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A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe Crohn’s disease
  1. W Reinisch1,
  2. D W Hommes2,
  3. G Van Assche3,
  4. J-F Colombel4,
  5. J-P Gendre5,
  6. B Oldenburg6,
  7. A Teml1,
  8. K Geboes7,
  9. H Ding8,
  10. L Zhang8,
  11. M Tang8,
  12. M Cheng8,
  13. S J H van Deventer2,
  14. P Rutgeerts3,
  15. T Pearce8
  1. 1Universitaetsklinik Innere Medizin IV, Abteilung Gastroenterologie and Hepatologie, Vienna, Austria
  2. 2Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, the Netherlands
  3. 3Universitaire Ziekenhuizen Gasthuisberg, Division of Gastroenterology, Leuven, Belgium
  4. 4Department D’Hepatogastroentérologie, CHU Hôpital Huriez, Lille Cedex, France
  5. 5Department Hépato-Gastroentérologie at Nutrition, Hôpital Rothschild, Paris Cedex, Paris, France
  6. 6Department of Gastroenterology, University Medical Centre, Utrecht, the Netherlands
  7. 7Universitaire Ziekenhuizen Gasthuisberg, Department of Pathology, Leuven, Belgium
  8. 8Protein Design Labs, Inc., Fremont, California, USA
  1. Correspondence to:
    Professor W Reinisch
    Universitaetsklinik Innere Medizin IV, Abteilung Gastroenterologie and Hepatologie, Waehringer Guertel 18-20, A-1090 Vienna, Austria; walter.reinisch{at}meduniwien.ac.at

Abstract

Introduction: This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe Crohn’s disease (CD).

Patients and methods: Forty five patients with a CD activity index (CDAI) of 250–450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates.

Results: Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn’s disease endoscopic index of severity (p = 0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry.

Conclusions: Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested.

  • AE, adverse event
  • ALP, alkaline phosphatase
  • AUC, area under the concentration curve
  • CD, Crohn’s disease
  • CDAI, Crohn’s disease activity index
  • CDEIS, Crohn’s disease endoscopic index of severity
  • CRP, C reactive protein
  • ELISA, enzyme linked immunosorbent assay
  • HRP, horseradish peroxidase
  • HuZAF, fontolizumab
  • IBDQ, inflammatory bowel disease questionnaire
  • IFN-γ, interferon γ
  • OD, optical density
  • Stat, signal transducer and activator of transcription
  • TNF-α, tumour necrosis factor α
  • interferon γ
  • monoclonal antibody
  • fontolizumab
  • immunogenicity
  • Crohn’s disease

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Footnotes

  • Published online first 21 February 2006

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