Severe Active Ulcerative Colitis Research Articles

P1155 Safety of Venous Thromboembolism Pharmacological Prophylaxis in Hospitalized Patients with Inflammatory Bowel Disease; A Single Center Retrospective Study (VISCOUS)

Abstract Background Hospitalization secondary to inflammatory bowel disease flare is a significant risk factor for venous thromboembolism (VTE). International guidelines recommend the use of pharmacological VTE prophylaxis; however, the risk of bleeding is unknown. We therefore aimed to evaluate the safety of pharmacological thromboprophylaxis in hospitalized patients with IBD. Methods This was a retrospective cohort study. A chart review of patients’ electronic health records with IBD hospitalized between August 2017 to December 2023 was reviewed. Our primary outcome is evaluating the safety of pharmacological VTE prophylaxis. This was investigated by examining increased bleeding risks during admission, which included worsening bloody stool frequency, drop in hemoglobin (>1g/dL from baseline) and development of hemorrhagic shock after starting VTE prophylaxis. Worsening bloody stool frequency was defined as increased bloody stool frequency >1 from baseline before starting VTE prophylaxis. Finally, any major bleeding was also considered. Results Between August 2017 and December 2023, 1045 patient encounters were reviewed. 524 patients met the study inclusion and exclusion criteria, of which 98 had missing information and 73 were duplicates and could not be included. Finally, 353 patients were included in our study. Mean age 34.7 years, 205 (58%) were female males and mean duration of hospitalization was 9 days. Majority of patients were hospitalized with acute severe ulcerative colitis (ASUC) 213 (60.3%), and 140 (39.7%) had Crohn’s disease (CD) flare. Of the total cohort, 264 (75%) patients received enoxaparin 40 mg for VTE prophylaxis, and the 89 (25%) patients received 5000 units of unfractionated heparin twice a day (figure 1). Eighteen (%5) patients had a history of VTE, and 4 female patients had VTE during admission. None of our cohort had any bleeding events including worsening bloody stool frequency, drop in hemoglobin, major bleeding and development of hemorrhagic shock after starting VTE prophylaxis up to the period patients were discharged. Conclusion we found no increased risk of gastrointestinal bleeding in patients admitted with IBD on pharmacological VTE prophylaxis. Therefore, it is important to reassure healthcare providers about the safety of pharmacological VTE prophylaxis in IBD and adopt strategies that guarantee prophylaxis is administered during hospitalization. Although that a balance should be established between the benefits and risks. References -Pleet JL, Vaughn BP, Morris JA, et al. The use of pharmacological prophylaxis against venous thromboembolism in hospitalised patients with severe active ulcerative colitis. Aliment Pharmacol Ther [Internet]. 2014;39(9):940–948. -Dawwas GK, Cuker A, Schaubel DE, et al. Effectiveness and safety of prophylactic anticoagulation among hospitalized patients with inflammatory bowel disease. Blood Adv [Internet]. 2024;8(5):1272–1280. -Kaddourah O, Numan L, Jeepalyam S, et al. Venous thromboembolism prophylaxis in inflammatory bowel disease flare-ups. Ann Gastroenterol. 2019;32(6):578–583.

P0717 Real-world data of Mirikizumab in the induction and maintenance therapy for ulcerative colitis

Abstract Background Mirikizumab, a humanized IgG4 monoclonal antibody binding subunit p19 of interleukin 23, has been approved for the therapy of ulcerative colitis since May 2023. Phase 3 studies showed significant efficacy in both inducing and sustaining clinical remission in patients with moderate to severe active ulcerative colitis. Methods All patients with active ulcerative colitis who began induction therapy with Mirikizumab at our outpatient clinic between July 2023 and June 2024 were analyzed retrospectively with a follow-up period until October 2024. Patients with prednisolone therapy exceeding 20 mg, loperamide intake or deviation of standard clinical application period were excluded. The primary endpoints were defined as achieving clinical remission following the completion of intravenous induction (at weeks 12, 16 or 24) and the maintenance of clinical remission at any time between week 8 and week 49 following the initiation of subcutaneous application. Secondary endpoints included rates of clinical remission and relapse in patients previously treated with Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin-12 and -23. Results A total of 40 patients started Mirikizumab induction therapy, with 23 meeting the inclusion criteria. Seventeen patients were observed in the maintenance period. After completion of induction, 20 out of 23 patients (87.0%) achieved clinical remission. Among these, 12 (60.0%) had previously been treated with Ustekinumab. During the maintenance period, 6 out of 17 patients (35.3%) experienced a relapse, of whom 5 (83.3%) had prior therapy with Ustekinumab. Within the Ustekinumab subgroup, 5 out of 10 patients (50.0%) suffered relapse after initially achieving clinical remission. Conclusion Mirikizumab is an effective therapy in patients with active ulcerative colitis, including those who had a prior loss of response to Ustekinumab therapy. Patients with prior Ustekinumab therapy exhibited a higher rate of relapse during the maintenance phase.

P0689 A clinical study on the optimization of vedolizumab induction therapy for moderate to severe active Ulcerative Colitis at week 10

Abstract Background To observe the clinical efficacy of adding one dose of vedolizumab induction therapy in the 10th week for the treatment of moderate to severe active Ulcerative Colitis (UC), evaluate its effectiveness and safety, and provide clinical reference for the treatment plan of UC patients. Methods This study included a total of 80 UC patients who sought medical treatment at the Department of Gastroenterology at Shengjing Hospital of China Medical University from January 2020 to January 2025. They were divided into two groups: the experimental group (31 cases) received treatment with vedolizumab at weeks 0, 2, 6, 10, and 14, while the control group (49 cases) received treatment with vedolizumab at weeks 0, 2, 6, and 14 for at least 14 weeks. The changes in indicators such as modified Mayo score, Mayo endoscopic score, C-reactive protein (CRP), and safety analysis were observed before and after treatment in both groups. Clinical remission rate, clinical response rate, endoscopic remission rate, and endoscopic response rate were compared. Results The clinical response rate of the experimental group was 100%, significantly higher than the control group’s 84.62% (P<0.05). The endoscopic response rate of the experimental group was 85.71%, significantly higher than the control group’s 57.50% (P<0.05). There was no significant difference between the experimental group and the control group in terms of clinical remission rate and endoscopic remission rate (P>0.05). The CRP levels before and after treatment were significantly reduced between the two groups (P<0.05), and there was no significant difference in the number of patients with normal CRP levels between the groups (P>0.05). Conclusion Adding vedolizumab induction once in week 10 can significantly improve clinical and endoscopic response rates, but more research is needed in terms of clinical and endoscopic response rates.

P1111 Infliximab is not Superior to Vedolizumab for the Treatment of Moderately to Severely Active Ulcerative Colotis with PR3-ANCA Positive : A Retrospective Multicentre Real-World Study

Abstract Background Current literature presents conflicting findings about the efficacy of Infliximab (IFX) versus vedolizumab (VDZ) in patients with moderately to severely active ulcerative colitis (UC). Patients with UC who are positive for anti-neutrophil cytoplasmic antibodies(ANCA) are known to respond poorly to IFX1-3 and VDZ4. We aimed to evaluate the comparative efficacy and safety of IFX versus VDZ in moderately to severely active UC patients with Proteinase 3-ANCA(PR3-ANCA) positive. Methods This retrospective multicentre real-world study was conducted in three centers in Hubei, China. Patients with moderate to severe active ulcerative colitis (UC) who are positive for PR3-ANCA were allocated to either the Vedolizumab (VDZ) group (n=19) or the Infliximab (IFX) group (n=26) depending on the biologics they received. The endpoints assessed at week 22 included clinical remission(primary endpoint), clinical response, endoscopic response, and endoscopic remission. Inverse probability of treatment weighting (IPTW) was employed to ensure the reliability and robustness of the clinical outcomes. Results In the original cohort, IFX was not superior to VDZ in terms of clinical remission (23.08% vs. 42.11%, P=0.173), clinical response (65.38% vs. 63.16%, P=0.878), endoscopic response (57.69% vs. 63.16%, P=0.712), and endoscopic remission (11.54% vs. 26.32%, P=0.253). Additionally, similar outcomes were observed in the IPTW cohort: for clinical remission (23.26% vs. 35.89%, P=0.384), clinical response (68.68% vs. 60.29%, P=0.583), endoscopic response (58.48% vs. 60.29%, P=0.912), and endoscopic remission (14.18% vs. 22.75%, P=0.494) when comparing IFX to VDZ. Conclusion IFX is not superior efficacy compared to VDZ in moderately to severely active UC patients with PR3-ANCA positive.

P0889 Efficacy and safety of obefazimod for the fourth and sixth year of open-label maintenance treatment in patients with moderately to severely active ulcerative colitis (UC): 2-year interim analysis after dose de-escalation to 25 mg

Abstract Background Obefazimod is an investigational, oral, once-daily (QD), small molecule which enhances expression of microRNA-124. Obefazimod demonstrated efficacy and safety in patients with moderate to severe active UC at week-8 in two double-blind, placebo-controlled induction trials and in subsequent open-label maintenance (OLM) studies [1-3], and a randomized controlled phase 3 study, ABTECT, is ongoing. Methods Patients with UC on obefazimod 50mg QD with endoscopic improvement (Mayo Endoscopic subscore = 0 or 1), could enrol in an open label study in which they were administered obefazimod 25mg QD for up to an additional 54 months. This interim analysis (cut-off date: September 11, 2024) reports the findings of patients who completed Weeks 48 (W48) and 96 (W96) visit (as observed analysis). Results Patients with UC were treated with obefazimod 50mg QD for approximately four years in the Phase 2a OLM study and for approximately two years in the Phase 2b OLM study. Out of 174 patients who completed these studies (10 in Phase 2a OLM, 164 in Phase 2b OLM), 138 were eligible. As of the cut-off date, 130 patients rolled over in the 25 mg OLM and were dosed. Among this cohort, 16 patients (12%) discontinued prior to W48 and 6 (5%) discontinued between W48 and W96. Overall, 113 patients (87%) completed the W48 visit, 74 (57%) completed the W96 visit. After dose de-escalation, rates of clinical remission at W48 and W96 were 84% (95/113) and 87% (64/74), respectively. At W48 and W96, 91% (103/113) and 91% (68/75) of patients were in symptomatic remission, respectively. Similar trends were observed with other efficacy analyses (Table 1). At W48, the levels of fecal calprotectin (FCP) were <250 and <150 µg/g for 90% (85/94) and 81% (76/94) of patients with available FCP values, respectively. At W96, 75% (49/65) of patients had FCP levels <250 µg/g, and 69% (45/65) had levels <150 µg/g. No new safety findings were identified over these 96 weeks. Conclusion Following 2-4 years of open-label treatment with obefazimod at a dose of 50 mg QD, large percentages of patients maintained efficacy measures on a lower maintenance dose of 25 mg od for two additional years. No new safety signals were observed over up to six years of obefazimod treatment, supporting a favorable long-term risk-benefit profile.

P0580 Efficacy and safety results of tulisokibart re-induction treatment in participants with ulcerative colitis in the Phase 2 ARTEMIS-UC clinical trial

Abstract Background Tulisokibart is a monoclonal antibody that targets tumor necrosis factor-like cytokine 1A (TL1A), a regulator of inflammation and fibrosis in inflammatory bowel disorders such as ulcerative colitis (UC). The Phase 2 ARTEMIS-UC study demonstrated a significantly higher proportion of tulisokibart vs. placebo participants achieving clinical remission after 12 weeks of treatment1. This analysis evaluates the effects of re-induction treatment in participants who were non-responders during the initial 12-week induction period of the study. Methods Participants (≥18 years) of moderate to severe active UC, with conventional or advanced treatment failure, were randomized (1:1 ratio) to placebo or the 12-week induction treatment (intravenous tulisokibart 1000 mg, Day 1 and 500 mg, Weeks 2, 6, and 10). The study population consisted of 2 cohorts based on a genetic diagnostic test (Dx) assessing likelihood for responding to anti-TL1A treatment. Cohort 1 included participants stratified by Dx results while Cohort 2 included only Dx positive participants. Cohort 1 is the population used in these post-hoc analyses evaluating induction non-responders. Induction non-responders in either the tulisokibart or placebo groups were assigned to an open label 12-week re-induction with aforementioned induction dosing regimen (non-responders are defined as participants who did not achieve reduction of ≥2 points and ≥30% in modified Mayo score from baseline, accompanied by a reduction ≥1 in rectal bleeding sub score or absolute rectal bleeding sub score ≤1 at week 12). Efficacy and safety were assessed following the re-induction treatment at Week 26. Results In Cohort 1, 67 and 68 participants were randomized to receive placebo or tulisokibart induction treatment, respectively. At Week 14, 41 (placebo) and 21 (tulisokibart) induction non-responders entered re-induction and received 12-week open label tulisokibart treatment. At Week 26, 48% and 63% of participants who received initial 12-week of tulisokibart treatment (total 24-week tulisokibart treatment) and 63% and 76% of participants who received initial 12-week placebo treatment (total 12-week tulisokibart treatment) achieved symptomatic improvement and symptomatic response, respectively (Table). Re-induction with tulisokibart was well tolerated with no serious AEs or discontinuations due to AEs and no new safety signals (Table). Conclusion Re-induction treatment with tulisokibart is effective in participants who did not respond to initial induction treatment. Additionally, up to two tulisokibart induction regimens totaling 24 weeks is well tolerated with no new safety signals identified.

P1048 Vedolizumab in Indian patients with Inflammatory Bowel Disease: Final results from a prospective, multicentre, open-label, phase 4 study

Abstract Background India has rising prevalence of Inflammatory Bowel Disease (IBD), with an estimated 1.4 million cases reported in 2010.¹ Vedolizumab (VDZ) has demonstrated safety and effectiveness internationally as an alternative for achieving clinical response and remission. 2,3 There is limited data on VDZ’s efficacy and safety for Indian patients. This study provides the first focused evaluation of VDZ in this population. Methods In this prospective, multicenter, open-label phase IV study (NCT04804540), patients aged 18–65 with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD) unresponsive to corticosteroids, immunomodulators or anti-TNF agents received VDZ 300 mg intravenously at weeks 0, 2, and 6 (induction) and at weeks 14, 22, 30, 38, and 46 (maintenance). Patients had diagnosis of moderate to severe active UC or CD with a Full Mayo Score of 6-12 for UC and Harvey Bradshaw Index (HBI) of ≥8 for CD at the time of enrollment. Clinical remission was defined as Simple Clinical Colitis Activity (SCCAI) ≤2 for UC or HBI ≤4 for CD, while clinical response was defined as an SCCAI decrease of ≥3 or physician assessed response for UC and HBI decrease of ≥3 for CD. The primary objective analyzed the safety of VDZ in Indian UC or CD patients, with a secondary objective of assessing efficacy. The final analysis included data up to Week 46 or patient discontinuation. Results Of 215 patients screened, 150 were enrolled (102 with UC: median age 39 years; 48 with CD: median age 31 years). The median treatment duration was 325 days for UC and 323 for CD. AEs affected 83 patients (55.3%), with mild AEs in 72 (48%). TEAEs occurred in 52 (51%) patients with UC and 29 (60.4%) with CD, while SAEs occurred in 8 (5.3%) patients, with 2 treatment- related. Additionally, 5 patients (3.3%) had at least 1 ADR, and 4 (2.7%) had AESI. Reported ADR/AESI cases included one patient each with pulmonary tuberculosis, tuberculous pleurisy, rectal adenocarcinoma, and hypertension. Anaemia was most common TEAE, and small intestinal obstruction was most frequent SAE. No AE related deaths occurred(Table 1). Overall clinical response rates were 60.7% at Week 14, 65.3% at Week 30, and 72% at Week 46. Remission rates were 42% at Week 14, 44% at Week 30, and 53.3% at Week 46(Fig 1). Mucosal healing was observed in 27/150 (18%) patients at week 46. Quality of life scores showed improvements across both UC and CD groups, with median Short Inflammatory Bowel Disease Questionnaire score increases noted from baseline of 5 at week 14 to 13 at week 46 in both groups. Conclusion This study demonstrates that vedolizumab has a good safety profile in Indian patients with moderate-to-severe UC and CD, offering well-tolerated option for achieving clinical response and remission.

Comparison of ustekinumab, infliximab and combination therapy in moderately to severely active ulcerative colitis - a study protocol of a randomized, multicenter, head-to-head COMBO-UC trial.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex etiology that affects the large intestine. Characterized by chronic, bloody diarrhea, UC can lead to severe complications, including an increased risk of colorectal cancer. Despite advancements in conservative treatment, including biologics like anti-TNF agents and ustekinumab (UST), many patients do not achieve full remission. Dual targeted therapy (DTT) combining infliximab (IFX) and UST is a promising approach to improve treatment outcomes. This prospective, randomized, multicenter, head-to-head controlled trial will evaluate the efficacy and safety of UST, IFX, and combination therapy (UST + IFX) in 172 patients with moderate to severe active UC across eight gastroenterology centers in Poland. The study includes a 14-16 week remission induction period followed by a 52-week maintenance phase. Patients will be randomly assigned to one of three treatment arms: IFX monotherapy, UST monotherapy, or IFX + UST combination therapy. Primary endpoint is clinical and endoscopic remission post-induction. Secondary endpoints include clinical response, biochemical remission, histological remission, and quality of life assessments using the Inflammatory Bowel Diseases Questionnaire and 36-Item Short Form Survey. Safety will be monitored through adverse event and serious adverse event reporting. This trial aims to determine whether combining IFX and UST can achieve higher remission rates and better long-term outcomes compared to monotherapy. The results could provide crucial insights into the optimal use of biologic agents in UC treatment, potentially establishing DTT as a standard therapy. The study's design, including extensive follow-up and robust endpoint measures, will contribute to understanding the therapeutic potential and safety profile of this combination therapy.

Safety and effectiveness of tofacitinib in Korean adult patients with ulcerative colitis: post-marketing surveillance study

BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea.MethodsThis open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator’s discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks.ResultsA total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks.ConclusionTofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib.SummaryThis study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings.Trial registrationThis study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019.

P718 Observational real-world evidence on the efficacy and safety of Janus Kinase inhibitors (JAKi) in the treatment of moderate to severe Active Ulcerative Colitis (UC)

Abstract Background Janus kinase inhibitors (JAKi) are the first orally administered treatment for Ulcerative Colitis (UC). The JAK family comprises of four intracellular tyrosine kinases inhibitors (JAK1, JAK2, JAK3 and Tyrosine Kinase 2). Inhibition of the JAK kinases lead to dampening of the inflammatory cytokines which drive Inflammatory Bowel Disease (IBD). Tofacitinib was the first generation pan-JAKi. This was followed by second generation JAKi: Filgotinib and Upadacinib which preferentially inhibit JAK1. We report on the real-world evidence on the efficacy and safety of JAKi in the treatment of UC in a tertiary IBD treatment centre. Methods Patients attending the IBD clinic at weeks 8-12 of initiation of therapy were included. Baseline demographics, disease activity and previous therapies were recorded. Clinical response was measured using the SCCAI and biochemical response was measured using calprotectin and CRP. We defined clinical response as ≥3 points reduction from baseline SCCAI, and clinical remission as SCCAI Score of <2.5, and / or biochemical remission as a CRP of less than 5 mg/L and a calprotectin level of < 250 mg/g. We also assessed treatment persistence, and the reasons for treatment cessation. Results The UC populations are shown in Table 1. 52 patients were included and an additional 24 patients who discontinued therapy early on were assessed to review secondary outcomes. Table 1 summarises the comparative outcomes of the JAKi. 81% and 63% of patients achieved clinical and biochemical remission respectively. Overall, 31% discontinued treatment due to lack of efficacy or adverse events. 60% of patients reported adverse events (AEs), 25 % of patients discontinued treatment due to AEs and 84% of patients continued treatment despite reporting AEs. The most common AEs were hypercholesteremia and cold and flu like symptoms and the most common AEs related with treatment discontinuation were recurrent infection or persistent deranged liver functions contributed to patients’ history of primary sclerosing cholangitis. No Serious Adverse Events were reported. 60% of patients on tofacitinib developed side effects and persisted with therapy, which included hypercholesteremia (67%), shingles (11%), flu like symptom (11%) and hair loss (11%). 53% had side effects with Filgotinib; hypercholesteremia (25%), cold like symptoms (25%), chest infection (13%), shingles (13%), acne (13%). 68% developed side effects with Upadacitinib; reports of acne (20%), cold and flu (33%), shingles and mood swings (7%) and high cholesterol (67%). Conclusion In this real-world cohort of UC patients, JAKi was effective in inducing remission and had an acceptable safety profile. The observed safety profile was as expected compared to clinical data results.

Health Status, Quality of Life, Psychosocial Well-being, and Wearables Data of Patients With Active Ulcerative Colitis Receiving Filgotinib Therapy (FilgoColitis Study): Protocol for a Real-world Observational Study.

Filgotinib was approved in Germany for treating patients with moderate to severe active ulcerative colitis in November 2021. It represents a preferential Janus kinase 1 inhibitor. The FilgoColitis study began recruiting immediately after approval and aims to assess filgotinib effectiveness under real-world conditions with a particular focus on patient-reported outcomes (PROs). The novelty of the study design is the optional inclusion of 2 innovative wearables, which could provide a new layer of patient-derived data. The study investigates quality of life (QoL) and psychosocial well-being of patients with active ulcerative colitis during long-term exposure to filgotinib. PROs related to QoL and psychometric profiles (fatigue and depression) are collected alongside with disease activity symptom scores. We aim to evaluate physical activity patterns collected by wearables as an addition to traditional PROs, patient-reported health status, and QoL in different phases of disease activity. This is a prospective, single-arm, multicentric, noninterventional, observational study with a sample size of 250 patients. QoL is assessed with validated questionnaires: the Short Inflammatory Bowel Disease Questionnaire (sIBDQ) for the disease-specific QoL, the EQ-5D for the general QoL, and the fatigue questionnaire (Inflammatory Bowel Disease-Fatigue [IBD-F]). Physical activity data are collected from patients using wearables (SENS motion leg sensor [accelerometry] and smartwatch, GARMIN vívosmart 4). The enrollment started in December 2021 and was still open at the date of submission. After 6 months of study initiation, 69 patients were enrolled. The study is expected to be completed in June 2026. Real-world data for novel drugs are important to assess effectiveness outside of highly selected populations represented by randomized controlled trials. We examine whether patients' QoL and other PROs can be supplemented with physical activity patterns measured objectively. Use of wearables with newly defined outcomes represents an additional observational tool for monitoring disease activity in patients with inflammatory bowel disease. German Clinical Trials Register DRKS00027327; https://drks.de/search/en/trial/DRKS00027327. DERR1-10.2196/42574.

Efficacy and safety of ustekinumab in Russian bionaive patients with moderately to severely active ulcerative colitis: a subanalys is of global phase 3 induction and maintenance studies (UNIFI) up to 3 years

AIM: to evaluate efficacy and safety of ustekinumab in Russian patients with ulcerative colitis in UNIFI study. PATIENTS AND METHODS: the UNIFI program (CNTO1275UCO3001) consisted of two randomized placebo-controlled trials: an 8-week induction study and a 44-week maintenance study and long-term period. This analysis included patients from 14 Russian centers.RESULTS: the induction study of the UNIFI program enrolled 74 patients from Russia, 89.2% patients (n = 66) were bionaive. The paper presents the results of bionaive patients. Sixty-six are included in the induction phase: 18 received ustekinumab 130 mg IV, 25 received ustekinumab 6 mg/kg IV, and 23 received a placebo. At week 8 in the groups of patients treated with ustekinumab at doses of 6 mg/kg and 130 mg, clinical remission was achieved in 24.0% and 16.7%, respectively, in the placebo group, the rate was 17.4%. The proportion of patients with clinical responses at week 8 was 68.0%, 50.0% and 39.1% in the ustekinumab 6 mg/kg, 130 mg and placebo groups, respectively. Mucosal healing at week 8 was achieved in 48.0% in the ustekinumab 6 mg/kg group, in 33.3% of patients in the ustekinumab 130 mg group, and in 21.7% of patients in the placebo group. Histoendoscopic mucosal healing at week 8 developed in 27.8% of patients in the ustekinumab 130 mg group, in 24.0% of patients in the ustekinumab 6 mg/kg group, and in 21.7% of patients in the placebo group. Forty bionaive patients were re-randomized for further participation in the maintenance phase: 13 patients received ustekinumab 90 mg subcutaneously every 12 weeks, 12 received ustekinumab every 8 weeks, and 15 received a placebo. At week 44, clinical remission was achieved in 46.2% of ustekinumab every 12 weeks, 75.0% of ustekinumab every 8 weeks (p = 0.054 compared with placebo), and 33.3% of placebo. Mucosal healing achieved in 46.2% of patients in the ustekinumab once every 12 weeks group, in 75.0% of patients in the ustekinumab once every 8 weeks group (p = 0.054 compared with. placebo), and in 33.3% of patients in the placebo group. Histoendoscopic mucosal healing achieved in 46.2% of patients in the ustekinumab once every 12 weeks group, while in the ustekinumab once every 8 weeks group, the percentage of such patients was 75.0% (p = 0.021 compared with placebo) and in the placebo group — 26.7%. Symptomatic remission at week 152 developed in 83.3% in the ustekinumab every 12 weeks group, 81.8% in the ustekinumab every 8 weeks group. In the induction phase decrease of CRP and FCP median levels detected in patients treated with ustekinumab, in the maintenance phase, median levels of laboratory inflammatory markers after induction were sustained by ustekinumab treatment. The rate of steroid-free symptomatic remission at week 152 was consistent with the rate of symptomatic remission. The safety profile of ustekinumab was generally consistent with placebo during all follow up period.CONCLUSION: subanalysis confirmed shortand long-term efficacy and safety in Russian patients with moderate to severe active ulcerative colitis. The results of subanalysis are consistent with previously obtained data in the population of patients participating in the global UNIFI program.

P628 Tofacitinib in pediatric ulcerative colitis: a retrospective multi-center experience from the Paediatric IBD Porto group of ESPGHAN

Abstract Background Tofacitinib, a Janus kinase (JAK) inhibitor, has recently been approved for treatment of moderate to severe active ulcerative colitis (UC) in adults. Data on efficacy and safety in pediatrics are limited. In this multicenter study from the Paediatric IBD Porto group of ESPGHAN, we describe the short-term effectiveness and safety of tofacitinib in an international pediatric IBD cohort. Methods Retrospective review of children (2-18 years) diagnosed with UC treated with tofacitinib from 15 pediatric centers internationally. Primary outcome was corticosteroid-free clinical remission (PUCAI<10) at week 8, with secondary outcomes including clinical response (≥20 point decrease in PUCAI), colectomy rate and safety. Primary outcome was calculated utilizing non-response imputation (NRI), whereby drug cessation for any reason was considered treatment failure. Results 78 patients (43 (55%) female, mean age at diagnosis 12.5 (±2.7) years, median disease duration 20 months (IQR 10.3-38.8)), all with previous biologic failure, including 20/78 (26%) with previous failure of three biologic classes. 15/78 (19%) patients achieved corticosteroid-free clinical remission at week 8 with a further 18/78 (23%) demonstrating clinical response. 9/78 (12%) underwent colectomy by week 8, and 21/78 (27%) by week 24. Twelve adverse events were reported including five infective (three of which deemed possibly related to treatment – zoster, HSV-2 cheilitis and septic arthritis), one case of pancreatitis, and abnormal blood test results in 5 children (anemia, lymphopenia, elevated hepatic transaminases and hypercholesterolemia). Conclusion In this largest real-life cohort of tofacitinib in pediatric UC to date, tofacitinib seemed effective in at least 19% of highly refractory patients by week 8. Adverse reactions and safety were largely consistent with adult data.

A PHASE II OPEN LABEL STUDY OF NEIHULIZUMAB, AN ANTI-CD162 (PSGL-1) ANTIBODY, IN PATIENTS WITH MODERATE TO SEVERE ACTIVE, ANTI-TNFα AND/OR ANTI-INTEGRIN REFRACTORY ULCERATIVE COLITIS

Abstract BACKGROUND Neihulizumab (ALTB-168) is a novel immune checkpoint agonistic antibody that binds to human CD162 (PSGL-1), and leads to downregulation of activated T-cells. Early-phase trials of neihulizumab have suggested a benefit in patients with immune conditions, including psoriasis, psoriatic arthritis and steroid-refractory acute graft-versus-host disease. Here, we report the results of a Phase II study investigating the use of neihulizumab for ulcerative colitis (UC) (ClinicalTrials.gov Identifier: NCT03298022). AIMS The aims of this study were to evaluate efficacy, safety, tolerability and immunogenicity of neihulizumab in patients with moderate to severe active UC who are refractory or intolerant to anti-TNFα and/or anti-integrin therapy. METHODS Two regimens were tested: 5 weekly IV doses plus 3 bi-weekly IV doses of 9 mg/kg neihulizumab (5 + 3 regimen), and 8 weekly IV doses plus 2 bi-weekly IV doses of 9 mg/kg neihulizumab (8 + 2 regimen). The primary efficacy outcome is the proportion of patients with clinical response at Week 12. The key secondary efficacy outcomes are the proportion of patients with clinical remission, mucosa healing, histological healing and the change in Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS 24 subjects enrolled in this study; study demographics and baseline disease characteristics are shown in Table 1. In the 5 + 3 regimen, 10 subjects were enrolled into this study and 2 (20%) subjects completed the study. The mean duration of study treatment exposure was 59.5 days. Among 10 enrolled subjects, 9 subjects were included in the efficacy analysis: 2 (22%) subjects achieved clinical response at Week 12 and 1 (11%) subject achieved clinical response at Week 2. The overall efficacy is summarized in Table 2. In this regimen, 9/10 (90%) subjects reported an AE: 7 (70%) subjects with AEs related to study treatment, 9 (90%) subjects with AEs that were not related to study treatment, 1 (10%) subject with an SAE not related to study treatment, and no deaths were reported in this regimen. In the 8 + 2 regimen, 14 subjects were enrolled into this study and 9 (64%) subjects completed the study. The mean duration of study treatment exposure was 78.1 days. Among 14 enrolled subjects, 7 (50%) subjects achieved clinical response at Week 12 and 5 (36%) subjects achieved clinical response at Week 26 (Table 2). In this regimen, 13/14 (93%) of subjects reported an AE: 2 (14%) subjects with AEs related to study treatment and 12 (86%) subjects with AEs that were not related to study treatment; there was no SAE reported and no deaths. CONCLUSIONS This phase 2 study of neihulizumab suggest efficacy and safety signals in treatment-refractory UC that warrant further investigation.

Latent variable indirect response modeling of clinical efficacy endpoints with combination therapy: application to guselkumab and golimumab in patients with ulcerative colitis.

Accurate characterization of longitudinal exposure-response of clinical trial endpoints is important in optimizing dose and dosing regimens in drug development. Clinical endpoints are often categorical, for which much progress has been made recently in latent variable indirect response (IDR) modeling with single drugs. However, such applications have not yet been used for trials employing multiple drugs administered concurrently. This study aims to demonstrate that the latent variable IDR approach provides a convenient longitudinal exposure-response modeling framework to assess potential interaction effects of combination therapies. This is illustrated by an application to the exposure-response modeling of guselkumab, a monoclonal antibody in clinical development that blocks the interleukin-23p19 subunit, and golimumab, a monoclonal antibody that binds with high affinity to tumor necrosis factor-alpha. A Phase 2a study was conducted in 214 patients with moderate-to severe active ulcerative colitis for which longitudinal assessments of disease severity based on patient-reported measures of rectal bleeding, stool frequency, and symptomatic remission were evaluated as categorical endpoints, and fecal calprotectin as a continuous endpoint. The modeling results suggested independent pharmacodynamic guselkumab and golimumab effects on fecal calprotectin as a continuous endpoint, as well as interaction effects on the categorical endpoints that may be explained by an additional pathway of competitive interaction.

The long-term effect of biologics in patients with ulcerative colitis emerging from a large Japanese cohort

To gain a better understanding of the effects of biologics, we evaluated clinical outcomes in patients with moderate to severe exacerbations of ulcerative colitis (UC). This retrospective, multicenter study retrieved the entire clinical courses of UC patients who began treatments between 2004 and 2018. All exacerbations and clinical parameters, including treatment details for exacerbations and both remission and re-exacerbation dates, were identified during the observation period. Two different endpoints, the cumulative incidence rates of surgical resection and re-exacerbation, were evaluated separately in moderate to severe exacerbation events. Among 1401 patients, 1626 exacerbation events were determined according to a partial Mayo score (remission: < 2, mild: 2–4, moderate: 5–7, and severe: > 7). During the observation period, as administration rates of biologics increased, both surgical resection and hospitalization rates decreased, for 959 moderate to severe exacerbation events. We confirmed that biologics significantly reduced the cumulative re-exacerbation rate in moderate to severe exacerbation events during the study period compared with suboptimal therapies (a 0.507-fold decreased risk according to COX regression analysis, P < 0.001). However, they had not enough impact in reducing the cumulative incidence rate of surgical resection in moderate to severe exacerbation events that were corticosteroid-refractory or dependent (a 0.878-fold decreased risk according to COX regression analysis, P = 0.606). Biologics may improve remission duration, but these agents had no significant impact in reducing the risk of surgical resection in moderate to severe active UC.

Early MOnitoring of REsponse (MORE) to Golimumab Therapy: Results of a Multicentre, Prospective Observational Trial

Background: The therapeutic goal of clinical remission in patients with moderate to severe ulcerative colitis (UC) is achieved after biological therapy only in 16–39%. Individualization of therapeutic intervention would benefit from prediction of early response. Study Objective: The primary objective of our study was to assess golimumab (GLM) trough serum level of ≥2.5 μg/mL in combination with a reduction of faecal calprotectin (FC) of ≥50% at week 6 compared to baseline to predict clinical response at week 26 after regular GLM intake. Methods: Patients with moderate to severe active UC and planned GLM treatment were recruited for a prospective, multicentre, observational study in Germany. Prediction of clinical response was assessed by FC and GLM trough level. Missing data were imputed as therapy failure according to the last observation carried forward method. Results: Fifty nine patients have been enrolled. 54% of patients were anti-TNF naïve. Clinical response at week 6 was a significant predictor for achieving clinical response at week 26 (odds ratio [OR] 10.97, confidence interval [CI], 2.96–40.68; p < 0.001). Moreover, patients with a GLM trough level of ≥2.5 μg/mL and a ≥50% reduction of FC at week 6 had an OR of 5.33 (95% CI, 0.59–47.84) to achieve clinical response at week 26. Conclusion: Clinical response at week 6 is the best predictive marker for achieving clinical response at week 26. Consideration of significant reduction of FC and trough GLM serum levels could improve prediction of response.

Steroid Resistance/Dependence Might Be an Alarming Feature for Cytomegalovirus Infection Among Ulcerative Colitis Patients With Increased Disease Activity.

Background/Aims This study aimed to determine the prevalence of cytomegalovirus (CMV) infection among patients with moderate to severe active ulcerative colitis (UC) and to determine the risk factors for CMV infection according to the demographic features of these patients. Patients/Methods A total of 183 patients with severe or moderate active UC were enrolled in the study after retrospective analysis. The disease severity of UC was determined according to the Mayo Score. CMV infection was investigated by real-time quantitative polymerase chain reaction (PCR) and the immunohistochemical (IHC) staining method in colonic mucosal biopsies. Results CMV infection was diagnosed in 33.9% of patients with UC. UC patients diagnosed with CMV infection had significantly higher Mayo Score levels (9.68 vs 8.56 and p=0.001). The long-term presence of UC disease, steroid, azathioprine (AZA), and anti-tumor necrosis factor-alpha (anti-TNF-alpha) usage increased the risk of CMV infection (p=0.001 and odds ratio=1.168; p=0.001 and odds ratio=2.967; p=0.004 and odds ratio=2.953; p=0.003 and odds ratio=3.861, respectively). CMV infection increases the risk of developing steroid resistance or dependency (p=0.002 and odds ratio=3.147; p=0.002 and odds ratio=5.085, respectively). Post-treatment clinical remission and mucosal healing rates were higher in CMV-negative patients than in CMV-positive patients (99.2% vs 91.9%, p=0.018 and 86.8% vs 70.9%, p=0.015). A higher rate of need for colectomy had been found in patients with CMV infection (5 patients vs 1 patient; p=0.034 and odds ratio=10.526). Conclusions The presence of CMV infection increases the severity of the diseaseand worsens clinical outcomes, leading to adverse treatment outcomes. CMV infection increases the requirement for colectomy. The presence of steroids, immunosuppressives such as AZA, and anti-TNF-alpha usage increases the occurrence of CMV infection. CMV infection should be suspected in patients with moderate to severe UC activity.

Early Clinical Remission Is a Predictor of Long-Term Remission with the Use of Vedolizumab for Ulcerative Colitis.

Vedolizumab (VDZ) is an α4β7 integrin-antibody used to manage refractory ulcerative colitis (UC). This retrospective multicenter study aimed to identify predictors of efficacy or the time points when evaluation of VDZ therapy for UC would be most useful. We compiled data on 87 patients with moderate to severe active UC that was treated with VDZ. Overall clinical remission (CR) rates at 6 weeks and 52 weeks after VDZ administration were 44.4% (bio-naïve 44.2%, bio-failure 44.8%) and 52.8% (bio-naïve 53.5%, bio-failure 51.7%) respectively. Also, 83.3% (bio-naïve 81.3%, bio-failure 85.7%) of patients achieved mucosal healing at week 52. Among patients with a CR at week 52, 73.3% had a CR at week 6. In contrast, of patients who discontinued VDZ, 82.4% had not reached a CR at week 6. Our study demonstrated that VDZ was effective in a large percentage of UC patients, with a high mucosal healing rate even after prior biological exposures. This suggests that VDZ can be a treatment option even in bio-failure cases. Additionally, it was considered that early CR can predict long-term remission and that week 6 can be a helpful evaluation point for treatment decisions when using VDZ for UC.

S722 Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Active Ulcerative Colitis Receiving 16 Weeks Extended Induction Treatment Followed by 52 Weeks Maintenance Treatment in U-ACHIEVE/U-ACCOMPLISH Trials

S722 Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Active Ulcerative Colitis Receiving 16 Weeks Extended Induction Treatment Followed by 52 Weeks Maintenance Treatment in U-ACHIEVE/U-ACCOMPLISH Trials