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In this 52-week randomized trial, the α 4 β 7 integrin antibody vedolizumab was effective in treating ulcerative colitis. There were not significantly more adverse events with vedolizumab than with placebo, but the trial was not large or long enough to fully assess safety. Ulcerative colitis is a chronic inflammatory bowel disease characterized by symptoms of bloody diarrhea, abdominal cramps, and fatigue. 1 Current medical therapy has important limitations. Aminosalicylates 2 – 4 are only modestly effective; glucocorticoids can cause unacceptable adverse events and do not provide a benefit as maintenance therapy. Tumor necrosis factor (TNF) antagonists, although efficacious, 5 , 6 predispose patients to serious infection. 7 Thus, new treatment strategies are needed. The migration of leukocytes into inflamed intestinal tissue is highly regulated by specific molecular mechanisms. The α 4 β 7 integrin, 8 a cell-surface glycoprotein variably expressed on circulating B and T lymphocytes, interacts with mucosal addressin-cell . . .

In this 52-week randomized trial, the α 4 β 7 integrin antibody vedolizumab was effective in treating Crohn's disease. The incidence of serious adverse events was higher with vedolizumab than with placebo. Crohn's disease is a chronic inflammatory bowel disease. 1 Current treatments include glucocorticoids, immunosuppressive agents (i.e., azathioprine, mercaptopurine, or methotrexate), and tumor necrosis factor (TNF) antagonists. 1 – 3 Many patients do not have a response to therapy, 4 and treatments are associated with important toxic effects. 5 , 6 Natalizumab, a monoclonal antibody that modulates gut and brain lymphocyte migration by antagonizing α 4 β 1 and α 4 β 7 integrin–mediated interactions, 7 is efficacious in the treatment of multiple sclerosis 8 , 9 and Crohn's disease. 10 – 12 Its use in patients with Crohn's disease has been limited by the development in some patients of progressive multifocal . . .

Vedolizumab is a gut-selective biologic that has shown efficacy in ulcerative colitis (UC) and Crohn's disease (CD). We studied the pharmacokinetics, pharmacodynamics, safety, tolerability, and efficacy of a new formulation of vedolizumab produced by an improved manufacturing process.MethodsUC 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.ResultsIn 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 μg/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 α4β7 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.ConclusionsVedolizumab demonstrated dose-proportional pharmacokinetics and maximally saturated α4β7 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)

Background and Objectives Vedolizumab, a humanized monoclonal antibody against the α 4 β 7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn’s disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers. Methods Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α 4 β 7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored. Results Vedolizumab maximum observed serum concentration ( C max ) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration–time curve from time 0 to infinity (AUC 0–inf ) and shorter terminal elimination half-life ( t 1/2 ) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α 4 β 7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent. Conclusions Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α 4 β 7 saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.

Vedolizumab (VDZ) was efficacious and safe in the GEMINI 11 and 22 studies of patients with ulcerative colitis (UC) and Crohn's disease (CD), respectively. In a long-term extension study (GEMINI LTS; ClinicalTrials.gov No. NCT00790933), we evaluated the effects of an increase in VDZ dosing frequency from every 8 weeks (Q8W) to every 4 weeks (Q4W) among patients who had lost response to VDZ Q8W during GEMINI 1 or 2.MethodsPatients in the randomized, placebo-controlled GEMINI 1 and 2 studies who responded to VDZ 300 mg during the 6-week induction phase but later discontinued the 46-week maintenance phase for lack of efficacy on VDZ 300 mg Q8W were among those eligible to receive open-label VDZ 300 mg Q4W in GEMINI LTS. Percentages of these patients in clinical remission (UC, partial Mayo Clinic [pMC] score ≤2 with no individual subscore >1; CD, Harvey-Bradshaw Index [HBI] score ≤4) and with a clinical response (UC, pMC score decrease of ≥2 and ≥25% from baseline with rectal bleeding subscore decrease of ≥1 from baseline or absolute rectal bleeding subscore ≤1; CD, HBI score decrease of ≥3 from baseline) were evaluated. These end points were also evaluated among subgroups of patients with and without prior tumor necrosis factor (TNF) antagonist failure. Average VDZ concentrations at week 52 for patients who discontinued GEMINI 1 or 2 were predicted to standardize pharmacokinetic data at the same time point relative to study entry.3 These concentrations were compared with those predicted for GEMINI 1 or 2 completers.ResultsAmong patients treated with VDZ Q8W in GEMINI 1 (n = 122) and GEMINI 2 (n = 154), 32 (26%) and 57 (37%), respectively, discontinued for lack of efficacy and entered GEMINI LTS to receive VDZ Q4W. After this increase in dosing frequency, clinical remission and response rates increased and were generally maintained through week 52 of GEMINI LTS (Tables 1 and 2) Median predicted average VDZ concentrations at week 52 were slightly higher in patients receiving VDZ Q8W who completed the studies (UC: 36.9 µg/mL, n = 75; CD: 39.5 µg/mL, n = 74) than in those who discontinued (UC: 30.5 µg/mL, n = 32; CD: 32.7 µg/mL, n = 57). Adverse event profiles were similar between the Q8W and Q4W regimens in GEMINI 1 and 21,2ConclusionsPercentages of clinical remission and response increased after VDZ dosing frequency was increased to Q4W for patients with UC or CD who had lost response to VDZ Q8W. Average VDZ concentrations at week 52 were predicted to be only slightly lower in these patients than in patients treated with VDZ Q8W who completed GEMINI 1 or 2. These uncontrolled data may help support the utility of VDZ Q4W dosing.

A relationship between the pharmacokinetics (PK) of tumor necrosis factor antagonists and mucosal healing in patients with ulcerative colitis (UC) or Crohn’s disease was recently reported.1,2 This analysis examines the relationship between the PK of vedolizumab (VDZ), an α4β7 integrin antagonist, and endoscopic outcomes in patients with UC using population PK analysis.MethodsIn GEMINI 1 (phase 3, randomized study), patients with UC received double-blind VDZ 300 mg or placebo (cohort 1) or open-label VDZ 300 mg (cohort 2) at weeks 0 and 2 during induction.3 Week 6 VDZ responders were rerandomized to placebo or VDZ 300 mg every 4 or 8 weeks during maintenance (up to week 52); induction placebo patients and week 6 nonresponders continued on placebo and VDZ 300 mg every 4 weeks, respectively. Endoscopic evaluation was performed at weeks 0, 6, and 52; blood samples for PK evaluation were collected at various time points. First, for all VDZ-treated patients (cohorts 1 and 2) with a week 6 Mayo Clinic endoscopic subscore, median week 6 VDZ trough concentrations were determined among patients with each endoscopic subscore (range, 0–3; higher scores indicate more active disease). Then, week 6 VDZ trough concentration quartiles and associated rates of mucosal healing (endoscopic subscore ≤1) were calculated. Finally, a population PK model4 was used to estimate individual VDZ clearance values for all VDZ-treated patients with a week 6 endoscopic subscore.ResultsAt week 6, mucosal healing was more common among patients with higher measured VDZ trough concentrations (Table 1). Week 6 median measured VDZ trough concentrations were 34.5 μg/mL for patients with an endoscopic subscore of 0 (n = 55), 30.4 μg/mL for those with a subscore of 1 (n = 223), 24.0 μg/mL for those with a subscore of 2 (n = 224), and 19.6 μg/mL for those with a subscore of 3 (n = 188) (subscores unavailable for 3 patients). Median week 6 measured VDZ trough concentrations for patients with the highest endoscopic subscores were below the overall week 6 median for GEMINI 1 (25.6 μg/mL). A trend toward higher individual estimated VDZ clearance values in patients with higher endoscopic subscores was noted (Figure 1), suggestive of faster VDZ elimination in these patients.ConclusionsAt week 6, endoscopic subscores were lower and mucosal healing was more common in patients with UC who had higher measured VDZ trough concentrations. The apparent association between higher endoscopic subscores and faster VDZ clearance could be attributable to several confounding factors and warrants further investigation. Additional analyses of the relationship between VDZ PK and endoscopic outcomes at week 52 of GEMINI 1 are ongoing.References1. Paul S, et al. Inflamm Bowel Dis. 2013;19(12):2568–2576.2. Roblin X, et al. Am J Gastroenterol. 2014;109(8):1250–1256.3. Feagan BG, et al. N Engl J Med. 2013;369(8):699–710.4. Rosario M, et al. J Crohns Colitis. 2014;8:S225–S226.The clinical study was funded by Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.). Medical writing assistance was provided by Elizabeth Barton of MedLogix Communications, LLC, and supported by Takeda Pharmaceuticals International, Inc. Sanhita Abrol assisted with the figures.

ObjectiveVedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab.DesignSafety 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.ResultsIn 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.ConclusionsVedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period.Trial registration numberNCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

Objective The α4β7 integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated. Design In this randomised, double-blind, placebo-controlled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750 mg (n=64) or placebo (n=63). After 4 days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre ≥10 IU/L). OCV seroconversion at day 74 (>4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point. Results A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) at day 74. A total of 60 (96.8%) placebo-treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs 3007.8 ELISA Units (EU)/mL) and day 32 (11629.3 vs 1575.4 EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo. Conclusions Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action. Trial registration number NCT Number: 01981616; EudraCT Number: 2011-001874-24.