A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials.

Introduction: Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g.

Polymalic Acid Tritryptophan Copolymer Interacts with Lipid Membrane Resulting in Membrane Solubilization.

Anionic polymers with membrane permeation functionalities are highly desirable for secure cytoplasmic drug delivery. We have developed tritryptophan containing copolymer (P/WWW) of polymalic acid (PMLA) that permeates membranes by a mechanism different from previously described PMLA copolymers of trileucine (P/LLL) and leucine ethyl ester (P/LOEt) that use the "barrel stave" and "carpet" mechanism, respectively. The novel mechanism leads to solubilization of membranes by forming copolymer "belts" around planar membrane "packages.

A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab.

Vedolizumab is a humanized anti-αβ integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the αβ-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations.

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 Crohn's 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.

Simultaneous blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme.

Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. GBM tumors are also notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database.

Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.

Background And Objectives: Vedolizumab, a humanized monoclonal antibody against the αβ 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.

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug.

HER2+ breast cancer is one of the most aggressive forms of breast cancer. The new polymalic acid-based mini nanodrug copolymers are synthesized and specifically characterized to inhibit growth of HER2+ breast cancer. These mini nanodrugs are highly effective and in the clinic may substitute for trastuzumab (the marketed therapeutic antibody) and antibody-targeted nanobioconjugates.

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

Objective: Vedolizumab is a gut-selective antibody to αβ integrin for the treatment of ulcerative colitis (UC) and Crohn's 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.

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

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.

Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed.

Background & Aims: There is an increasing need for new treatments for patients with Crohn's disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4β7, as induction therapy.

Methods: Patients with moderately to severely active CD (CD activity index [CDAI] score, 220-400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6.

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 Crohn's 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.

Vedolizumab as induction and maintenance therapy for Crohn's disease.

Background: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's 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 Crohn's 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.

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.

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 Crohn's 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.

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 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.

Methods: UC patients were randomized to receive vedolizumab (2, 6, or 10 mg/kg) or placebo on days 1, 15, 29, and 85.

Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.

Background: Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases.

Methods: We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.