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A dose-escalating, placebo-controlled, double-blind, single-dose and multi-dose, safety and tolerability study of fontolizumab, a humanised anti-interferon-gamma antibody, in patients with moderate-to-severe Crohn's disease.
Reinisch W, Hommes DW, Van Assche G, Colombel JF, Gendre JP, Oldenburg B, Teml A, Geboes K, Ding H, Zhang L, Tang M, Cheng M, van Deventer SJ, Rutgeerts P, Pearce T.
Gut. 2006 Feb 21; [Epub ahead of print]
INTRODUCTION: This study was designed to evaluate the safety of fontolizumab, a humanized anti-interferon- gamma antibody, in patients with moderate-to-severe Crohn's disease (CD). PATIENTS AND METHODS: Forty-five patients with a Crohn's Disease Activity Index (CDAI) of 250 to 450 were randomized 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-randomized 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 the clinical activity parameters were noted between any of the active treatment groups and placebo, latter associated with a particularly favorable outcome (60% response and 40% remission). By day 29, a more enhanced decrease of 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 up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested.
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