title: Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial.
abstract: BACKGROUND
  Etrolizumab is a humanised monoclonal antibody that selectively binds the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. We aimed to assess etrolizumab in patients with moderately-to-severely active ulcerative colitis.
  
  
  METHODS
  In this double-blind, placebo-controlled, randomised, phase 2 study, patients with moderately-to-severely active ulcerative colitis who had not responded to conventional therapy were recruited from 40 referral centres in 11 countries. Eligible patients (aged 18-75 years; Mayo Clinic Score [MCS] of 5 of higher [or ≥6 in USA]; and disease extending 25 cm or more from anal verge) were randomised (1:1:1) to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2; or 420 mg loading dose [LD] at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo. The primary endpoint was clinical remission at week 10, defined as MCS of 2 or less (with no individual subscore of >1), analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who had received at least one dose of study drug, had at least one post-baseline disease-activity assessment, and had a centrally read screening endoscopic subscore of ≥2). This study is registered with ClinicalTrials.gov, number NCT01336465.
  
  
  RESULTS
  Between Sept 2, 2011, and July 11, 2012, 124 patients were randomly assigned, of whom five had a endoscopic subscore of 0 or 1 and were excluded from the mITT population, leaving 39 patients in the etrolizumab 100 mg group, 39 in the etrolizumab 300 mg plus LD group, and 41 in the placebo group for the primary analyses. No patients in the placebo group had clinical remission at week 10, compared with eight (21% [95% CI 7-36]) patients in the etrolizumab 100 mg group (p=0·0040) and four (10% [0·2-24]) patients in the 300 mg plus LD group (p=0·048). Adverse events occurred in 25 (61%) of 41 patients in the etrolizumab 100 mg group (five [12%] of which were regarded as serious), 19 (48%) of 40 patients in the etrolizumab 300 mg plus LD group (two [5%] serious), and 31 (72%) of 43 patients in the placebo group (five [12%] serious).
  
  
  CONCLUSIONS
  Etrolizumab was more likely to lead to clinical remission at week 10 than was placebo. Therefore, blockade of both α4β7 and αEβ7 might provide a unique therapeutic approach for the treatment of ulcerative colitis, and phase 3 studies have been planned.
  
  
  BACKGROUND
  Genentech.
authors.affiliation: University of Leuven, Leuven, Belgium. Electronic address: severine.vermeire@uzleuven.be.
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: O'Byrne
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Keir
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Marna
authors.initials: M
authors.lastname: Williams
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Lu
authors.affiliation: University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Mansfield
authors.affiliation: University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lamb
authors.affiliation: University of Western Ontario, London, ON, Canada.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Feagan
authors.affiliation: Hospital Clinic de Barcelona, Barcelona, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Panes
authors.affiliation: Hospital Clinic de Barcelona, Barcelona, Spain.
authors.forename: Azucena
authors.initials: A
authors.lastname: Salas
authors.affiliation: Charité Medical School, Humboldt-University of Berlin, Berlin, Germany.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Baumgart
authors.affiliation: Christian Albrechts University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Tel Aviv Medical Centre, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Dotan
authors.affiliation: University of California San Diego, La Jolla, CA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Sandborn
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Gaik W
authors.initials: GW
authors.lastname: Tew
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Luca
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Meina T
authors.initials: MT
authors.lastname: Tang
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Clementine
authors.initials: C
authors.lastname: Perrier
authors.affiliation: Research and Early Development, Genentech, South San Francisco, CA, USA.
authors.forename: Jackson G
authors.initials: JG
authors.lastname: Egen
authors.affiliation: University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Kirby
authors.affiliation: University of Leuven, Leuven, Belgium; University of Toronto, Toronto, ON, Canada.
authors.forename: Gert
authors.initials: G
authors.lastname: van Assche
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D012074:Remission Induction / Q000379:methods; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C559198:etrolizumab