重组因子IX Fc融合蛋白治疗儿童B型血友病（Kids B-LONG）：一项多中心、非随机3期研究的结果
Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre, non-randomised phase 3 study.
作者信息
Fischer Kathelijn, Kulkarni Roshni, Nolan Beatrice, Mahlangu Johnny, Rangarajan Savita, Gambino Giulia, Diao Lei, Ramirez-Santiago Alejandra, Pierce Glenn F, Allen Geoffrey
机构信息
Van Creveldkliniek, University Medical Center Utrecht, Utrecht, Netherlands.
Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA.
出版信息
Lancet Haematol. 2017 Feb;4(2):e75-e82. doi: 10.1016/S2352-3026(16)30193-4.
BACKGROUND
Kids B-LONG was a multicentre, open-label, phase 3 study assessing the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) in previously treated paediatric patients younger than 12 years with severe haemophilia B.
METHODS
The study enrolled 30 previously treated boys younger than 12 years with haemophilia B (≤2 IU/dL [≤2%] endogenous coagulation factor IX [FIX] activity). All patients were initially given rFIXFc prophylaxis (50-60 IU/kg) once per week with adjustments to dose (≤100 IU/kg per infusion) or dosing frequency (up to two times per week) as needed. The primary outcome measure was development of inhibitors (neutralising antibodies). Secondary outcomes were pharmacokinetics, annual bleeding rate (ABR), spontaneous joint ABR, the number of infusions and dose required to resolve a bleed, time from last infusion of rFIXFc to a bleeding episode, assessment of response to treatment, and total annualised rFIXFc consumption for prevention and treatment of bleeding episodes. All patients underwent sequential pharmacokinetic evaluations of their prestudy FIX and rFIXFc. The completed trial is registered with ClinicalTrials.gov, number NCT01440946.
FINDINGS
No patients developed inhibitors to rFIXFc; in the 30 enrolled patients the most common adverse events were nasopharyngitis (n=7; 23%) and fall (n=6; 20%); four patients (13%) had serious adverse events. Overall, rFIXFc exhibited a prolonged half-life of 68·6 h (95% CI 61·8-76·0), reduced clearance, and similar recovery compared with prestudy FIX. The median ABR was 2·0 (0·0-3·1) overall and 0·0 (0·0-0·0) for spontaneous joint bleeds; ten (33%) of 30 patients reported no bleeding, and 19 (63%) reported no joint bleeding on-study. The median average prophylactic dose of rFIXFc was 58·6 IU/kg (IQR 52·3-64·8) per week. Throughout the study, 29 (97%) of 30 patients remained on once per week infusions.
INTERPRETATION
Weekly infusions of rFIXFc were well tolerated and resulted in low bleeding rates in children with severe haemophilia B.
FUNDING
Biogen, Sobi.
背景
Kids B-LONG是一项多中心、开放标签的3期研究，旨在评估重组因子IX Fc融合蛋白（rFIXFc）在既往接受治疗的12岁以下重度B型血友病儿科患者中的安全性、有效性和药代动力学。
方法
该研究纳入了30名既往接受治疗的12岁以下B型血友病男孩（内源性凝血因子IX [FIX]活性≤2 IU/dL [≤2%]）。所有患者最初每周接受一次rFIXFc预防治疗（50 - 60 IU/kg），并根据需要调整剂量（每次输注≤100 IU/kg）或给药频率（每周最多两次）。主要结局指标是抑制剂（中和抗体）的产生。次要结局包括药代动力学、年出血率（ABR）、自发性关节ABR、止血所需的输注次数和剂量、从最后一次输注rFIXFc到出血发作的时间、治疗反应评估以及预防和治疗出血发作的年度rFIXFc总消耗量。所有患者在研究前对FIX和rFIXFc进行了序贯药代动力学评估。该完成的试验已在ClinicalTrials.gov注册，编号为NCT01440946。
结果
没有患者产生针对rFIXFc的抑制剂；在30名入组患者中，最常见的不良事件是鼻咽炎（n = 7；23%）和跌倒（n = 6；20%）；4名患者（13%）发生了严重不良事件。总体而言，与研究前的FIX相比，rFIXFc的半衰期延长至68.6小时（95%CI 61.8 - 76.0），清除率降低，回收率相似。总体ABR中位数为2.0（0.0 - 3.1），自发性关节出血的ABR中位数为0.0（0.0 - 0.0）；30名患者中有10名（33%）报告无出血，19名（63%）报告在研究期间无关节出血。rFIXFc的每周平均预防剂量中位数为58.6 IU/kg（IQR 52.3 - 64.8）。在整个研究过程中，30名患者中有29名（97%）仍保持每周一次输注。
解读
每周输注rFIXFc耐受性良好，在重度B型血友病儿童中导致低出血率。
资助
百健公司、山德士公司。
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