Fontolizumab,一种人源化的抗干扰素γ抗体:临床治疗中重度克罗恩病的安全性与有效性

Introduction:Interferon γ is a potent proinflammatory cytokine implicated in the inflammation of Crohn’s disease(CD) .We evaluated the safety and efficacy of fontolizumab,a humanised anti-interferon γ antibody,in patients with moderate to severe CD.Methods:A total of 133 patients with Crohn’s disease activity index(CDAI) scores between 250 and 450,inclusive,were randomised to receive placebo or fontolizumab 4 or 10 mg/kg.Forty two patients received one dose and 91 patients received two doses on days 0 and 28.Investigators and patients were unaware of assignment.Study end points were safety,clinical response(decrease in CDAI of 100 points or more) ,and remission(CDAI ≤ 150) .Results:There was no statistically significant difference in the primary end point of the study(clinical response) between the fontolizumab and placebo groups after a single dose at day 28.However,patients receiving two doses of fontolizumab demonstrated doubling in response rate at day 56 compared with placebo:32%(9/28) versus 69%(22/32,p = 0.02) and 67%(21/31,p = 0.03) for the placebo,and 4 and 10mg/kg fontolizumab groups,respectively.Stratification according to elevated baseline C reactive protein levels resulted in a decreased placebo response and pronounced differences in clinical benefit.Two grade 3 adverse events were reported and were considered to be related to CD.One death(during sleep) and one serious adverse event(an elective hospitalisation) occurred,both considered unrelated.Conc-lusion:Treating active CD with fontolizumab was well tolerated and resulted in increased rates of clinical response and remission compared with placebo.

Fontolizumab,人源化抗干扰素γ抗体治疗中重度克罗恩病的临床研究:一项关于剂量升级、安慰剂对照、双盲、药物单剂量应用和多剂量应用的安全性与耐受性的研究

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.