STUDY OF THE SAFETY AND EFFICACY OF FABRAZYME IN PATIENTS WITH FABRY DISEASE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。法布里病的共同表现是严重的内皮功能障碍，影响血管的结构、血管反应性和完整性。最终，内皮血管床的失效会导致无数的病理生理事件，导致中枢、外周和自主神经系统疾病，心脏和肾脏疾病。Genzyme公司制造了一种重组形式的人α-半乳糖苷酶A(r-HA-Gal；Fradzyme)，用于为Fabry病患者提供替代酶。1-2阶段的单中心、开放标签、剂量发现、安全性和药代动力学研究已经完成。这项研究提供了储存的鞘糖脂从靶组织中清除的药效学证据，表明生理改善和潜在的临床益处。一项多国家、随机、双盲、安慰剂对照的关键阶段3期研究也已完成。与安慰剂相比，接受Fradzyme治疗的患者最常见的不良反应是输液相关反应，包括僵硬和发烧。此外，包括临床化学、血液学和尿液分析在内的实验室研究没有表明使用Fradzyme治疗有任何毒性作用。这两项试验都表明，将储存在血管内皮细胞床上的糖旋糖脂降低到正常或接近正常水平，作为替代终点，可能预测Fabry患者的临床益处。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The common element in the manifestations of Fabry disease is severe endothelial dysfunction affecting the structure, vasoreactivity and integrity of blood vessels. Ultimately, failure of endothelial vascular beds result in the myriad pathophysiologic events leading to central, peripheral and autonomic nervous system disease, cardiac and renal disease. Genzyme Corporation has manufactured a recombinant form of human a-galactosidase A (r-ha-GAL; Fabrazyme) to provide replacement enzyme to patients with Fabry disease. A Phase 1-2 single center, open label, dose finding, safety and pharmacokinetic studies have been completed. This study provided evidence of pharmacodynamic clearance of stored glycosphingolipid from target tissues, suggesting physiologic improvement and potential for clinical benefit. A multi-national, randomized, double blind placebo controlled pivotal Phase 3 study has also been completed. The most frequent adverse events for those patients who received Fabrazyme compared to placebo were infusion-associated reactions including rigors and fever. In addition, laboratory studies including clinical chemistry, hematology, and urinalysis did not show that treatment with Fabrazyme had any toxic effects. Both trials have demonstrated pharmacodynamic reduction to normal or near-normal levels of stored glycospingolipids from vascular endothelial beds as surrogate endpoints likely to predict clinical benefit in Fabry patients.