Sharon O'Byrne

Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial

BACKGROUND Etrolizumab is a humanised monoclonal antibody that selectively binds the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. We aimed to assess etrolizumab in patients with moderately-to-severely active ulcerative colitis. METHODS In this double-blind, placebo-controlled, randomised, phase 2 study, patients with moderately-to-severely active ulcerative colitis who had not responded to conventional therapy were recruited from 40 referral centres in 11 countries. Eligible patients (aged 18-75 years; Mayo Clinic Score [MCS] of 5 of higher [or ≥6 in USA]; and disease extending 25 cm or more from anal verge) were randomised (1:1:1) to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2; or 420 mg loading dose [LD] at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo. The primary endpoint was clinical remission at week 10, defined as MCS of 2 or less (with no individual subscore of >1), analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who had received at least one dose of study drug, had at least one post-baseline disease-activity assessment, and had a centrally read screening endoscopic subscore of ≥2). This study is registered with ClinicalTrials.gov, number NCT01336465. FINDINGS Between Sept 2, 2011, and July 11, 2012, 124 patients were randomly assigned, of whom five had a endoscopic subscore of 0 or 1 and were excluded from the mITT population, leaving 39 patients in the etrolizumab 100 mg group, 39 in the etrolizumab 300 mg plus LD group, and 41 in the placebo group for the primary analyses. No patients in the placebo group had clinical remission at week 10, compared with eight (21% [95% CI 7-36]) patients in the etrolizumab 100 mg group (p=0·0040) and four (10% [0·2-24]) patients in the 300 mg plus LD group (p=0·048). Adverse events occurred in 25 (61%) of 41 patients in the etrolizumab 100 mg group (five [12%] of which were regarded as serious), 19 (48%) of 40 patients in the etrolizumab 300 mg plus LD group (two [5%] serious), and 31 (72%) of 43 patients in the placebo group (five [12%] serious). INTERPRETATION Etrolizumab was more likely to lead to clinical remission at week 10 than was placebo. Therefore, blockade of both α4β7 and αEβ7 might provide a unique therapeutic approach for the treatment of ulcerative colitis, and phase 3 studies have been planned. FUNDING Genentech.

A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis

Objective Etrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC. Design In the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD). Results In the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively. Conclusion Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.

A humanized monoclonal antibody targeting the β7 integrin selectively blocks intestinal homing of T lymphocytes

BACKGROUND AND PURPOSE rhuMAb Beta7 is a humanized anti‐human β7 monoclonal antibody currently in phase I in inflammatory bowel disease. rhuMAb Beta7 binds the β7 subunit of the integrins α4β7 and αEβ7, blocking interaction with their ligands. These integrins play key roles in immune cell homing to and retention in mucosal sites, and are associated with chronic inflammatory diseases of the gastrointestinal tract. The goal of this study was to evaluate the mucosal specificity of rhuMAb Beta7.

EMerging BiomARKers in Inflammatory Bowel Disease (EMBARK) Study Identifies Fecal Calprotectin, Serum MMP9, and Serum IL-22 as a Novel Combination of Biomarkers for Crohn's Disease Activity: Role of Cross-Sectional Imaging

Objectives:In Crohns disease (CD), clinical symptoms correspond poorly to inflammatory disease activity. Biomarkers reflective of mucosal and bowel wall inflammation would be useful to monitor disease activity. The EMBARK study evaluated disease activity in patients with ulcerative colitis (UC) and CD, and used endoscopy with or without cross-sectional imaging for biomarker discovery.Methods:UC (n=107) and CD (n=157) patients were characterized and underwent ileocolonoscopy (ICO). A subset of CD patients (n=66) also underwent computed tomography enterography (CTE). ICO and CTE were scored by a gastroenterologist and radiologist who incorporated findings of inflammation into a single score (ICO-CTE) for patients that underwent both procedures. Serum and fecal biomarkers were evaluated for association with the Mayo Clinic endoscopy score in UC patients and with ICO alone or ICO-CTE in CD patients. Individual biomarkers with a moderate degree of correlation (P≤0.3) were evaluated using multivariate analysis with model selection using a stepwise procedure.Results:In UC, ordinal logistic regression using Mayo Clinic endoscopy subscore selected the combination of fecal calprotectin and serum matrix metalloproteinase 9 (MMP9; pseudo R2=0.353). In CD, we found that use of the ICO-CTE increased specificity of known biomarkers. Using ICO-CTE as the dependent variable for biomarker discovery, the selected biomarkers were the combination of fecal calprotectin, serum MMP9, and serum IL-22 (r=0.699).Conclusions:Incorporation of both ICO and CTE into a single measure increased biomarker performance in CD. Combinations of fecal calprotectin and serum MMP9 for UC, and combinations of fecal calprotectin, serum MMP9, and serum interleukin-22 in CD, demonstrated the strongest association with imaging/endoscopy-defined inflammation.

Magnetic resonance enterography is feasible and reliable in multicenter clinical trials in patients with Crohn's disease, and may help select subjects with active inflammation

Reliable tools for patient selection are critical for clinical drug trials.

αEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis.

Abstract Background and Aims: The αEβ7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEβ7–E-cadherin interactions. Methods: αEβ7+ and αEβ7− colonic T cell localization, inflammatory cytokine production and expression of regulatory T cell-associated markers were evaluated in cohorts of control subjects and patients with active UC by immunohistochemistry, flow cytometry and real-time PCR of FACS-purified cell populations. Results: CD4+αEβ7+ T lymphocytes from both healthy controls and UC patients had lower expression of regulatory T cell-associated genes, including FOXP3, IL-10, CTLA-4 and ICOS in comparison with CD4+αEβ7− T lymphocytes. In UC, CD4+αEβ7+ lymphocytes expressed higher levels of IFNγ and TNFα in comparison with CD4+αEβ7− lymphocytes. Additionally the CD4+αEβ7+ subset was enriched for Th17 cells and the recently described Th17/Th1 subset co-expressing both IL-17A and IFNγ, both of which were found at higher frequencies in UC compared to control. Conclusion: αEβ7 integrin expression on human colonic CD4+ T cells was associated with increased production of pro-inflammatory Th1, Th17 and Th17/Th1 cytokines, with reduced expression of regulatory T cell-associated markers. These data suggest colonic CD4+αEβ7+ T cells are pro-inflammatory and may play a role in UC pathobiology.

Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating β7 Receptor Occupancy in Patients With Ulcerative Colitis

Etrolizumab, a humanized monoclonal antibody, specifically binds to the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism‐based model to simultaneously describe the kinetics of serum etrolizumab concentration and free β7 receptors on circulating intestinal‐homing CD4+ T lymphocytes. Included in the analysis were 38 phase 1 UC patients who received single or 3 monthly doses of etrolizumab intravenously or subcutaneously across a dose range of 0.3 to 10 mg/kg. A quasi–steady‐state target‐mediated drug disposition model was developed to describe the dynamic interaction between serum etrolizumab concentration and free β7 receptors on intestinal‐homing CD4+ T lymphocytes in UC patients. The time profiles of serum etrolizumab and absolute counts of β7+ lymphocytes (expressed as percentage of baseline level) were well described by the quasi–steady‐state target‐mediated drug disposition model. The model was able to characterize the maximum drug occupancy of β7 receptors on intestinal‐homing CD4+ T lymphocytes and the concentration‐dependent duration of occupancy. The 90% effective concentration for etrolizumab to saturate the β7 receptors on intestinal homing CD4+ T cells was 1.3 μg/mL. PK and PD profiles predicted by the model were consistent with observations from a subsequent phase 2 study. In conclusion, an integrated PK/PD model developed in this analysis reasonably described serum etrolizumab PK profiles and the relationship between PK and PD (free β7 receptors on circulating intestinal‐homing CD4+ T lymphocytes) in UC patients.

995 Feasibility, Precision and Reproducibility of MR Enterography for Detection of Inflammation in Crohn's Disease in a Multicenter Clinical Trial

Conclusions: The majority of strictures in CD patients treated by surgery are consistent with a mixed type inflammation (acute inflammation plus fibrosis). The presence of stratified BS pattern shows a significantly higher degree of fibrosis while the evidence of high mural signal intensity on T2-weighted fatsaturated images on MRI reflects histological features of acute inflammation. Even if the ideal definition of the type of the strictures in CD still remains significantly far to be obtained, the combined use of BS and MRI can offer useful information in a sub-group of patients needing surgery for complicating CD.

Mo1680 Assessing Crohn's Disease Inflammatory Biomarker Diagnostic Accuracy Using Ileocolonoscopy or a Combined Ileocolonoscopy-CTE Score in the Embark Study

Background: Crohns disease (CD), a transmural inflammation of the bowel wall, presents most commonly in the terminal ileum and ascending colon, resulting in challenges in the accurate diagnosis of intestinal inflammation. Non-invasive biomarkers are attractive alternatives to ileocolonoscopy (Ico) to monitor inflammatory CD activity. We assessed the performance of two well-characterized biomarkers, fecal calprotectin and serum CRP, for diagnosis of active mucosal inflammation as measured by Ico alone or a score deduced from combination of Ico and CT enterography (CTE). Methods: 153 CD patients enrolled in the EMBARK study underwent Ico and a subset of patients (n=65) also underwent CTE. Previous intestinal resection rates and disease activity were similar between the groups (resection in 52% and median HBI of 8 in both groups). Both Ico and CTE were scored separately by central read then a novel scoring system that incorporates disease activity visible by either Ico or CTE was developed by both central readers to jointly assess disease activity in IcoCTE patients. Disease severity and length scores were assigned for individual bowel segments based on ulcer size, hyperenhancement and wall thickening. ELISA was used to measure CRP and calprotectin. Results: Active CD was observed in 22% (34/153) of patients by Ico alone using ulcerated area ≥2 and 34% (52/153) of patients using SES-CD>4. CRP was significantly higher in patients using either definition of CD activity, while calprotectin was increased only when SES-CD>4 was used to identify active CD. In the cohort of patients where both Ico and CTE were performed, more patients were observed to have active CD by Ico-CTE score ≥4 (42 of 65, 65%) than by Ico alone using ulcerated area (9 of 65, 14%) or SES-CD>4 (13 of 65, 20%). Patients with ileal disease by Ico-CTE were likely to have missed CD activity by Ico alone (12 out of 22, 55%). Calprotectin was significantly different at the 1% level between active and inactive CD patients when the combined IcoCTE was used (p=0.004) but not by Ico alone using ulcerated area (p=0.26) or SES-CD≥4 (p=0.06). Use of the combined Ico-CTE score also increased specificity of calprotectin in detecting inflammation using a 100 μg/g cutoff. Calprotectin performed similarly in detecting CD activity in the ileum as ileocolonic or colonic disease (77/79 vs. 68/85 sensitivity/ specificity) measured by Ico-CTE. Conclusion: The use of a novel Ico-CTE scoring system increases the detection of mucosal inflammation, particularly in patients with ileal disease. Calprotectin had increased performance in active CD patients when mucosal activity was measured by a combination of Ico and CTE. Ico alone is likely to underestimate the number of active CD patients and therefore the performance of calprotectin as a biomarker of inflammation.

P209 Long-term effectiveness and safety of vedolizumab in patients with ulcerative colitis: 5-year cumulative exposure of GEMINI 1 completers rolling into the GEMINI open-label extension study

P209 – Table 1. Effectiveness outcomes in patients with UC and cumulative VDZ exposure for up to 248 wks W. Sandborn5, B. Sands6, S. Danese7, G. D’Haens8, A. Kaser9, R. Panaccione10, D. Rubin11, I. Shafran12, S. O’Byrne13, P. Geransar13, A. James14, A. Kaviya15, J.M. Khalid16 1Mayo Clinic College of Medicine, Gastroenterology and Hepatology, Rochester, United States; 2Icahn School of Medicine at Mount Sinai, Gastroenterology, New York, United States; 3Robarts Research Institute, University of Western Ontario, Robarts Clinical Trials, London, Canada; 4University hospitals Leuven, Department of clinical and experimental medicine, Leuven, Belgium; 5University of California San Diego, Division of Gastroenterology, La Jolla, United States; 6Icahn School of Medicine at Mount Sinai, Division of Gastroenterology, New York, United States; 7Humanitas University, Italy, Gastrointestinal Immunopathology, Milan, Italy; 8Academic Medical Centre, Dept. of Gastroenterology, Amsterdam, Netherlands; 9University of Cambridge, Division of Gastroenterology and Hepatology, Cambridge, United Kingdom; 10University of Calgary, Department of Medicine, Calgary, Canada; 11University of Chicago Medicine Inflammatory Bowel Disease Center, Section of Gastroenterology, Hepatology, and Nutrition, Chicago, United States; 12Shafran Gastroenterology Research center, Gastroenterology, Winter Park, United States; 13Takeda Pharmaceuticals International AG, Global Medical Affairs, Zurich, Switzerland; 14Takeda Development Centre Europe Ltd, Global Statistics and Statistical Programming, London, United Kingdom; 15Takeda Development Centre Europe Ltd, Clinical Development, London, United Kingdom; 16Takeda Development Centre Europe Ltd, Evidence and Value Generation, London, United Kingdom Background: Approval of vedolizumab (VDZ) for moderately to severely active ulcerative colitis (UC) was based on the phase 3 GEMINI 1 study. [1] The GEMINI open-label extension (OLE) trial is an ongoing study investigating the long-term safety of VDZ (NCT00790933). Here we report the 5-year exploratory analyses of effectiveness and safety in patients (pts) with UC who had completed GEMINI 1 and were enrolled in GEMINI OLE. Methods: Analyses included pts who responded to VDZ induction at Week (Wk) 6 and had received VDZ maintenance (every 8 or 4 wks; data were combined) to Wk 52 of GEMINI 1, followed by VDZ every 4 wks in GEMINI OLE. Pts with 248 wks of cumulative VDZ treatment (data were collected from 22 May 2009 to 21 May 2015) were assessed for clinical response (decrease in partial Mayo Score Abstracts of the 12th Congress of ECCO – European Crohn’s and Colitis Organisation S183s of the 12th Congress of ECCO – European Crohn’s and Colitis Organisation S183 [PMS] of ≥2 points and ≥25% change from baseline [BL], with an accompanying decrease in rectal bleeding subscore of ≥1 point from BL or absolute rectal bleeding subscore of ≤1 point), clinical remission (PMS of ≤2 with no individual subscore >1) and health-related quality of life (HRQoL), including IBD Questionnaire (IBDQ) and Euro Quality of Life-5D visual analogue scale (EQ-5D VAS). Safety was also assessed. Results: Of 247 pts in GEMINI 1 who responded to VDZ induction at Wk 6 and received VDZ in maintenance, 154 (62%) completed VDZ maintenance and were enrolled in GEMINI OLE (anti-TNFαnaïve n=107; anti-TNFα failure n=42). At the time of this analysis, 63 pts had completed 248 wks of cumulative VDZ treatment; 54 had discontinued (n=19 [35%] due to lack of continued benefit) and 37 are ongoing (have not yet reached 248 wks of treatment). Of pts with data at Wk 248 (n=63), 98% had clinical response and 90% were in remission (Table). HRQoL improvements were observed at Wk 248, with mean change from BL IBDQ and EQ-5D-VAS scores of 58.7 and 24.0, respectively. In the safety population, 137 pts had adverse (AEs); 17 discontinued due to AEs. Serious AEs were reported in 44 pts (in 7 pts these were drug-related; 8 pts discontinued as a consequence of serious AEs). No deaths were reported. Conclusions: In UC patients who were responders at Wk 6 of GEMINI 1 (who continued to respond during the study), long-term VDZ therapy (∼5 years) was associated with clinical benefits including clinical response, clinical remission and HRQoL improvements. The safety profile was consistent with that previously observed in a 3year interim analysis of the OLE study. References: [1] Feagan BG, Rutgeerts P, Sands BE, et al. (2013), Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis, N Engl J Med, 699–710 P210 The associations of optimism, social support, and coping strategies with health-related quality of life in a cohort of patients after proctocolectomy with ileal Pouch-anal anastomosis I. Cohen*1, Y. Benyamini2, H. Tulchinsky3, I. Dotan1 1Tel Aviv Sourasky Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Department of Gastroenterology and Liver Diseases, Tel-Aviv, Israel; 2Tel Aviv University, Bob Shapell School of Social Work, Tel-Aviv, Israel; 3Tel Aviv Sourasky Medical Center, affiliated to Sackler Faculty of Medicine, Proctology Unit, Department of Surgery, Tel-Aviv, Israel Background: Inflammatory bowel diseases (IBD) are associated with reduced health-related quality of life (HRQoL). We aimed to identify factors that influence patients HRQoL by exploring the role of optimism, social support and coping strategies in contributing to patients’ HRQoL. We focused on patients with ulcerative colitis (UC) after pouch surgery representing a distinct population which is followed up in a dedicated referral clinic. Methods: Patients were recruited at the Comprehensive Pouch Clinic and completed six questionnaires: demographics, HRQoL (IBDQ), dispositional optimism (revised Life Orientation Test, LOT-R), social support inventory (ENRICHD), Coping strategies (brief COPE), and illness acceptance (DDAQ). Pouch behavior was determined clinically and defined as normal pouch (NP) or pouchitis. Results: A total of 151 pouch patients were recruited: 75 (50%) females, average age 47.91±15.51 years, average age of UC diagnosis 27.11±13.53 years, mean time since pouch surgery 10.03±8.09 years. At the time of recruitment 48 (32%) had NP. Women had lower HRQoL than man (p=0.04), education level was correlated with HRQoL (r=0.27, p=0.001), age at diagnosis was negatively correlated to HRQoL (r=−0.19, p=0.02). Optimism was associated with higher HRQoL (R=0.40. p<0.001). Pessimism was associated to older age at diagnosis (r=0.23, p=0.01) and to lower education level (r=−0.20, p=0.02). Optimists and pessimists differed in the manner they cope with disease – optimists used more positive reframing and tended to find alternative meaningful activities, while pessimists tended to use self-blame, behavioral and mental disengagement. Furthermore, optimists reported better social support (r=0.29, p=0.00). Social support was also associated with higher HRQoL (R=0.40. p<0.001). Patients with pouchitis had lower HRQoL and social support (all p<0.01 compared to NP) but did not differ in the level of optimism. Predictors of HRQoL in the multivariate Hierarchical Regression analysis were gender (β=−0.12; p<0.05), educational level (β=0.22; p<0.001), social support (β=0.12; p<0.05) and coping strategies: behavioral disengagement (β=−0.19; p=0.05), mental disengagement (β=−0.22; p<0.001), activities engagement (β=0.29; p<0.001), and symptom tolerance (β=0.19; p=0.05). Conclusions: Factors affecting HRQoL levels in UC pouch patients are Gender, education level, age at disease diagnosis and pouch behavior. Dispositional optimism, social support and coping strategies play significant role in patients HRQoL. P211 Differences in therapeutic approaches and outcomes in paediatric and adult onset Crohn’s disease with perianal fistula: comparison of 2 multicentre fistula cohorts S. Sebastian*1,2, C. Black2, M.V. Nair1,3, T. Drskova4, O. Hradsky4, C. Tzivinikos5, K. Sahnan6, R. Muhammed7, D. Devadason8, R.S. Parmar5, K. Crook6, A. Akbar6, M. Thomson3, D. Pugliese9, A. Armuzzi9, K.H. Katsanos10, D.K. Christodoulou10, C. Selinger11, G. Maconi12, G. Fiorino13, U. Kopylov14, M.M. Bosca-Watts15, K. Karmiris16, P. Ellul17, S. Ben-Horin14, S. Danese13, A.L. Hart6 1Hull & East Yorkshire NHS Trust, Hull, United Kingdom; 2Hull & East Yorkshire NHS Trust, IBD Unit, Hull, United Kingdom; 3Sheffied Children’s Hospitals NHS Foundation Trust, Sheffiled, United Kingdom; 4Motol University Hospital, Prague, Czech Republic; 5Alder Hey Children’s Hospital, Liverpool, United Kingdom; 6St Marks Hospital, London, United Kingdom; 7Birmingham Children’s Hospital, Birmingham, United Kingdom; 8Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; 9Gemelli Hospital Catholic University, Rome, Italy; 10University of Ioannina, Ioannina, Greece; 11Leeds Teaching hospitals NHS Trust, Leeds, United Kingdom; 12Louigi Sacco University Hospital, Milan, Italy; 13Humanitas Research Hospital, Milan, Italy; 14Sheba Medical Center, Tel-Aviv, Israel; 15University Clinic Hospital, Valencia, Spain; 16Venizeleio General Hospital, Crete, Greece; 17Mater Dei Hospital,