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诺华crizanlizumab获FDA突破性疗法认定,用于预防镰状细胞病疼痛危象

青瓦 青瓦 来源:医药魔方
2019-01-09
诺华
原文

诺华1月8日宣布,单克隆抗体候选药物crizanlizumab(SEG101)近日获得FDA突破性疗法认定资格,用于预防所有镰状细胞疾病(SCD)基因型患者的血管闭塞性危象(VOCs)。


镰状细胞疾病是一种遗传性血红蛋白分子功能紊乱疾患,当血红蛋白分子暴露在各种环境中,红细胞血红蛋白发生聚合,扭曲变形成镰状。P-选择素驱动血管闭塞过程,这是一种镰状细胞病的痛苦并发症,一般在血管循环被镰状红细胞阻塞时发生。该疾病最严重的病症形式之一是急性胸部综合征,当血液流向肺部时受到限制。


Crizanlizumab是一种人源化单克隆抗体,可与P-选择素结合,后者是一种在内皮细胞和血小板表面发现的蛋白质,在血小板内皮细胞表达,主要引起细胞间相互作用,参与血栓形成或镰刀细胞病相关疼痛危象。


FDA授予crizanlizumab突破性疗法认定是基于一项双盲、随机、安慰剂对照II期临床试验的数据。198例受试者随机接受低剂量crizanlizumab(2.5 mg/kg,n=66)、高剂量crizanlizumab(5 mg/kg, =67)或安慰剂(n=65)静脉注射,共14次,为期52周。研究表明,对于镰状细胞病患者,crizanlizumab可显著降低镰状细胞病相关疼痛危象的发生率,并且不良事件发生率也较低。 


具体结果显示:高剂量crizanlizumab组的每年发生危象中位病例数为1.63,安慰剂组为2.98(高剂量crizanlizumab组危象发生率低45.3%,P=0.01)。高剂量crizanlizumab组第一次与第二次危象之间的中位时间间隔明显长于安慰剂组(4.07 vs 1.38个月,P=0.001),发生第二次危象的中位时间也明显延长(10.32 vs 5.09个月,P=0.02)。高剂量crizanlizumab组每年无并发症危象中位发生1.08例,而安慰组为2.91例(高剂量crizanlizumab组无并发症危象发生率低62.9%,P=0.02)。两治疗组10%以上的患者发生了不良事件,但安慰剂组不良事件发生率更高,是crizanlizumab组的2倍以上,主要包括关节痛、腹泻、皮肤瘙痒、呕吐和胸痛等。


诺华在2012年通过收购Selexys Pharmaceuticals获得了crizanlizumab的所有权。

机器翻译

Novartis announced on January 8 that the monoclonal antibody candidate crizanlizumab (SEG101) has recently received FDA breakthrough therapy qualification for the prevention of vaso-occlusive crises (VOCs) in patients with all sickle cell disease (SCD) genotypes.

Sickle cell disease is an inherited disorder of hemoglobin molecule function. When hemoglobin molecules are exposed to various environments, red blood cell hemoglobin polymerizes and distorts to form sickles.P-selectin drives the process of vascular occlusion, a painful complication of sickle cell disease that generally occurs when the vascular circulation is blocked by sickle red blood cells.One of the most severe forms of the disease is acute chest syndrome, which is limited when blood flows to the lungs.

Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin, a protein found on the surface of endothelial cells and platelets, and is expressed on platelet endothelial cells, causing mainly cell-cell interactions and involved in thrombosis- or sickle cell disease-related pain crises.

The FDA accreditation for crizanlizumab breakthrough therapy was based on data from a double-blind, randomized, placebo-controlled phase II trial.198 subjects were randomized to receive low-dose crizanlizumab (2.5 mg/kg, n = 66), high-dose crizanlizumab (5 mg/kg, = 67), or placebo (n = 65) intravenously for 14 doses for 52 weeks.Studies have shown that crizanlizumab significantly reduces the incidence of sickle cell disease-related pain crises and has a lower incidence of adverse events in patients with sickle cell disease.

Specific results showed that the median number of crisis cases per year in the high-dose crizanlizumab group was 1.63, placebo group 2.98 (low incidence of crisis in the high-dose crizanlizumab group 45.3%, P = 0.01).The median time interval between the first and second crisis was significantly longer in the high-dose crizanlizumab group than in the placebo group (4.07 vs 1.38 months, P = 0.001), the median time to second crisis was also significantly longer (10.32 vs 5.09 months, P = 0.02).Median annual incidence of uncomplicated crisis in the high-dose crizanlizumab group 1.08 cases, compared with 2 in the placebo group.91 cases (low incidence of uncomplicated crisis in high-dose crizanlizumab group 62.9%, P = 0.02).Adverse events occurred in more than 10% of patients in both treatment groups, but the incidence of adverse events was higher in the placebo group, which was more than twice that of the crizanlizumab group and mainly included arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Novartis acquired ownership of crizanlizumab through the acquisition of Selexys Pharmaceuticals in 2012.

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