OP010 AlphaE integrin expression as a predictive biomarker for induction of clinical remission by etrolizumab: Analysis of a phase II trial in moderate-to-severely active ulcerative colitis

s of the 9th Congress of ECCO the European Crohn’s and Colitis Organisation S7 (biventricular heart dysfunction and sepsis) that occurred between wks 54 and 104. Conclusions: These data continue to support a positive benefit/ risk profile for GLM in the treatment of moderate to severe UC; GLM treatment for up to 2 y maintained clinical benefit including a reduction in corticosteroid use. No new safety signals were observed with continued GLM treatment through wk 104; safety profile was similar to wk 54. OP010 AlphaE integrin expression as a predictive biomarker for induction of clinical remission by etrolizumab: Analysis of a phase II trial in moderate-to-severely active ulcerative colitis M. Keir1 *, G.W. Tew1, D. Luca1, J. Eastham-Anderson1, L. Diehl1, J.G. Egen1, S. Vermeire2, J.C. Mansfield3, C.A. Lamb3, J. Panes4, D.C. Baumgart5, S. Schreiber6, I. Dotan7, W.J. Sandborn8, G. De Hertogh2, J.A. Kirby3, G. Van Assche2, P. Rutgeerts2, S. O’Byrne1. 1Genentech, Research and Early Development, South San Francisco, United States, 2KU Leuven, Division of Gastroenterology, Leuven, Belgium, 3Royal Victoria Infirmary, Gastroenterology, Newcastle upon Tyne, United Kingdom, 4Hospital Clinic Barcelona, Gastroenterology, Barcelona, Spain, 5HumboldtUniversity of Berlin, Charite Medical School, Berlin, Germany, 6Christian Albrechts University, Institute of Clinical Molecular Biology, Kiel, Germany, 7Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel, 8University of California, San Diego, Gastroenterology, San Diego, United States Background: Etrolizumab is a humanized monoclonal antibody to the beta7 integrin subunit that blocks alpha4beta7: MAdCAM-1 and alphaEbeta7:E-cadherin interactions and has been shown to be effective at inducing remission in patients with moderate to severely active ulcerative colitis (UC). Methods: Patients enrolled in the Phase 2 study of etrolizumab in UC were assessed for baseline biopsy gene expression of MAdCAM1, alphaE and alpha4 integrin by qPCR (n = 106) as well as baseline alphaE+ cells per total cells in biopsies from the inflamed colon by immunohistochemistry (n = 76). Enrichment of baseline measures was evaluated using the primary outcome measure of the study, remission at week 10, defined as a total MCS of 2 with no individual subscore >1. Results: AlphaE gene expression and alphaE+ cells were lognormally distributed in baseline biopsies from UC patients. No difference in baseline characteristics was observed between alphaE high and alphaE low groups. Enrichment in response to treatment with 100mg/dose etrolizumab as measured by remission was observed in patients with higher than median levels of alphaE gene expression at screening (38% alphaE high vs. 13% alphaE low). No enrichment was observed in alpha4 high patients (27% alpha4 high vs. 24% alpha4 low) or MAdCAM1 high patients (27% MAdCAM1 high vs. 24% MAdCAM1 low). Enrichment in response to treatment as measured by remission was observed in TNF antagonist naive patients with high levels of alphaE gene expression at screening (67% alphaE high vs. 17% alphaE low). Similarly, enrichment of remission in response to treatment was observed in patients with higher than median levels of alphaE+ cells per total cells (50% alphaE high vs. 7% alphaE low). TNF antagonist naive patients with high levels of alphaE+ cells per total cells at screening had enriched response to treatment with etrolizumab as measured by remission (67% alphaE high vs. 25% alphaE low). Conclusions: These results suggest that higher than median levels of alphaE gene expression and/or alphaE+ cells per total cells in the inflamed colon are associated with increased clinical benefit of etrolizumab treatment in patients. Thus alphaE gene expression or alphaE+ cells in colonic biopsies may be predictive biomarkers to identify UC patients most likely to benefit from etrolizumab treatment. OP011 Tralokinumab (CAT-354), an interleukin 13 antibody, in moderate to severe ulcerative colitis: A phase 2 randomized placebo-controlled study S. Danese1, J. Rudzinski2, W. Brandt3, J.L. Dupas4, L. Peyrin-Biroulet5, Y. Bouhnik6, D. Kleczkowski7, P. Uebel8, M. Lukas9, M. Knutsson10, F. Erlandsson10, M. Berner Hansen10 *, S. Keshav11. 1Istituto Clinico Humanitas, IBD Center, Milan, Italy, 210 Wojskowy Szpital Kliniczny z Poliklinik?, Kliniczny Oddzia? Gastroenterologii, Warsaw, Poland, 3Facharzt fur Innere Medizin, Internal Medicine, Potsdam, Germany, 4CHU d’Amiens Hopital Nord, Hepato-Gastroenterology, Amiens, France, 5CHU Nancy Brabois, Gastrology, Vandoeuvre les Nancy, France, 6Hopital Beaujon APHP, Gastroenterologie, Clichy, France, 7Endoskopia Sp.z o.o., Gastroenterology, Sopot, Poland, 8Haus der Gesundheit, Internal Medicine, Ludwigshafen, Germany, 9Iscare, Gastroenterology, Prague, Czech Republic, 10AstraZeneca, Innovative Medicines, Molndal, Sweden, 11John Radcliffe Hospital, Translational Gastroenterology Unit, Oxford, United Kingdom Background: Interleukin 13 (IL-13) is a central cytokine effector in the Th2 immune response and potentially a key player in ulcerative colitis (UC) pathogenesis. Tralokinumab (CAT-354) is a humanized IgG4 antibody that binds and inhibits IL-13. The purpose of this study was to evaluate the efficacy and safety of tralokinumab in subjects with moderate to severe active UC. Methods: Subjects (18 75 yrs) with UC and total Mayo score 6 12 received tralokinumab or placebo as add-on therapy in this European multicenter, randomized, double-blind, placebocontrolled study sponsored by AstraZeneca (ClinicalTrials.gov #NCT01482884). Subjects received subcutaneous tralokinumab (300mg) or placebo every 2 wks during a 12-wk treatment phase followed by a 12-wk safety follow-up. The primary endpoint was clinical response at wk 8 defined as a reduction of 3 points and 30% or more from baseline total Mayo score. Secondary endpoints included clinical remission (Mayo score 2 with no subscore >1 point), mucosal healing (endoscopic Mayo score 0), improvement in Mayo score at wk 8, partial Mayo score, and safety. Allowed background medications included stable doses of 5-ASA, prednisolone ( 20mg daily), and thiopurines. Results: 111 subjects were randomized (tralokinumab n = 56; placebo n = 55). Baseline subject and disease characteristics were similar in both arms. The median baseline Mayo score was 8 in both arms; 23% and 31%, respectively, had received prior TNF-a therapies; 43 (77%) tralokinumab subjects and 37 (67%) placebo subjects, respectively, completed the study. Improvements in mean partial Mayo scores were greater in the tralokinumab subjects ( 1.8 vs. 0.8, p = 0.04). Results at week 8 Tralokinumab Placebo P value Clinical response (%) 38 33 0.41 Clinical remission (%) 18 6 0.03 Mucosal healing (%) 32 20 0.10 Mean improvement in Mayo Score 3.2 2.6 0.39 Serum eosinophil counts and total IL-13 levels increased during therapy with tralokinumab. Symptoms of UC were the most frequently reported adverse events (AEs). The number of subjects experiencing AEs and AEs leading to discontinuation of drug were similar in both groups. There were no clinically relevant changes in laboratory variables, vital signs, and electrocardiograms. No new safety signals were identified for tralokinumab. Conclusions: Multiple efficacy measures were numerically higher in the tralokinumab arm. However, the difference in clinical response at wk 8 (primary endpoint) between by gest on Feruary 5, 2016 http://eccoxfordjournals.org/ D ow nladed from