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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。半乳糖苷酶A （aGAL）是一种溶酶体水解酶，负责球三烷基神经酰胺（GL-3）的代谢，这是该酶的主要糖鞘脂底物。在法布里病中，遗传性aGAL缺乏导致GL-3广泛沉积，并在较小程度上导致其他含有半乳糖苷酶的糖脂在心脏、肾脏、肝脏、皮肤和肠道中沉积。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、肢端剧痛、感觉异常、自主神经功能障碍、心脏病和肾功能衰竭。微血管中进行性糖脂沉积可导致目标器官衰竭，在生命的第三至第五十年导致死亡。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（随机失活一条X染色体）而受到影响。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，内皮血管床的衰竭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、心脏病和肾脏疾病。最近，法布里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几个全球市场上市。Genzyme公司生产了一种重组形式的人a-半乳糖苷酶a (r-haGAL; agalsidase beta, Fabrazyme)，为法布里病患者提供替代酶。1/2期单中心、开放标签、剂量测定、安全性和药代动力学研究已经完成。该研究提供了从靶组织中清除储存鞘糖脂的药效学证据，提示生理改善和潜在的临床益处。一项多国、随机、双盲、安慰剂对照的关键3期研究也已完成。与安慰剂相比，最常见的不良事件是输液相关的（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显示Fabrazyme治疗有任何直接的毒性作用。两项试验均表明，作为替代终点，血管内皮床储存的鞘糖脂降低到正常或接近正常的药效学水平，可能预测Fabry患者的临床获益。这项开放标签试验旨在进一步评估agalsidase β (Fabrazyme)在Fabry病患者中的安全性和有效性。主要目的是通过估计AGAL-008-00研究中安慰剂患者的血清肌酐斜率与开放标签扩展研究（AGAL02503）中血清肌酐斜率的差异来评估agalsidase 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).