MULTI-CENTER, OPEN LABEL STUDY OF THE SAFETY AND EFFICACY OF FABRAZYME IN PTS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。α-半乳糖苷酶A（aGAL）是一种溶酶体水解酶，负责神经酰胺三己糖苷（GL-3）（酶的主要鞘糖脂底物）的代谢。在法布里病中，aGAL的遗传性缺乏导致GL-3在心脏、肾脏、肝脏、皮肤和肠道中广泛沉积，并在较小程度上导致其他含α-半乳糖苷酶的糖脂沉积。法布里病的主要临床体征和症状包括皮肤病变、良性角膜和晶状体混浊、极度疼痛、感觉异常、自主神经功能障碍、心脏病和肾衰竭。微血管系统中进行性糖脂沉积导致靶器官衰竭，导致生命的第三至第五个十年死亡。由于X染色体携带aGAL基因，大多数受影响的患者是半合子男性，尽管一些杂合子女性也可能由于Lyonization（一条X染色体的随机失活）而受影响。法布里病临床表现的共同点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，内皮血管床的衰竭导致无数病理生理事件，导致中枢、外周和自主神经系统疾病、心脏病和肾病。最近，Fabry病的酶替代疗法已被批准在包括欧盟、澳大利亚和美国在内的多个全球市场上市。Genzyme Corporation已生产重组形式的人α-半乳糖苷酶A（r-haGAL;半乳糖苷酶β，Fabrazyme），为法布里病患者提供替代酶。已完成一项I/II期单中心、开放标签、剂量探索、安全性和药代动力学研究。本研究提供了从靶组织中清除储存鞘糖脂的药效学证据，表明生理改善和潜在临床获益。一项多国、随机、双盲、安慰剂对照的关键III期研究也已完成。与安慰剂相比，最常见的不良事件为输注相关（寒战和发热）。此外，包括临床生化、血液学和尿分析在内的实验室研究未显示Fabrazyme治疗有任何直接毒性作用。两项试验均证明，作为替代终点，血管内皮床储存的鞘糖脂的药效学降低至正常或接近正常水平，可能预测法布里病患者的临床获益。这项开放标签试验旨在进一步评价半乳糖苷酶β（Fabrazyme）在法布里病患者中的安全性和有效性。主要目的是通过估计研究AGAL-008 - 00中安慰剂患者血清肌酐斜率倒数与开放标签扩展研究（AGAL 02503）中血清肌酐斜率倒数之间的差异，评价半乳糖苷酶β对肾功能的稳定作用。

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. A-galactosidase A (aGAL) is a lysosomal hydrolase enzyme responsible for the metabolism of globotriaosylceramide (GL-3), the enzyme's major glycosphingolipid substrate. In Fabry disease, an inherited deficiency of aGAL leads to widespread deposition of GL-3, and to a lesser extent other a-galactosidase-containing glycolipids, in the heart, kidney, liver, skin, and intestines. The major clinical signs and symptoms of Fabry disease include skin lesions, benign corneal and lenticular opacities, excruciating acral pain, paresthesias, autonomic dysfunction, cardiac disease, and renal failure. Progressive glycolipid depostion in the microvasculature leads to failure of target organs resulting in death in the third to fifth decades of life. Because the X-chromosome carries the aGAL gene, most affected patients are hemizygous males, although some heterozygous females can also be affected due to lyonization (random inactivation of one X- chromosome). 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 results in the myriad pathophysiologic events leading to central, peripheral and autonomic nervous system disease, cardiac disease and renal disease. Recently, enzyme replacement therapy for Fabry disease has been approved to market in several global markets including the European Union, Australia, and the United States. Genzyme Corporation has manufactured a recombinant form of human a-galactosidase A (r-haGAL; agalsidase beta, Fabrazyme) to provide replacement enzyme to patients with Fabry disease. A Phase 1/2 single center, open label, dose finding, safety and pharmacokinetic study has 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 compared to placebo were infusion related (rigors and fever). In addition, laboratory studies including clinical chemistry, hematology, and urinalysis did not show that treatment with Fabrazyme had any direct toxic effects. Both trials demonstrated pharmacodynamic reduction to normal or near-normal levels of stored glycosphingolipid from vascular endothelial beds as surrogate endpoints likely to predict clinical benefit in Fabry patients. This open-label trial is designed to further evaluate the safety and effectiveness of agalsidase beta (Fabrazyme) in patients with Fabry disease. The primary objective is to evaluate the stabilization of renal function with agalsidase beta by means of estimating the difference within the placebo patients' inverse serum creatinine slope while in study AGAL-008-00 versus the inverse serum creatinine slope while in the open label extension study (AGAL02503).