title: AVX-470, an Orally Delivered Anti-Tumour Necrosis Factor Antibody for Treatment of Active Ulcerative Colitis: Results of a First-in-Human Trial.
abstract: OBJECTIVE
  AVX-470 is an oral, polyclonal bovine-derived anti-tumour necrosis factor (TNF) antibody in development for treatment of inflammatory bowel disease (IBD). AVX-470 neutralizes TNF locally in the gastrointestinal tract, minimizing systemic exposure. This was a double-blind, placebo-controlled, first-in-human trial designed to assess the safety, pharmacokinetics, immunogenicity and preliminary efficacy of 4 weeks of AVX-470 in patients with active ulcerative colitis (UC).
  
  
  METHODS
  Thirty-seven patients with active UC were randomized and 36 received AVX-470 (0.2, 1.6 or 3.5g/day) or placebo over 4 weeks. Endoscopic activity was assessed by colonoscopy pre- and post-treatment. The primary endpoint was safety. Secondary endpoints included pharmacokinetics and immunogenicity. Clinical and endoscopic response and remission were assessed as exploratory endpoints.
  
  
  RESULTS
  Thirty-three (92%) patients completed treatment and follow-up. The incidence of adverse events was similar across treatment groups and no allergic reactions or opportunistic infections were reported. AVX-470 therapy did not induce human anti-bovine antibodies (HABA). Bovine immunoglobulin (Ig) with TNF binding capacity was detected in stool, while bovine Ig levels in serum were low. Across all AVX-470 doses, 25.9% of patients achieved clinical response compared with 11.1% on placebo, with greatest improvements in the 3.5g/day group associated with proximal colon endoscopic improvement and reductions in serum CRP and IL-6.
  
  
  CONCLUSIONS
  AVX-470 was safe and well tolerated in this first-in-human trial in UC, with efficacy trends for clinical, endoscopic and biomarker endpoints in the highest dose group (3.5g/day). Results suggest benefit of an orally delivered locally active agent in moderate to severe UC.
  
  
  BACKGROUND
  This trial was registered with Clinicaltrials.gov as study NCT01759056 and with EudraCT as study 2012-004859-27.
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA harris@middleburgconsultants.com.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Harris
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hartman
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Lemos
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Erlich
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Spence
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Toronto Digestive Disease Associates, Toronto, Canada.
authors.forename: Theadore
authors.initials: T
authors.lastname: Ptak
authors.affiliation: Nashville Medical Research Institute, Nashville, TN, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Pruitt
authors.affiliation: University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Fox
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C588404:AVX-470; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies
keywords: Anti-TNF; clinical trial; ulcerative colitis