AN OPEN-LABEL EXTENSION OF STUDY TKT024 EVALUATING LONG-TERM SAFETY AND CLINI

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 摘要 假设 酶替代疗法将改善MPS II患者的肺活量、关节活动度和6分钟步行试验结果。 具体目标 这项扩展研究旨在允许处于研究TKT024双盲阶段的艾度硫酶接受者继续接受长期治疗。同样重要的是，它还将允许TKT024研究中的安慰剂接受者交叉并开始使用艾度磺酶进行积极治疗。这项扩展研究的主要目的是收集正在接受艾度硫酶治疗的MPS II患者的长期安全性和临床结果数据。为了实现这一目标，安全性评估和临床结果将在研究的第一年期间每隔4个月进行一次，这与研究TKT024中的测试一致。此外，将监测和记录反映患者长期MPS II疾病进展的临床事件。这项研究的次要目的是获得商业规模生产的艾杜硫酶的安全性数据。一旦可用于临床，该药物产品将立即用于试验中的患者。这种材料的药代动力学数据也将从第一年进行的PK研究中产生。商业规模药品的PK和安全性数据将单独分析，并作为完整数据集的一部分进行分析。 背景和意义 粘多糖症是一组溶酶体储存性疾病，由分解糖胺多聚糖(GAG)所需的酶缺乏引起。结果，GAG聚集在受影响组织的溶酶体中。每个患者的临床后果可能不同，但常见的病理生理学是GAG分子的溶酶体积聚，导致细胞充血、器官肿大、组织破坏和器官系统功能障碍。GAG的储存是渐进性的；因此，临床症状都是慢性和渐进性的。这些疾病总是与严重和致残的发病率以及很早的死亡率有关。这些疾病中的许多都与婴儿期或儿童期早期死亡有关。 MPS II或Hunter综合征是一种X连锁隐性疾病，由溶酶体酶艾杜酸-2-硫酸酯酶(I2S)缺乏引起，I2S功能是从硫酸皮肤素和硫酸乙酰肝素中裂解O-连接的硫酸盐部分；因此，由于I2S缺乏，这些分子逐渐积累在MPS II中，MPS II是一种罕见的疾病，估计发病率为1/162,000活产儿。MPS II的临床表型非常不同，是由于GAG在几乎所有细胞类型、组织和器官中的慢性和进行性积聚。MPS II的特点是在呼吸道、心脏、肝脏、脾、软脑膜、骨骼、关节、口咽、头、颈部和中枢神经系统聚集。口咽部和呼吸道的沉积会导致严重的呼吸道阻塞，原因是舌音过大、声门上狭窄和沙眼。这种阻塞的解剖学和生理学导致睡眠呼吸暂停和呼吸道阻塞。心脏、肝脏和脾中GAG的沉积会导致器官肿大，心脏瓣膜也会受到影响。骨骼和关节受累会导致严重的骨骼脱皮和关节活动受限。在MPS II患者中有广泛的临床严重性。在最严重的情况下，中枢神经系统受累会导致智力低下和进行性神经功能衰退。MPS II的临床表现通常会导致出生后第一或第二个十年的死亡。在不太严重的MPS II中，死亡可能发生在成年早期，但一些患者已经存活到第五和六十年。 目前，MPS II还没有标准的治疗方法。对症治疗是适当的。

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. ABSTRACT HYPOTHESIS That enzyme replacement therapy will improve vital capacity, joint range of motion, and six minute walk test results in patients with MPS II. SPECIFIC AIMS This extension study is designed to allow idursulfase recipients in the double-blind phase of Study TKT024 to continue to receive therapy on a long-term basis. Equally important, it will also allow the placebo recipients in Study TKT024 to cross-over and begin active treatment with idursulfase. The primary objective of this extension study is to collect long-term safety and clinical outcome data in MPS II patients who are receiving idursulfase therapy. To achieve this objective, safety evaluations and clinical outcomes will be conducted at 4-month intervals during the first year of the study, which is consistent with the testing in Study TKT024. In addition, clinical events reflecting long-term MPS II disease progression in patients will be monitored and documented. The secondary objective of this study is to objtain safety data on idursulfase manufactured at commercial-scale. This drug product will be administered to patients in the trial as soon as it is available for clinical use. Pharmacokinetic data on this material will also be generated from the PK studies to be conducted during the first year. The PK and safety data on the commercial-scale drug product will be analyzed separately as well as part of the complete data set. BACKGROUND AND SIGNIFICANCE The mucopolysaccaridoses are a set of lysosomal storage disease caused by deficiencies of enzymes required to catabolize glycosaminoglycans (GAGs). As a result, GAGs accumulate in the lysosomes of the affected tissues. The clinical consequences can vary for each individual patient, but the common pathophysiology is lysosomal accumulation of GAG molecules leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction. The storage of GAGs is progressive; thus, the clinical syndromes are all chronic and progressive. Invariably these diseases are associated with profound and disabling morbidity as well as very early mortality. Many of these diseases are associated with death in infancy or early childhood. MPS II or Hunter Syndrome is an X-linked recessive disease caused by the deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S), I2S functions to cleave O-linked sulfate moieties from both dermatan sulfate and heparan sulfate; therefore, due to the deficiency of I2S, these molecules progressively accumulate in MPS II, MPS II is a rare disease with an estimated incidence of 1 in 162,000 live births. The clinical phenotype of MPS II is extremely heterogeneous and is due to the chronic and progressive accumulation of GAGs in nearly all cell types, tissues, and organs of the body. MPS II is characterized by GAG accumulation in the respiratory tract, heart, liver, spleen, leptomeninges, bones, joints, oropharynx, head, neck and central nervous system. Oropharyngeal and respiratory deposition of GAGs leads to severe airway obstruction due to macroglossia, supraglottic narrowing, and trachemalacia. This obstructive anatomy and physiology lead to sleep apnea and airway obstruction. Deposition of GAGs in the heart, liver, and spleen leads to organomegaly, and cardiac valves are affected as well. The bone and joint involvement leads to severe skeletal derormities and limitations of joint mobility. There is a wide spectrum of clinical severity among MPS II patients. In the most severe cases, central nervous system involvement leads to mental retardation and progressive neurologic decline. The clinical manifestations of MPS II generally lead to death in the first or second decade of life. In the less severe form of MPS II, death may occur in early adulthood, but some patients have survived into the fifth and sixth decades of life. Currently, no standard treatment exists for MPS II. Symptomatic treatment is provided, as appropriate.