risk, the benefit plateaus beyond ADR 34%, suggesting limited additional clinical advantage. Of note, the absolute risk reduction in CRC after colonoscopy is overall modest. Additional quality measures could provide a more comprehensive assessment of colonoscopy effectiveness.

References

Pilonis ND, Spychalski P, Kalager M, et al. Adenoma Detection Rates by Physicians and Subsequent Colorectal Cancer Risk. JAMA. Published Online First: 16 December 2024.
Wisse PHA, Erler NS, de Boer SY, et al. Adenoma Detection Rate and Risk for Interval Postcolonoscopy Colorectal Cancer in Fecal Immunochemical Test-Based Screening : A Population-Based Cohort Study. Ann Intern Med. 2022;175:1366–73.
Zorzi M, Antonelli G, Barbiellini Amidei C, et al. Adenoma Detection Rate and Colorectal Cancer Risk in Fecal Immunochemical Test Screening Programs : An Observational Cohort Study. Ann Intern Med. 2023;176:303–10.
Schottinger JE, Jensen CD, Ghai NR, et al. Association of Physician Adenoma Detection Rates With Postcolonoscopy Colorectal Cancer. JAMA. 2022;327:2114–22.
Waldmann E, Penz D, Šinkovec H, et al. Interval cancer after colonoscopy in the Austrian National Screening Programme: influence of physician and patient factors. Gut. 2021;70:1309–17.
Lam AY, Li Y, Gregory DL, et al. Association between improved adenoma detection rates and interval colorectal cancer rates after a quality improvement program. Gastrointest Endosc. 2020;92:355-364.e5.
Polychronidis G, He M-M, Vithayathil M, et al. Risk of colorectal neoplasia after removal of conventional adenomas and serrated polyps: a comprehensive evaluation of risk factors and surveillance use. Gut. 2024;73:1675–83.