title: Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis.
abstract: Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis.
  
  
  
  To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis.
  
  
  
  We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches.
  
  
  
  Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation.
  
  
  
  This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.
authors.affiliation: Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.|University of California, San Diego, CA, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Sandborn
authors.affiliation: Delta Research Partners, LLC, Monroe, LA, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Bhandari
authors.affiliation: Clinical Research Institute of Michigan, LLC, Chesterfield, MI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fogel
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Onken
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Yen
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ge
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: French
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Silverman
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kanwar
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.
authors.forename: L M
authors.initials: LM
authors.lastname: Shackelton
authors.affiliation: Mayo Clinic Arizona, Scottsdale, AZ, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Pai
authors.affiliation: Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.
authors.forename: B G
authors.initials: BG
authors.lastname: Levesque
authors.affiliation: Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.|Department of Medicine, University of Western Ontario, London, ON, Canada.|Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.
authors.forename: B G
authors.initials: BG
authors.lastname: Feagan
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000276:immunology*; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000621903:andecaliximab; D020780:Matrix Metalloproteinase 9