title: Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study.
abstract: 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. 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 μg/mL, and then fell nonlinearly. Vedolizumab maximum serum concentration (C(max) ) and area under the curve (AUC) increased approximately proportionally as a function of dose. Vedolizumab maximally saturated α(4) β(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 α(4) β(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.
authors.affiliation: Millennium: A Takeda Company, Cambridge, Massachusetts, USA.
authors.forename: Asit
authors.initials: A
authors.lastname: Parikh
authors.forename: Timothy
authors.initials: T
authors.lastname: Leach
authors.forename: Tim
authors.initials: T
authors.lastname: Wyant
authors.forename: Catherine
authors.initials: C
authors.lastname: Scholz
authors.forename: Serap
authors.initials: S
authors.lastname: Sankoh
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
authors.forename: Terry
authors.initials: T
authors.lastname: Ponich
authors.forename: Irving
authors.initials: I
authors.lastname: Fox
authors.forename: Brian G
authors.initials: BG
authors.lastname: Feagan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C543529:vedolizumab