bluuebunny/crossref_metadata_2025 huggingface dataset:
P389 Switching infliximab to subcutaneous from intravenous therapy (SWIMSUIT) – A prospective, real-world, single centre, phase IV interventional study.
Authors: Rahmany S , Young D , Moyses H , Gonclaves J , Latter S , Cummings F
Published: January 2023

Background

Subcutaneous (SC) infliximab (CT-P13) was approved in 2020 by the EMA for use in IBD. This offers patients greater choice, flexibility and the convenience of administering their treatment at home as well as other potential therapeutic benefits. We aim to evaluate the clinical outcomes of patients switching from intravenous (IV) infliximab to SC CT-P13.

Methods

We offered IBD patients established on IV infliximab (>4 doses) the opportunity to switch to SC CT-P13. Patients who agreed to switch were followed up every 12 weeks for 24 weeks. Demographics, disease history, disease activity scores, IBD CONTROL PROM, SF36, calprotectin, standard blood tests, infliximab drug levels, antidrug antibodies (ADA) and adverse events were collected at each visit. The primary endpoint was the maintenance of clinical status at week 24 (W24). A failure to maintain clinical status was defined as an increase in disease activity scores (mHBI or SCCAI) of ≥3, and/or a decline in IBD-Control PROM score of ≥4 points at any time during the study period.

Results

We approached 204 patients receiving IV infliximab, of which 120 patients switched to SC CT-P13 (75.8% CD, 22.5% UC, 1.7% IBDU). 24 patients had perianal disease at baseline. Median age was 38. The median time taken by patients (leaving home to returning home) to receive their infusions was 180 minutes (range 60 to 660). 96 participants were on concomitant immunomodulators (79 thiopurines, 17 methotrexate) and 105 were treated with SB2 preswitch. The median duration of IV infliximab prior to switching was 45 months. 70 (58%) of the patients were on the standard dosing (5mg/kg Q8W) regimen. All patients were switched to 120mg of SC CT-P13 every other week, regardless of their baseline regimen. 11 (9.2%) patients discontinued the treatment prior to finishing the study. 75% (CI 0.65, 0.82) of the whole cohort reached the primary endpoint of maintaining clinical status at week 24. There was no statistically significant difference in disease activity scores or IBD-Control PROM between baseline and W24. 31 (25.8%) of the patients had evidence of immunogenicity at baseline (ADA of > 50ng/ml). Of the 89 patients with no immunogenicity at baseline, 69 (77.5%) maintained this at W24. The median serum infliximab levels increased by 72.8 % from baseline to W24 (3.05 µg/ml to 5.27 µg/ml (figure 1)). Median ADA levels increased from 8.46 ng/ml at baseline to 10.6 ng/ml at W24 (figure 2). Patient satisfaction with SC CT-P13 was very high (figure 3).

Conclusion

Switching patients from IV to SC CT-P13 is safe, effective, and well-accepted with higher infliximab serum levels. The majority of the patients with no immunogenicity at baseline maintained this at W24.
P405 Long-term safety of 3 years of ozanimod in moderately to severely active ulcerative colitis: an interim analysis of the True North open-label extension
Authors: Panaccione R , Danese S , Wolf D C , Canavan J B , Jain A , Wu H , Petersen A , Charles L , Afzali A , Abreu M T
Published: January 2023

Background

The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod in UC. This analysis evaluated the cumulative long-term safety of ozanimod in these studies, which included pts with up to ~3 years of treatment exposure.

Methods

In TN, pts were randomised to once-daily ozanimod 0.92 mg or placebo, or to open-label ozanimod for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo in the maintenance period through Week 52. TN pts were eligible to enrol in the OLE and receive ozanimod if they did not achieve clinical response at the end of induction (Week 10), lost response during maintenance, or completed maintenance at Week 52. This interim analysis of the TN OLE (data cutoff: 10 January 2022) included all pts who entered the OLE from TN (n=823). Safety was monitored from the first dose of ozanimod in TN and throughout the subsequent OLE. Exposure-adjusted incidence rates per 100 patient-years (PY) were calculated.

Results

The average age of TN OLE study participants was 41.7 years (±13.6), 41% were female, 62% had left-sided UC disease, and 35% had prior exposure to tumor necrosis factor inhibitors. Total PY exposure to ozanimod was 2219 years (mean [SD] exposure = 2.7 [1.6]). The most frequent treatment-emergent adverse events (TEAEs) reported through OLE Week 94 (up to 146 weeks of continuous treatment) are listed in the Table. Most TEAEs were nonserious; TEAEs leading to discontinuation were uncommon. Bradycardia was reported in 3 pts (0.4%; EAIR 0.1/100 PY; 2 in TN and 1 in OLE; no pts were discontinued from treatment). Macular edema was reported in 2 (0.2%; EAIR 0.1/100 PY) pts. Reductions in ALC were common (470 [57.1%] had ALC < 500 cells/mm3), as previously described, but ALC reductions were not associated with the occurrence of TEAEs. Malignancies were uncommon (n=13 [1.6%]; EAIR 0.6/100 PY), and included 6 basal cell carcinomas and 3 colorectal neoplasms. Two deaths were reported: 1 due to COVID-19 and 1 sudden death. Investigators deemed both to be unrelated to treatment. Ozanimod was not associated with an increased risk of ischemic heart disease or thromboembolic events.

Conclusion

Long-term exposure to ozanimod for up to 3 years was well tolerated in pts with moderately to severely active UC. No new safety signals were observed with long-term ozanimod use in UC (2219 PY exposure). Safety findings are consistent with previous reports from the UC and multiple sclerosis development programs (>16,512 PY exposure).
P434 Upadacitinib improved fatigue and health-related quality of life in patients with moderately to severely active Crohn’s disease: Results from induction and maintenance phase 3 trials
Authors: Ghosh S , Feagan B , Parra R S , Lopes S , Steinlauf A , Kakuta Y , Joshi N , Lee W J , Remple V , Lacerda A P , Zhou Q , Xuan S , Louis E
Published: January 2023

Background

Upadacitinib (UPA) demonstrated efficacy and safety in the phase 3 U-EXCEED (NCT03345836) and U-EXCEL (NCT03345849) induction, and U-ENDURE (NCT03345823) maintenance trials in patients (pts) with moderately to severely active Crohn’s disease (CD). We evaluated the impact of UPA on health-related quality of life (QoL) in pts with CD.

Methods

Clinical responders to UPA 45 mg (UPA45) in U-EXCEED and U-EXCEL induction trials were re-randomised at Week 12 (1:1:1) to UPA 15 mg (UPA15), UPA 30 mg (UPA30), or placebo (PBO) for 52 weeks of maintenance treatment in U-ENDURE; data from these induction and maintenance trials were included in this analysis. Endpoints included the percentage of pts who achieved an Inflammatory Bowel Disease Questionnaire (IBDQ) response (≥16 points), IBDQ remission (≥170 points), a meaningful within-person change (MWPC) from baseline of ≥9 points on the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F), and of ≥4.1 and ≥3.9 points on the 36-item Short-Form Health Survey (SF-36) physical (PCS) and mental (MCS) component summary scores, respectively, at Weeks 4/12 of induction and Week 52 of maintenance. Adjusted risk differences compared to PBO, 95% confidence intervals, and p-values were calculated based on the Cochran-Mantel-Haenszel test.

Results

In U-EXCEED (n=324 UPA; 171 PBO) and U-EXCEL (n=350 UPA; 176 PBO), a greater proportion of UPA45- vs PBO-treated pts had an IBDQ response at Weeks 4 (U-EXCEED: 71.6% vs 47.6%; U-EXCEL: 71.0% vs 50.2%; p≤0.001) and 12 (U-EXCEED: 63.9% vs 44.4%; U-EXCEL: 68.4% vs 46.5%; p≤0.001; Figure 1). In UPA- vs PBO-treated pts, a greater proportion achieved IBDQ remission at Weeks 4 (U-EXCEED: 41.4% vs 22.4%; U-EXCEL: 44.2% vs 23.7%; p≤0.001) and 12 (all p≤0.001; Figure 1). At Week 12, a significantly greater proportion of UPA-treated pts vs PBO demonstrated a MWPC in FACIT-F, and SF-36 PCS and MCS from baseline (p≤0.001; Figure 1). Similar results for UPA45 vs PBO were achieved as early as Week 4 in FACIT-F (U-EXCEED: 42.3% vs 20.0%; U-EXCEL: 42.0% vs 27.0%), SF-36 PCS (U-EXCEED: 56.6% vs 37.2%; U-EXCEL: 53.0% vs 37.5%; p≤0.001) and MCS (p≤0.05). In the maintenance study U-ENDURE (n=168 UPA30; 169 UPA15; 165 PBO), a greater proportion of pts receiving UPA15 and UPA30 vs PBO achieved an IBDQ response (39.1%, 53.5% vs 20.4%), IBDQ remission (36.1%, 45.2% vs 13.5%), and a meaningful improvement from baseline in FACIT-F, SF-36 PCS and MCS through 52 weeks (p≤0.01; Figure 2).

Conclusion

In pts with moderately to severely active CD, UPA treatment significantly improved fatigue, disease-specific and generic QoL, compared with PBO, as early as Week 4 of induction. The effects were sustained through 52 weeks of maintenance treatment.
P446 The INTESTINE study: INtended TEmporary STomas In crohN’s diseasE
Authors: Perrott C , Calini G , Gori A , Rottoli M , Garoufalia Z , Wexner S , Celentano V ,   The INTESTINE Study Group
Published: January 2023

Background

Patients with ileocolic Crohn’s disease may require surgery resulting in temporary stoma formation. The impact on quality of life and morbidity related to stomas is well recognised and timely reversal should be targeted to alleviate this affect. This study aims to determine the proportion of stomas reversed, the timing and reasons for non-reversal in patients with Crohn’s disease.

Methods

This international retrospective trainee-led observational study included patients who underwent surgery for ileocolic Crohn’s disease between January 2017 and December 2020. Patients undergoing proctectomy or proctocolectomy were excluded. The primary outcome was the proportion of patients who still had a stoma at 18 months post-operatively. Secondary outcomes included: interval between formation and reversal of stoma, assessing complications and risk factors from non-reversal of the stoma. Evaluation of these outcomes were documented for short-term (6 months) and mid-term (18 months).

Results

Currently there are 38 collaborating centres collecting data across 18 countries. We present an intermediate analysis, with full results available in January 2023.

Baseline and surgical characteristics are described in Tables 1 and 2. The intermediate analysis included 110 patients of which 37% had their stoma reversed at 6 month follow up (mean time to reversal 3.2 ± 1.4 months), and 56% reversed at 18 months (mean 5.9 ± 4.0 months). Reasons for non-reversal at 6 months included: ongoing Crohn’s disease (30%), patient unfit for surgery (14%), waiting lists (9%) and patient’s preference (8%). Stoma related complications at 6 months were reported in 16% of patients, consisting of: high output (6%), parastomal hernia (5%), stoma stenosis (3%) and peristomal cutaneous lesions (1%). 30-day postoperative outcomes and follow up at 6 and 18 months are reported in Tables 3 and 4.

Conclusion

This trainee-led international study will provide information on the proportion of stomas that are reversed and the reasons for non-reversal of stomas in Crohn’s disease. Preliminary results demonstrate that 18 months after stoma formation, 1 in 2 patients still had a stoma.
P464 Effects of ozanimod on histologic remission and mucosal healing over 3 years of continuous treatment in patients with ulcerative colitis
Authors: Panaccione R , Danese S , Wolf D C , Canavan J B , Jain A , Wu H , Petersen A , Afzali A , Abreu M T
Published: January 2023

Background

Ozanimod is approved in the European Union, United States, and other countries for the treatment of moderately to severely active ulcerative colitis in adults (UC). The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients with moderately to severely active UC. The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod. This interim analysis of the TN OLE evaluated the efficacy of ozanimod on histologic remission (HR) and mucosal healing (MH) in patients who received approximately 3 years of continuous ozanimod treatment.

Methods

In TN, patients were randomised to once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo (Cohort 1) or to open-label ozanimod (Cohort 2) for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo for a 42-week maintenance period (MP). Patients with clinical response to ozanimod at Week 52 in TN were eligible to continue receiving ozanimod in the ongoing OLE. This interim analysis of the OLE (data cutoff: 10 January 2022, the point at which patient disposition was available for patients until OLE Week 94) included all patients on continuous ozanimod in the TN MP who achieved clinical response at Week 52 and enrolled in the OLE (n=131). Endoscopic and histologic endpoints were evaluated at OLE Weeks 46 and 94 (98 and 146 weeks of continuous ozanimod treatment, respectively) and reported using observed case analysis. Mean Mayo endoscopy scores were evaluated from TN baseline to OLE Week 94.

Results

Of the 131 total patients included in this analysis, 87% completed OLE Week 46 (98 weeks of continuous ozanimod) and 72% completed OLE Week 94 (146 weeks of continuous ozanimod). Patients had a mean age of 44 years and 52% were female. Most patients (68%) had left-sided UC, 69% had prior use of corticosteroids, 99% had prior use of 5-aminosalicylic acid, and 32% had prior use of tumor necrosis factor inhibitors. Most TN Week 52 clinical responders achieved endoscopic improvement (EI), HR, and MH at OLE Weeks 46 and 94 (Figure 1). Ozanimod treatment was associated with a reduction in mean Mayo endoscopy score to 1.0 at TN Week 52; this was sustained through OLE Week 94 (Figure 2).

Conclusion

In this interim analysis of the TN OLE, a large proportion of clinical responders after 1 year of ozanimod who remained on ozanimod for up to 2 years thereafter, achieved EI, HR, and MH after 2 and 3 years of continuous treatment. Long-term ozanimod use may be associated with sustained endoscopic and histologic benefits in patients with UC.
P476 Characterization of cardiac conduction abnormalities reported in the phase 3 ELEVATE programme
Authors: Vermeire S , Yarur A , Rubin D T , Dubinsky M C , Regueiro M , Irving P , Peyrin-Biroulet L , Goetsch M , Gu G , Wu J , Modesto I , McDonnell A , Rabbat C J , Green J , Anthopoulos P
Published: January 2023

Background

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). First-dose, transient heart rate (HR) reduction and cardiac conduction aberrations are a known, on-target effect of S1P receptor modulators. Here, we report characteristics of patients for whom adverse events (AEs) of bradycardia or atrioventricular (AV) block were reported in the phase 3 ELEVATE programme.

Methods

In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo on study day 1 with no dose titration regimen. Cardiac conduction was evaluated in all patients with a 12-lead ECG during the screening period, prior to randomisation on day 1 (baseline), and 4-hours post-dose. Bradycardia was considered an AE of special interest if the HR was <40 bpm, or <50 bpm with associated symptoms, or the event led to study discontinuation. AV conduction delays were considered an AE of special interest if second degree AV block (Mobitz Type I/II) or higher, first degree AV block with PR interval >230 ms, or if associated with clinical symptoms.

Results

A total of 9 events of bradycardia were reported in patients receiving etrasimod across both trials (Table 1). All but 1 event (8/9) were first reported on day 1 of treatment, with the remaining first reported on day 2 (none reported after day 2). Seven of 9 events were asymptomatic; the 2 symptomatic events (moderate dizziness; mild dizziness, palpitations) led to therapy discontinuation and resolved without additional intervention. No serious or severe events of bradycardia or hemodynamic changes were reported. Three AEs of AV block were reported in patients on etrasimod across both trials. All events occurred on day 1 during in-clinic ECG monitoring per study protocol and were nonserious, asymptomatic, and resolved without interventional treatment. Two events were first degree, one of which was pre-existing (treatment was discontinued); the other patient continued treatment and completed the study. The third event was second-degree (Mobitz Type I) (treatment was discontinued). Among the small sample size of 11 patients who experienced ≥1 AE of bradycardia or AV block, there were no baseline characteristics that could be used to predict these events (Table 2).

Conclusion

Cardiac AEs with etrasimod were generally rare, mild, asymptomatic, and occurred on day 1 in association with the first dose. This is consistent with other S1P receptor modulators. Data from the ongoing 5-year open-label extension will further characterize the etrasimod safety profile.
P483 Golimumab response in Ulcerative Colitis as early as week 2: What can we take from this?
Authors: Kumar L , O’Morain N , Sheridan J , Coe C , Egan C , Jones F , Cullen G , Doran P , Leyden J , Galligan M , McCarthy J , O’Toole A , Kevans D , Egan L , Doherty G ,   Investigator Network for Inflammatory Bowel Disease Therapy in Ireland (INITIative)
Published: January 2023

Background

Golimumab is a monoclonal anti-TNF drug used in the treatment of Ulcerative Colitis (UC). GOAL-ARC is a multi-centered investigator initiated randomized control trial seeking to evaluate the utility of personalized Golimumab dose adjustment in UC versus standard dosing as per summary of product characteristics (SMPC) post-induction. From early analysis data, we aimed to ascertain if Golimumab induces response at 2 weeks and if this early response impacts disease activity at 6 weeks and the need for dose escalation at this interval.

Methods

Patients recruited to the trial were randomized to an intervention or a standard dosing arm. Golimumab was administered at 200mg at week 0 and 100mg at week 2 with assessments at weeks 0, 2, and 6. Baseline data was obtained including patient demographics and burden of disease. Outcomes measured were clinical response (defined by a decrease in partial mayo score of 2 points or a decrease of ≥30% from baseline), change in Faecal Calprotectin (FCP) as well as improvement in Short Health Scale (SHS) score and serum golimumab levels at 6 weeks. We also looked at FCP≤250μg/g (STRIDE II – intermediate treatment target) as an outcome.

Results

A total of 94 patients were recruited with 90 (95.7%) patients completing 2-week follow up and 79 (84%) patients completing 6-week follow-up. The median age was 37 years (IQR 28-46), 58.5% were male, and 76.6% (n=72) had a Mayo endoscopic subscore of 2 and the median DUBLIN Score was 4 (IQR 4-6).

At 2 weeks, a clinical response was observed in 68.9% of patients (n=62). There was a significantly lower median modified partial mayo score (2 vs 4, p<0.001), rectal bleeding score (0 vs 2, p<0.001), stool frequency score (1 vs 2, p<0.001) and total SHS score (21.0 vs 25.8, p<0.001) after 2 weeks of treatment. The median FCP was numerically lower (354.7μg/g vs 1111.5μ/g, p=0.207) with an overall reduction by 32.5%. Patients who achieved a clinical response at 2 weeks were noted to have a lower baseline total SHS score (23.9 vs 29.0, p=0.017). 2-week response did not correlate with 6-week outcomes.

Median FCP was significantly lower at 6 weeks (254.2μg/g vs 1111.5μ/g, p=0.008) with an overall reduction by 74.0%. There was a significantly higher median Golimumab level in patients with FCP≤250μg/g at 6 weeks (5.59μg/ml vs 2.41μg/ml, p<0.001).

Conclusion

Golimumab shows efficacy in Ulcerative Colitis as early as 2 weeks with significant clinical response and a biochemical response. Early data suggests that response at 2 weeks, however, is not a reliable indicator of a sustained clinical response.
P488 Switch from intravenous to subcutaneous infliximab in patients with Inflammatory Bowel Disease: efficacy, safety and patients’ acceptance
Authors: Caballol Oliva B , Fernàndez-Clotet A , Panés J , Masamunt M C , Gallego M , Barastegui R , Vara A , Giner À , Ricart E , Ordás I
Published: January 2023

Background

A new formulation of biosimilar infliximab (IFX) has recently been approved for subcutaneous administration (SC) that may offer pharmacokinetic advantages resulting in higher drug exposure. Our purpose was to evaluate the efficacy, safety, pharmacokinetic changes and patients’ acceptability after switching from intravenous (IV) to SC IFX in a cohort of patients with Inflammatory Bowel Disease (IBD) in clinical practice.

Methods

Observational, prospective and single-center study including patients with IBD in sustained (≥6 months) clinical remission under IV IFX that were switched to SC IFX 120 mg every 2 weeks. Prospective monitoring was performed with clinical and laboratory data including IFX trough levels prior to the last IV infusion (W-IV), prior to the first SC administration (W-0), and after 16 weeks (W-16) and 52 weeks (W-52) of SC treatment. Patients’ satisfaction has been evaluated at W-52. A descriptive analysis of the data has been carried out with the R Studio statistical program using means and Wilcoxon signed rank test.

Results

Sixty patients have been included, all have achieved W-16 and twelve W-52. Thirty-five (58,3%) are men with a median age of 42,5 (20-71) years. Thirty-eight (63,3%) have Crohn’s disease and twenty-two (36,7%) ulcerative colitis, with a median disease duration of 11,3 years. They have been receiving IV IFX (5mg/kg/8 weeks in 95% of cases) for 5,7 (0,6-21,1) years, at a stable dose (≥6 months). Twenty-seven (45%) received concomitant immunomodulatory treatment and IFX was the first biological in 75% of patients. None of the patients presented clinical relapse during follow-up (Table 1). Median trough IFX levels under IV treatment were 3,9 µg/dl (W-IV) and 4,3 µg/dl (W-0). Compared to W-0, IFX trough levels were significantly higher both in W-16 [17,05 µg/dl (5,59–57,60), p<0,005] and in W-52 [16,75 µg/dl (8,65 –35,01), p=0,007], without significant differences between W-16 and W-52 (p=0,74) (Figure 1). None of the patients developed immunogenicity. Three adverse effects have been detected: 1 allergic reaction to the first SC dose and 2 mild skin reactions. At W-16 and W-52 the number of patients maintaining SC IFX treatment were 58/60 (96,7%) and 10/12 (83,4%) respectively. At W-52, all patients expressed high satisfaction with the change and would not like to return to IV treatment. All place the SC route as a preference above the IV.

Conclusion

Switching from IV to SC IFX is safe, effective, and well accepted by patients with stable IBD. A significant increase in IFX trough levels is observed with the SC formulation.
P504 Guselkumab, an IL-23p19 subunit–specific monoclonal antibody, binds CD64+ myeloid cells and potently neutralises IL-23 produced from the same cells
Authors: Atreya R , Abreu M T , Krueger J G , Eyerich K , Sachen K , Greving C , Hammaker D , Bao P , Lacy E , Sarabia I , Deming J , Elloso M M , Ritchlin C , McInnes I B , Allez M , Fourie A
Published: January 2023

Background

Monoclonal antibodies targeting the interleukin (IL)-23p19 subunit are effective in the treatment of inflammatory bowel diseases (IBD), but have different molecular attributes that may translate to differences in clinical efficacy. Within this class, guselkumab (GUS) is a fully human IgG1 monoclonal antibody with a native Fc region, and risankizumab (RIS) is a humanised IgG1 antibody with a mutated Fc region. Binding of these therapeutic antibodies to Fcγ receptor (FcγR) I, or CD64, is of particular interest, as CD64+ IL-23-producing myeloid cells are increased in the inflamed colon in IBD and correlated with endoscopic disease severity (Chapuy L, et al. Mucosal Immunol. 2019; Chapuy et al. J Crohns Colitis. 2020). Here, we compared functional characteristics of the antigen-binding and Fc regions of GUS and RIS.

Methods

IL-23 binding affinity of GUS and RIS was compared in vitro using KinExA and surface plasmon resonance. In vitro cellular potency of GUS and RIS was measured by impact on IL-23-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in human peripheral blood mononuclear cells. Binding of GUS and RIS to FcγRs was assessed in cells transfected with individual FcγRs. In primary human “inflammatory” monocytes differentiated with granulocyte-macrophage colony-stimulating factor and interferon-γ (IFN-γ) followed by toll-like receptor stimulation to induce IL-23 production, binding of GUS and RIS to CD64 and capture of endogenously secreted IL-23 was assessed using flow cytometry. The potential impact of GUS binding to CD64 was assessed in IFN-γ primed monocytes using a human 41-plex cytokine bead assay.

Results

GUS and RIS displayed comparable picomolar binding affinity for IL-23 and equivalent high potency for inhibition of IL-23-induced STAT3 phosphorylation. GUS showed strongest binding to CD64 compared with other FcγRs, whereas RIS had negligible binding to any FcγR. GUS, but not RIS, showed dose-dependent Fc-mediated binding to CD64 in primary human “inflammatory” monocytes. Moreover, CD64-bound GUS was able to simultaneously capture IL-23 endogenously secreted from the same cells (Figure). GUS binding to CD64 on monocytes did not induce cytokine production.

Conclusion

GUS, but not RIS, can simultaneously bind CD64+ myeloid cells via its Fc region and neutralise IL-23 with high affinity and potency. Our in vitro data suggest a mechanistic benefit through enhanced localization of GUS within the inflamed colon, where CD64+ IL-23-producing myeloid cells are increased, and GUS can potently neutralise IL-23 at its source of production. These findings may contribute to differences in therapeutic profiles between antibodies.
P518 Safety of upadacitinib in ulcerative colitis: Long-term data from the phase 3 open-label extension study (U-ACTIVATE)
Authors: Panaccione R , Lichtenstein G , Nakase H , Armuzzi A , Kucharzik T , Levy G , Palac H , Kujawski M , Klaff J , Cheon J H
Published: January 2023

Background

Upadacitinib (UPA), an oral reversible and selective JAK inhibitor, has demonstrated efficacy, with a well-characterised safety profile, in two replicate induction studies of UPA 45 mg once daily (QD; U-ACHIEVE induction and U-ACCOMPLISH), and a maintenance study of UPA 15 mg or UPA 30 mg QD (U-ACHIEVE maintenance).1 Here, we report safety data from the ongoing, Phase 3, open-label, 288-week long-term extension (LTE) study in patients with ulcerative colitis (UC) who previously participated in the induction studies.

Methods

Rates of treatment-emergent adverse events (TEAEs) and TEAEs of special interest were calculated by treatment sequence in patients who received ≥1 dose of UPA in the induction studies, maintenance study, or by the data cut-off of 13 December 2021 in the LTE study. Rates are presented as exposure-adjusted event rates (EAERs; events/100 patient-years [PYs]), except for events that typically occur as a single instance, which are presented as exposure-adjusted incidence rates (EAIRs; n/100 PYs). PYs were calculated from the first dose of UPA 45 mg received during induction through to the last UPA dose received or the data cut-off date for ongoing patients.

Results

Overall, 1,308 patients representing 2,350.2 PYs of UPA exposure were evaluated (mean age: 43 years; female: 38%). Across treatment groups, EAERs of serious TEAEs, severe TEAEs, TEAEs leading to UPA discontinuation, TEAEs with reasonable possibility of being related to UPA, or TEAEs leading to death were numerically similar across all UPA treatment sequences (Table 1). EAERs of serious infections, herpes zoster, neutropenia, hepatic disorder, and creatine phosphokinase elevation were numerically higher with UPA 15 mg and 30 mg vs placebo; and creatine phosphokinase elevation with UPA 30 mg vs UPA 15 mg (Table 2). The EAER of anaemia was numerically lower with UPA 30 mg vs UPA 15 mg and placebo. Of note, no remarkable differences were observed in EAIRs of adjudicated major adverse cardiovascular events, adjudicated venous thromboembolic events, or malignancy (excluding non-melanoma skin cancer).

Conclusion: Long-term use of UPA 15 or 30 mg among patients with UC continuing to benefit from prolonged therapy representing 2,350.2 PYs of exposure was well tolerated. The ongoing safety profile of UPA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses following 52 weeks’ maintenance therapy,1,2 or other immune-mediated indications for which UPA is approved.3,4
P532 1-Year Clinical Outcome of Subcutaneous Infliximab compared with Intravenous Infliximab in Patients with Inflammatory Bowel Disease During Maintenance Therapy
Authors: Song J H , Hong S N , Kim E R , Kim J E , Chang D K , Kim Y H
Published: January 2023

Background

Although pharmacokinetic profile of subcutaneous infliximab (SC IFX) is superior to conventional intravenous infliximab (IV IFX), long-term efficacy and safety of SC IFX have not been compared with those of IV IFX in patients with inflammatory bowel disease (IBD). This cohort study aimed to evaluate the loss of response (LOR) and durable remission in IBD patients treated with SC IFX after switching from IV IFX compared with those in IBD patients who continued IV IFX.

Methods

This prospective cohort study enrolled 61 IBD patients with clinical remission who received scheduled IFX maintenance therapy from May to September 2022. Of them, 38 patients were switched to SC IFX with a shared decision-making between patients and physician. After dose optimization, they were followed up for one year. Clinical remission was defined as HBI < 5 in in patients with Crohn’s disease (CD) and partial Mayo ≥ 2 in in patients with ulcerative colitis (UC). Biochemical relapse was defined as CRP ≥ 0.5 mg/dL in patients with CD and UC.

Results

LOR occurred in three (8%) patients of the SC IFX group and 5 (22%) patients of the IV IFX group, showing no significant difference between both groups (p = 0.140). The clinical and biochemical remission were not significantly different between the SC and IV groups (clinical remission: 20/23, 87% vs 33/38, 87%, p = 1.000; biochemical remission: 22/23, 96% vs. 34/38 89%, p = 0.641). The patients with IFX trough level < 3 μg/mL was significantly lower in the SC IFX group (0/38, 0%) than in the IV IFX group (10/23, 43%; p < 0.001). The incidence of IFX-related adverse events did not differ significantly between both groups (26% vs. 39%; p = 0.446).

Conclusion

SC IFX switch induced similar 1-year durable remission rate and safety profile with continuing IV IFX in patients with IBD during maintenance therapy. Pharmacokinetic profile was superior in patients treated with SC IFX compared with IV IFX.
P582 Efficacy of etrasimod at week 52 among subjects who reached clinical response at week 12: post hoc analysis of the phase 3 ELEVATE UC 52 trial
Authors: Vermeire S , Sands B E , Dubinsky M C , Feagan B G , Panaccione R , Jairath V , Yarur A , Chiorean M , Panés J , Goetsch M , Rabbat C J , Shah P , Wu J , Ghosh S
Published: January 2023

Background

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of ulcerative colitis (UC). The ELEVATE UC 52 trial utilized a treat-through design which evaluated efficacy at week 52 among all subjects randomised from baseline. Here, we report a post hoc analysis of efficacy at week 52 among subjects who did or did not achieve clinical response at the end of the 12-week induction period in ELEVATE UC 52.

Methods

In ELEVATE UC 52 (NCT03945188), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). This post hoc analysis assessed achievement of clinical remission, 12-week corticosteroid-free remission, endoscopic improvement, endoscopic improvement-histologic remission, and symptomatic remission at week 52 among subjects with baseline MMS 5-9 who did or did not achieve clinical response criteria at week 12 (defined as a ≥2-point and ≥30% decrease from baseline in MMS and a ≥1-point decrease from baseline in rectal bleeding subscore or an absolute rectal bleeding subscore ≤1).

Results

At week 12 in ELEVATE UC 52, 171 (62.4%) etrasimod-treated subjects vs 46 (34.1%) PBO-treated subjects achieved clinical response (P<0.001) and were included in the week 52 clinical responder analysis. Among clinical responders at week 12, subjects treated with etrasimod were more likely to be in clinical remission at week 52 vs PBO (49.1% [n=84/171] vs 17.4% [n=8/46]; P<0.001) (Figure 1). Similar results were observed for the achievement of all other efficacy endpoints at week 52 among those who met clinical response criteria at week 12 (all P<0.05). At week 12 in ELEVATE UC 52, 103 (37.6%) etrasimod-treated subjects and 89 (65.9%) PBO-treated subjects either did not achieve clinical response at week 12 or had discontinued the study prior to the week 12 assessment. There were no significant treatment differences in achievement of efficacy endpoints at week 52 among subjects who did not achieve clinical response at week 12.

Conclusion

Among subjects who reached clinical response criteria at week 12, greater proportions of etrasimod-treated subjects vs PBO-treated subjects achieved week 52 efficacy across both objective and subjective measures of disease activity. Among subjects who did not reach clinical response or had discontinued prior to week 12, no significant treatment differences were observed at week 52 between etrasimod-treated subjects vs PBO-treated subjects. These results may help contextualize the 52-week efficacy results of ELEVATE UC 52 when considering other treatments that utilized re-randomisation of responder designs.
P613 Switch from intravenous to subcutaneous maintenance infliximab in real world IBD cohort
Authors: Mcgrory L , Goess C , Lynch K
Published: January 2023

Background

During the COVID-19 pandemic, there has been concern regarding patients attending hospitals for intravenous (IV) infusions due to increased COVID-19 exposure risk and demand on hospital resources. Data on switching patients from escalated dosing of IV infliximab (IFX) are limited. We describe a real-world experience of electively switching a cohort of patients on maintenance IV IFX for inflammatory bowel disease (IBD), at both standard and escalated dosing, to subcutaneous CT-P13 (Remsima®).

Methods

Adult patients with IBD on IV IFX at Royal Adelaide Hospital were invited to switch to fortnightly dosing of subcutaneous IFX. We collected demographic data using medical records, and prospectively measured clinical assessment scores (CDAI/HBI for Crohn’s disease (CD) and partial Mayo/SCCAI for Ulcerative Colitis (UC)), faecal calprotectin (FCal), CRP and trough IFX levels prior to switching to subcutaneous IFX, and at 6 months post switch. Clinical remission was defined as CDAI≤150/HBI≤4 (CD) or partial Mayo≤3 (no subscore>1)/SCCAI≤2 (UC).

Results

29 patients were switched from IV IFX to subcutaneous CT-P13 between March 2021 and May 2022 (see Table 1 for baseline demographics). 23 had Crohn’s disease (79%). 10/29 patients (31%) were on intensified IV dosing at baseline prior to switch. The majority of patients, 25/29 (86%) were in remission pre-switch.

Of 19 patients with paired trough IFX levels, these increased significantly from baseline to 6 months post-switch (5.9mg/ml to 13.9mg/ml, respectively (p=0.0003), see Fig 1). The median FCal did not change pre- vs post switch (73mcg/g vs 80mcg/g, p=0.540), see Fig 2). Median CRP did not change pre- vs. post switch (1 µg/ml vs 2 µg/ml). Clinical assessment scores remained stable pre- vs. post-switch (CDAI 31 vs 31, (p=0.316) see Fig 3; HBI. 1 vs 2 (p=0.940); partial Mayo 0 vs 0, (p>0.999); and SCCAI 1 vs 2 (p=0.5000)).

Regarding the subset of patients on escalated dosing at baseline, all patients were in clinical remission at 6 months post-switch. There was no significant change in IFX levels (8.4 vs 13.3, p=0.253). FCal did not significantly change (76mcg/g vs 79mcg/g (p=0.563), nor did median CDAI (37 vs 21 (p=0.5312) and median HBI (2 vs 2 (p=0.750)).

Overall, only 1/29 (3%) patients were not in remission at 6 month follow-up. No patients in required steroids or surgery. Of the 9 patients with perianal disease, none had a flare. All patients with weight>100kg (n=4) remained in remission.

Conclusion

Switching patients from IV to subcutaneous IFX delivered stable clinical outcomes in this real world cohort, with no change in disease biomarkers and clinical indices. IFX levels increased overall and all patients on escalated IV dosing were in clinical remission at 6 months post-switch.
P618 Long-term real-world data of Ustekinumab in Ulcerative Colitis – the Stockholm Ustekinumab study – STOCUSTE
Authors: Sabhan H ,   C1 Lördal M2 Johansson F3 Bello F4 Muhsen S2 Wennerström C5 Forsberg O5 Borin A6 Almer S4 Höög C7 Söderman C1
Published: January 2023

Background

Background: Ustekinumab (UST) is an anti-interleukin-12/23 antibody in the treatment of inflammatory bowel disease (IBD), mainly used in patients failing anti-TNF-agents. The STOCUSTE study includes patients treated at four hospitals in Stockholm to provide long-term real-world data.

Methods

Methods: This was a retrospective study including patients diagnosed with ulcerative colitis and treated with UST between years 2016 and 2021. The patients were followed from start of UST until withdrawal of treatment for any reason, or until end of study follow-up, July 31, 2021.We assessed disease activity; Physician Global Assessment (PGA); Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score, laboratory parameters and drug persistence. The primary outcome was remission (PGA = 0) and response (decrease PGA ≥ 1 from baseline) at 3 and 12 months, respectively.

Results

Results: 96 patients, 44 women and 52 men were included. The patients had either extensive colitis (68%), left-sided colitis (29%) or proctitis (3%). All but two patients were anti-TNF-experienced; 94 (98%) had failed ≥1, 59 (61%) ≥2 and 34 (35%) ≥3 anti-TNF-drugs. At inclusion 92 patients (96%) had active disease and 4 patients were in remission, 48 (50%) were on oral or topical corticosteroids, 13 (14%) had thiopurines. At 12 months only 9% were on oral or topical corticosteroids. Among patients who were treated with UST, 9/71 (6%) were in remission at 3 months, and 26/33 (78%) patients were in remission at 12 months. Withdrawal from treatment during the first 12 months was 36 (38 %), mainly due to persisting disease activity (20%); 8% were withdrawn due to adverse events, 2% needed bowel surgery, and 2% were lost to follow up.

Conclusion

Conclusions: In this group of difficult-to-treat patients with ulcerative colitis, Ust was shown to be effective in the majority, with high drug persistence at 12 months in combination with a favorable safety profile.
P621 Combination treatment of biologics with immunomodulator increases risk of infection after discharge in biologics naive steroid refractory acute severe ulcerative colitis patient: A KASID multicenter study
Authors: Kim S J , Lee J , Kim D H , Park S H , Kim E S , Kim K O , Lee Y J , Song E M , Kim D S ,   IBD Research Group in Korean Association for the Study of the Intestinal Diseases (KASID)
Published: January 2023

Background

Biologics such as infliximab is the main treatment for steroid refractory acute severe ulcerative colitis (ASUC), However, there are only a few studies on the effectiveness and safety of biologics in steroid refractory ASUC. In this study, we evaluated the effectiveness and safety of biologics as a rescue therapy for biologics naïve steroid refractory ASUC patient in Korea.

Methods

We retrospectively included patients who were hospitalized at seven tertiary medical centers for ASUC management between January 2015 to December 2020, and data on the demographic and clinical variables, disease activity, treatment method, treatment response, adverse event, readmission due to any reasons were checked

Results

A total of 230 ASUC patients were included, of which 220 were biologic naïve patient. The response rate of steroid in these patients was 74%, and infliximab was administered as rescue therapy to 53 patients who failed initial steroid treatment. The response rate to infliximab as rescue therapy was 96%, and 2 patients who did not respond received colectomy. One of the two patients who underwent colectomy died of sepsis. There was no infliximab-related adverse event during hospitalization. Although infliximab itself was not a factor associated with infection after discharge (10% vs. 16%, p=0.355), combination therapy with thiopurine was a risk factor for infection after discharge. (Odd ratio 7.302, 95% CI 2.101-25.372, p=0.002). A total of 12 infections occurred in patients treated with infliximab after discharge (3 pneumonia, 1 skin infection, 3 cytomegalovirus colitis, 4 Clostridium difficile infection) and were associated with readmission. (40.1% vs. 75%, p=0.031)

Conclusion

As a rescue therapy in biologics naive steroid refractory ASUC, infliximab showed a 96% therapeutic response. Although infliximab itself did not increase the risk of infection after discharge, the combination with thiopurine increased the risk of infection after discharge
P693 Italian real-life study evaluating the long-term effectiveness of vedolizumab for the treatment of Inflammatory Bowel Disease- An IG-IBD study
Authors: Pugliese D , Privitera G , Armuzzi A ,   IG-IBD LIVE Studygroup
Published: January 2023

Background

Real-world studies on vedolizumab (VDZ) are often limited by small sample size and short follow-up and there is still lack of knowledge regarding predictors of response. Our study aims to evaluate the long-term effectiveness and safety of VDZ in a large cohort, and to identify clinical features for precision medicine.

Methods

The Long-term Italian VDZ Effectiveness (LIVE) study included CD and UC patients started on VDZ from 04/2016 to 06/2017 at 47 Italian centers and prospectively followed-up until 06/2019. The primary endpoint was steroid-free clinical remission (SFCR) at 12 months (mo), defined as clinical remission + no steroid therapy in the previous 3 mo. Secondary endpoints included treatment persistence and safety. An eXplainable Artificial Intelligence (XAI) model (XGBoost) was used to predict 12 mo-SFCR. To assess the model performances, F1-score was adopted.

Results

We enrolled 1111 patients (564 CD, 547 UC). At baseline, mean age and disease duration were 47.7(±16) and 11.8(±9) years; 256 (23%) patients were bionaïve. SFCR was reported in 193 (34.3%) and 178 (31.6%) CD patients, and in 205 (41.9%) and 215 (42.6%) UC patients, at 12 and 24 mo (p=ns for all). Cumulative treatment persistence at 12 and 24 mo was 73.3% and 67.3%, respectively. A significantly longer persistence was observed among bionaïve compared to bioexperienced CD patients (p=0.04), but not in UC. At least 1 adverse event (AE) was experienced by 230 patients (20.8%), causing VDZ withdrawal in 58 (5.2%) of them; the most common AEs were infections. The trained machine learning (ML) algorithm was used to predict 12 mo-SFCR. To minimize the bias introduced by the imbalanced dataset, a data augmentation technique (Synthetic Minority Over-sampling Technique, SMOTE) was introduced. The predictive model’s accuracy (F1 score) was 0.85. To explore the relations among the variables for the predicted outcome, Shapley Additive exPlanations (SHAP) was adopted. Figure 1 presents the 8 best features, hierarchically listed, with their average impact on the outcome. Figure 2 shows how the value taken by each feature contributes to predicting 12 mo-SFCR (dots close to the 0 line predict SFCR). The most important variables. correlating with 12 mo-SFCR were No exposure to anti-TNF, male sex and no baseline steroid therapy.

Conclusion

In this preliminary analysis, about 1/3 of VDZ-treated patietns achieved 12 mo-SFCR. With ML, we identified the most important predictors of SFCR and estimated their impact on it. XAI is a promising tool in precision medicine, as it helps reconciling sophisticated models with the biological explainability of data.
P773 Extended induction in the True North open-label extension study: clinical outcomes of ~2 years of ozanimod treatment
Authors: Vermeire S , Colombel J F , Chiorean M V , Ghosh S , Jain A , Lawlor G , Osterman M T , Wu H , Canavan J B , Rubin D T
Published: January 2023

Background

Ozanimod is approved in the EU, US, and other countries for the treatment of moderately to severely active ulcerative colitis in adults. In the phase 3, 52-week, double-blind True North (TN) study, Week 10 clinical nonresponders to ozanimod could enter the open-label extension (OLE) to continue treatment. Previous analysis showed that approximately 50% of Week 10 nonresponders achieved symptomatic clinical response with extended induction during the OLE in as early as 5 weeks. The current analysis evaluated long-term clinical and symptomatic endpoints up to 2 years in this delayed responder subgroup.

Methods

Efficacy data were analysed for TN Week 10 ozanimod nonresponders who subsequently received open-label ozanimod in the OLE, both by whole subgroup and original study arms (double-blind [Cohort 1] and open-label ozanimod [Cohort 2]) (data cutoff: January 10, 2022). Endpoints included symptomatic clinical response, symptomatic clinical remission, total Mayo score, clinical response, clinical remission, and corticosteroid (CS)-free remission up to OLE Week 94 (104 weeks of continuous ozanimod treatment). Data were evaluated using observed case (OC) and nonresponder imputation (NRI) analyses.

Results

A total of 226 nonresponders at TN Week 10 entered the OLE (Cohort 1, n=150; Cohort 2, n=76). Males comprised 67% of this subgroup, and mean (SD) age was 39.6 (13.6) years. Symptomatic clinical response (Figure 1), symptomatic clinical remission, and reduction in partial Mayo scores were observed as early as OLE Week 5 and were maintained through OLE Week 94. Minimal change in total Mayo score was observed from TN Week 0 (baseline) to TN Week 10 (OLE Week 0), but significant reductions from baseline occurred by OLE Week 46 (–4.2 [2.7]) and OLE Week 94 (–5.3 [2.6]). Overall, 62% of patients achieved clinical response, 26% achieved clinical remission, and 24% achieved CS-free remission at OLE Week 46; these increased to 74%, 35%, and 33%, respectively, by OLE Week 94 in the OC analysis (Figure 2). Data were similar between Cohorts 1 and 2.

Conclusion

Symptomatic response in ozanimod nonresponders was observed as early as 5 weeks after extended induction with ozanimod. Delayed response to ozanimod was maintained for up to 2 years as demonstrated by both symptomatic and objective endpoints. Even in those with delayed initial response, efficacy of ozanimod was durable.