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Background: Direct comparisons are lacking between vedolizumab and tumour necrosis factor (TNF)-antagonist therapy in Crohn's disease (CD)., Aim: To compare safety and effectiveness of vedolizumab and TNF-antagonist therapy in adult CD patients., Methods: Retrospective observational cohort (May 2014-December 2017) propensity score-weighted comparison of vedolizumab vs TNF-antagonist therapy (infliximab, adalimumab, certolizumab) in CD. Propensity scores were weighted for age, prior treatments, disease complications, extent and severity, steroid dependence, and concomitant immunosuppressive drug use. The primary outcome was comparative risk for infections or non-infectious serious adverse events (requiring antibiotics, antivirals, antifungals, hospitalisation, or treatment discontinuation, or resulting in death). Secondary comparative effectiveness outcomes were clinical remission (resolution of CD-related symptoms), steroid-free clinical remission and endoscopic remission (absence of ulcers/erosions)., Results: We included 1266 patients (n = 659 vedolizumab). Rates of non-infectious serious adverse events (odds ratio [OR] 0.072, 95% confidence interval [CI] 0.012-0.242), but not serious infections (OR 1.183, 95% CI 0.786-1.795), were significantly lower with vedolizumab vs TNF-antagonist therapy. Safety comparisons for non-infectious serious adverse events remained significant after adjusting for differences in duration of exposure. No significant difference was observed between vedolizumab and TNF-antagonist therapy for clinical remission (hazard ratio [HR] 0.932, 95% CI 0.707-1.228), steroid-free clinical remission (HR 1.250, 95% CI 0.677-2.310) or endoscopic remission (HR 0.827, 95% CI 0.595-1.151). TNF-antagonist therapy was associated with higher treatment persistence compared with vedolizumab., Conclusions: There was a lower risk of non-infectious serious adverse events, but not serious infections, with vedolizumab vs TNF-antagonist therapy, with no significant difference for achieving disease remission., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: A clinical decision support tool (CDST) has been validated for predicting treatment effectiveness of vedolizumab (VDZ) in Crohn's disease., Aim: To assess the utility of this CDST for predicting exposure-efficacy and disease outcomes., Methods: Using data from three independent datasets (GEMINI, GETAID and VICTORY), we assessed clinical remission rates and measured VDZ exposure, rapidity of onset of action, response to dose optimisation and progression to surgery by CDST-defined response groups (low, intermediate and high)., Results: A linear relationship existed between CDST-defined groups, measured VDZ exposure, rapidity of onset of action and efficacy in GEMINI through week 52 (P < 0.001 at all time points across three CDST-defined groups). In GETAID, CDST predicted differences in clinical remission at week 14 (AUC = 0.68) and rapidity of onset of action (P = 0.04) between probability groups. The high-probability patients did not benefit from shortening of infusion intervals, and differences in onset of action between the high-intermediate and low-probability groups within GETAID were no longer significant when including low-probability patients who received a week 10 infusion. CDST predicted a twofold increase in surgery risk over 12 months of VDZ therapy among low- to intermediate-probability vs high-probability patients (adjusted HR 2.06, 95% CI 1.33-3.21)., Conclusions: We further extended the clinical utility of a previously validated VDZ CDST, which accurately predicts at baseline exposure-efficacy relationships and rapidity of onset of action and could be used to help identify patients who would most benefit from interval shortening and those most likely to require surgery while on active therapy., (© 2019 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Prospectively designed studies assessing the exposure-response profile of vedolizumab are lacking. Observational exposure-response data for vedolizumab are limited and have not been adjusted for potential confounding factors, particularly those that may affect vedolizumab clearance., Aims: To (a) investigate the vedolizumab exposure-response relationship after adjusting for potential confounding variables; (b) propose potential target serum vedolizumab concentrations for future study; (c) ascertain whether early vedolizumab serum concentrations were associated with short- and long-term clinical outcomes in adults with ulcerative colitis in GEMINI 1., Methods: Propensity-score-based case-matching analysis was performed using data from GEMINI 1 and an earlier large population pharmacokinetic study, with vedolizumab clearance or concentration as predictors of clinical remission and response, adjusted for age, weight, anti-tumour necrosis factor alpha therapy history, serum albumin and faecal calprotectin concentrations. Potential vedolizumab concentration targets at weeks 6, 14 and steady state were proposed. Association between early vedolizumab concentrations at weeks 2, 4 and 6 and clinical remission at weeks 14 and 52 was evaluated., Results: Among 693 patients with pharmacokinetic data at week 6, potential target vedolizumab concentrations at weeks 6, 14 and steady state were 37.1, 18.4 and 12.7 µg/mL respectively. Week 6 was identified as the earliest time at which vedolizumab concentrations were consistently associated with clinical remission at weeks 14 and 52., Conclusions: In this comprehensively adjusted analysis, vedolizumab concentrations at week 6 were associated with short- and long-term remission. Potential induction and maintenance target concentrations were proposed for further study., (© 2019 John Wiley & Sons Ltd.)

Background: Vedolizumab is a gut-selective immunoglobulin G 1 monoclonal antibody to α 4 β 7 integrin for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Prospective clinical studies of vedolizumab in pregnancy have not been conducted; therefore, existing safety data of vedolizumab in pregnancy were examined., Aim: To assess pregnancy outcomes in females and partners of males who received vedolizumab., Methods: All pregnancy data collected during the clinical programme (from 14 May 2007 to 27 June 2013) and in the post-marketing setting (to 19 November 2015) were analysed., Results: Across six studies, there were 27 pregnancies in female participants and 19 pregnancies in partners of male participants. Among 24 vedolizumab-treated females (23 with CD/UC, one healthy volunteer), there were 11 live births, five elective terminations, four spontaneous abortions and four undocumented outcomes. A congenital corpus callosum agenesis anomaly was reported in one live birth from a healthy volunteer with extensive obstetric history exposed to single-dose vedolizumab 79 days before estimated conception. Of 19 pregnancies in partners of male participants, there were 11 live births, two spontaneous abortions, three elective terminations and three undocumented outcomes. Post-marketing reports recorded 81 pregnancies, resulting in four live births, 11 spontaneous abortions and 66 pregnancies that were on-going or reported undocumented outcomes., Conclusions: Initial analysis, limited by sample size and follow-up, identified no new safety concerns for pregnancy outcomes in females directly or indirectly exposed to vedolizumab. However, vedolizumab should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother/unborn child., (© 2017 John Wiley & Sons Ltd.)

Background: Health-related quality of life (HRQL) is often diminished in patients with ulcerative colitis., Aim: To evaluate the effects of vedolizumab on HRQL in patients with ulcerative colitis., Methods: Using maintenance phase data from the GEMINI 1 study, an analysis of covariance model was used to calculate mean differences between the vedolizumab and placebo groups in changes from baseline to week 52 for 3 HRQL instruments: The Inflammatory Bowel Disease Questionnaire (IBDQ), 36-Item Short Form Health Survey (SF-36), and EQ-5D. Proportions of patients meeting minimal clinically important difference (MCID) thresholds for changes on these instruments were compared between treatment groups for the overall population and for clinically important subgroups. Concordance between clinical remission and remission defined using IBDQ scores was examined., Results: Compared with placebo-treated patients, vedolizumab-treated patients had greater improvements (152-201%) in IBDQ, EQ-5D visual analogue scale (VAS), and EQ-5D utility scores. Greater proportions (6.9-19.9%) of vedolizumab-treated patients than placebo-treated patients met MCID thresholds for all the instruments. Vedolizumab-treated patients with lower baseline disease activity and those without prior tumour necrosis factor (TNF) antagonist failure had greater HRQL improvements. Among 127 patients with clinical remission based on complete Mayo Clinic scores, >80% also had IBDQ remission; >70% of the 150 patients with IBDQ remission demonstrated clinical remission., Conclusions: Vedolizumab therapy was associated with significant improvements in HRQL measures compared with placebo. Benefits were greater in patients with lower disease activity and no prior TNF antagonist failure., (© 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Chronic constipation (CC) is a highly prevalent health problem, potentially associated with increased risk of colorectal cancer (CRCancer)., Aim: To investigate the association between CC, its severity, and CRCancer by estimating the relative risk of developing CRCancer and benign colorectal neoplasm (BCN) among severity-stratified patients with and without CC., Methods: Chronic constipation patients from a large retrospective US claims database were matched 1:3 with CC-free controls by demographic characteristics. CRCancer and BCN prevalence were measured over 1 year. In pre-index CRCancer- and BCN-free patients, incidence rate ratios (IRRs) of new CRCancer and BCN were calculated. Multivariate regression models adjusted for comorbidities and family history. CC patients' disease severity was rated based on CC-related resource use. IRRs for new CRCancer and BCN were estimated for CC severity groups and controls., Results: Chronic constipation (N = 28,854) and CC-free (N = 86,562) patients had mean age 61.9 years; 66.7% were female. One-year CRCancer prevalence was 2.7% and 1.7%, and BCN prevalence was 24.8% and 11.9% for CC and CC-free patients, respectively. Adjusted IRRs between CC and CC-free patients were 1.59 [95% confidence interval (CI): 1.43-1.78] and 2.60 [95% CI: 1.51-2.70] for CRCancer and BCN, respectively. Patients with severe and very severe CC had significantly greater incidence of CRCancer and BCN. At ≥ 2 and ≥ 5 years of observation, CRCancer and BCN incidence remained consistently and significantly higher for CC patients., Conclusions: Patients with chronic constipation are associated with significantly higher prevalence and incidence of colorectal cancer and benign colorectal neoplasm than matched chronic constipation-free patients. These risks increase with the severity of chronic constipation., (© 2014 John Wiley & Sons Ltd.)