I. Fox

Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis

BACKGROUND Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. METHODS We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. RESULTS Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. CONCLUSIONS Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

Vedolizumab as induction and maintenance therapy for Crohn's disease

BACKGROUND The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohns disease is unknown. METHODS In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohns disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohns Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS Vedolizumab-treated patients with active Crohns disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

Vedolizumab for the treatment of active ulcerative colitis: A randomized controlled phase 2 dose‐ranging study

Background: Vedolizumab is a gut‐selective biologic that has shown efficacy in ulcerative colitis (UC) and Crohns disease (CD). We studied the pharmacokinetics, pharmacodynamics, safety, tolerability, and efficacy of a new formulation of vedolizumab produced by an improved manufacturing process. Methods: UC patients were randomized to receive vedolizumab (2, 6, or 10 mg/kg) or placebo on days 1, 15, 29, and 85. Safety, pharmacokinetics, pharmacodynamics, and immunogenicity evaluations were performed at multiple timepoints through day 253. Partial Mayo Scores and fecal calprotectin levels were used to assess efficacy. Results: In all, 46 patients (9 placebo, 37 vedolizumab) received at least one dose of study medication. The vedolizumab serum concentration declined monoexponentially until concentrations reached 1–10 &mgr;g/mL, and then fell nonlinearly. Vedolizumab maximum serum concentration (Cmax) and area under the curve (AUC) increased approximately proportionally as a function of dose. Vedolizumab maximally saturated &agr;4&bgr;7 receptors on peripheral serum lymphocytes at all measurable serum concentrations. Vedolizumab was well tolerated, with no deaths and no adverse events leading to discontinuation. At every assessment from day 29 through day 253, over 50% of vedolizumab‐treated patients were in clinical response, while placebo response rates generally ranged between 22% and 33%. Vedolizumab treatment reduced fecal calprotectin levels compared with placebo. Conclusions: Vedolizumab demonstrated dose‐proportional pharmacokinetics and maximally saturated &agr;4&bgr;7 receptors over the tested dose range. Multiple dosing up to 10 mg/kg was well tolerated. Over the course of follow‐up a greater proportion of patients treated with vedolizumab were in clinical response than those who were assigned to placebo. (Inflamm Bowel Dis 2012)

The safety of vedolizumab for ulcerative colitis and Crohn's disease

Objective Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohns disease (CD). We report an integrated summary of the safety of vedolizumab. Design Safety data (May 2009–June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. Results In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1–1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. Conclusions Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. Trial registration number NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

Population pharmacokinetics‐pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease

Vedolizumab, an anti‐α4β7 integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohns disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing.

Long-term clinical experience with vedolizumab in patients with inflammatory bowel disease.

Background: Vedolizumab, a gut-selective, anti-inflammatory monoclonal antibody, has shown preliminary efficacy in ulcerative colitis (UC) and Crohns disease (CD). We report long-term experience with vedolizumab for active UC and CD. Methods: After a placebo-controlled study, 38 patients with UC were randomized to a loading regimen of vedolizumab 2, 6, or 10 mg/kg on days 1, 15, and 43, followed by maintenance dosing every 8 weeks. Thirty-four vedolizumab-naive patients (15 UC; 19 CD) were randomized to vedolizumab 2, 6, or 10 mg/kg on the same schedule. Rollover patients were treated up to 630 days and treatment-naive patients were treated up to 547 days. Results: Seventy-two patients were dosed; 52 (72%) completed the study. In exploratory analyses, 28 of 72 (39%; UC: 21 of 53, CD: 7 of 19) achieved clinical response and 42 of 72 (58.3%; UC: 38 of 53, CD: 4 of 19) achieved clinical remission. Mean partial Mayo scores declined from baseline through day 155 in both treatment-naive patients with UC (5.4 to 1.7, respectively) and rollover patients with UC (2.3 to 1.4, respectively), leveling off thereafter. Mean Crohns Disease Activity Index scores decreased from 295 (baseline) to 238 at day 43, continued to trend downward through day 155, and remained below baseline through day 491. Mean Inflammatory Bowel Disease Questionnaire scores increased in all treatment groups. No deaths or systemic opportunistic infections were reported. Conclusion: Vedolizumab every 8 weeks for up to 78 weeks had an adverse event profile similar to that previously observed. Mean disease activity indices (partial Mayo score and Crohns Disease Activity Index score) improved with all 3 doses investigated.

Vedolizumab, a monoclonal antibody to the gut homing α4β7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype

Vedolizumab, a gut-homing α4β7 integrin antagonist, has demonstrated efficacy in ulcerative colitis and Crohns disease. Development of progressive multifocal leukoencephalopathy, a serious brain infection associated with natalizumab (an α4β7 and α4β1 integrin antagonist), has raised concern that vedolizumab may convey a similar risk. Natalizumab is believed to impair central nervous system immune surveillance by affecting cerebrospinal fluid (CSF) lymphocyte counts and the CD4:CD8 ratio. To determine if vedolizumab elicits similar effects, we examined CSF of healthy volunteers by flow cytometry for T-lymphocyte surface markers 5 weeks after administration of intravenous vedolizumab 450 mg. No significant changes were observed in CSF T-lymphocyte populations.

Exposure-efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn's Disease

Background and Aims A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohns disease [CD] has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. Methods Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage] as exposure measure. Results Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. Conclusions Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation.

P497 Efficacy of continued vedolizumab therapy in patients with Crohn's disease who did not respond to vedolizumab induction therapy at week 6

The authors regret that an inaccuracy in the published abstract has been brought to their attention and is described …

Occurrence of adverse events among patients with inflammatory bowel disease in the HealthCore Integrated Research Database

Abstract Objectives: Inflammatory bowel disease (IBD) is a chronic condition commonly requiring lifelong care. Both IBD and IBD-related treatments can cause significant morbidity, and it is often difficult to differentiate their relative etiologic contribution to adverse events (AEs). The objectives of this study were to assess the rates of select AEs among patients with IBD as a function of disease severity and of the use of anti-tumor necrosis factor alpha (anti-TNFα) medications. Methods: We conducted a retrospective cohort study of IBD patients in the HealthCore Integrated Research Database (HIRDTM) between January 2004 and January 2011 to determine rates of AEs in patients with mild and moderate to severe IBD. Key study endpoints were select prespecified malignant neoplasms, infections, and other AEs of interest. Results: A total of 33,386 IBD patients (52.7% ulcerative colitis; 47.3% Crohns disease) met the inclusion criteria, and 60% had been followed for ≥1 year. Patients with moderate to severe IBD had increased rates of infections, lymphatic and digestive tract cancers, gastrointestinal (GI) perforations, and myocardial infarctions versus patients with mild IBD. Patients with IBD who used anti-TNFα therapies during the study had increased incidence of many types of infections, certain GI cancers (including rectal and anal cancer), intestinal perforations, and kidney stones compared with patients who had never used anti-TNFα therapies. Conclusions: Results from this large US cohort provide descriptive information on AE rates in a population of IBD patients undergoing routine care, estimating background incidence rates of AEs that are not readily available in the published literature. Our study findings may be limited owing to a lack of generalizability and potential for misclassification due to reliance on medical diagnosis and treatment and procedure codes to identify disease, comorbidities, and treatments. Further research and validation of our findings in other populations and databases are needed.