Sustained Clinical Remission With Vedolizumab in Patients With Moderate-to-Severe Ulcerative Colitis.

Background: Sustaining clinical remission is an important treatment goal in moderate-to-severe UC. This post hoc exploratory analysis assessed the long-term efficacy of vedolizumab in the subset of patients with UC in the GEMINI 1 study who were in clinical remission by week 14 after 3 induction doses, administered at weeks 0, 2, and 6.

Methods: Sustained clinical remission (primary endpoint) was evaluated using 2 definitions: (1) a partial Mayo Score (pMS) of ≤2 with no subscore >1 and (2) a rectal bleeding subscore (RBS) of 0 throughout weeks 14, 26, 38, and 52.

Incidence of Arthritis/Arthralgia in Inflammatory Bowel Disease with Long-term Vedolizumab Treatment: Post Hoc Analyses of the GEMINI Trials.

Background And Aims: Extraintestinal manifestations [EIMs] such as arthritis/arthralgia are common in inflammatory bowel disease. We performed post hoc analyses of data from the GEMINI studies to evaluate the effect of vedolizumab, a gut-selective anti-trafficking agent, on arthritis/arthralgia.

Methods: Sustained resolution of baseline arthritis/arthralgia, worsening of baseline arthritis/arthralgia, the occurrence of new arthritis/arthralgia, and the composite of new/worsening arthritis/arthralgia were evaluated.

Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease.

Integrins are cell surface receptors with bidirectional signalling capabilities that can bind to adhesion molecules in order to mediate homing of leukocytes to peripheral tissues. Gut-selective leukocyte homing is facilitated by interactions between α4β7 and its ligand, mucosal addressin cellular adhesion molecule-1 [MAdCAM-1], while retention of lymphocytes in mucosal tissues is mediated by αEβ7 binding to its ligand E-cadherin. Therapies targeting gut-selective trafficking have shown efficacy in inflammatory bowel disease [IBD], confirming the importance of leukocyte trafficking in disease 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.

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

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.

Discovery of Biomarkers of Response in Early Drug Development.

Ulcerative colitis and Crohn's disease have traditionally been managed by incrementally stepping up within a hierarchy of therapeutic classes consequent to failing a given therapeutic─necessitated by the notion that any type of therapeutic will only induce clinical response and remission in a fraction of, but not all, patients. Hence, the selection of therapies approximates stage of disease rather than patient-specific characteristics that would allow selection of a specific mechanism of action for therapeutic intervention. Development of prognostic biomarkers [to identify patients with more aggressive disease and a worse prognosis], as well as predictive biomarkers [to predict response or non-response to a particular therapy], has been identified as a key requirement for attainment of better overall response rates or to improve the response of the most severely ill patient subgroup.

Agreement Between Rectosigmoidoscopy and Colonoscopy Analyses of Disease Activity and Healing in Patients With Ulcerative Colitis.

Background & Aims: Endoscopy limited to the rectosigmoid colon is the standard technique used to measure endoscopic healing in ulcerative colitis (UC) clinical trials. We evaluated whether rectosigmoidoscopy adequately measures UC activity in the more proximal colon.

Methods: We analyzed data from a phase 2, placebo-controlled study that evaluated the efficacy and safety of etrolizumab in patients with moderate to severely active UC who had not responded to standard therapy.

Association Between Response to Etrolizumab and Expression of Integrin αE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis.

Background & Aims: Etrolizumab is a humanized monoclonal antibody against the β7 integrin subunit that has shown efficacy vs placebo in patients with moderate to severely active ulcerative colitis (UC). Patients with colon tissues that expressed high levels of the integrin αE gene (ITGAE) appeared to have the best response. We compared differences in colonic expression of ITGAE and other genes between patients who achieved clinical remission with etrolizumab vs those who did.

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.

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 Crohn's 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.

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.

The effects and metabolic fate of nitroflurbiprofen in healthy volunteers.

Objective: Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are a new class of cyclooxygenase (COX) inhibitors. To investigate whether these drugs actually release nitric oxide (NO), we labeled the nitroxy group of nitroflurbiprofen with nitrogen 15 to determine the metabolic fate of this compound in humans.

Method: Six healthy volunteers who fasted were given an oral dose of 15 N-nitroflurbiprofen (100 mg).