Phase 1/2 Study of Clenbuterol for the Treatment of Pompe Disease

描述(由申请人提供)： 庞培病是一种肌病，类似于晚发的四肢带状肌营养不良症。它是由于横纹肌和平滑肌中酸性α-葡萄糖苷酶(GAA)缺乏所致，导致溶酶体糖原积聚，破坏骨骼肌、平滑肌和心肌。重组人GAA的酶替代疗法(ERT)从肺和运动角度显示晚发型庞贝病的疾病过程稳定。然而，ERT的局限性已经变得明显，包括高剂量要求以及成人患者的肌肉无力和肺部受累无法完全逆转。临床的逐渐下降和死亡率的增加强调了需要新的治疗方法来改善这些患者的结果。如果阳离子非依赖性甘露糖-6-磷酸受体(CI-MPR)摄取障碍能够被清除，溶酶体储存障碍，如庞贝病，可能会得到更有效的治疗。成年哺乳动物肌肉中CI-MPR的缺乏强调了CI-MPR限制了Pompe病ERT的概念。低水平的CI-MPR在GAA基因敲除小鼠的骨骼肌中被证明，特别是在主要由II型肌纤维组成的肌肉中。在小鼠模型中的初步结果显示，β-2激动剂治疗增强了CI-MPR的表达，并提高了GAA替代治疗的疗效，从而证实了CI-MPR在庞贝病替代治疗中的关键作用。 这项申请提出了一项为期52周的安慰剂对照双盲研究，将β-2激动剂克伦特罗作为ERT的辅助治疗，用于20名晚发性庞贝病成人患者。本研究的具体目的1是确定克伦特罗作为辅助治疗的安全性和有效性。这项初步评估将包括肌肉力量测试，即6分钟步行 检测，肺功能检测。安全性评估将包括在研究药物期间的标准血液测试和心电图。本研究的具体目标2是确定克伦特罗治疗对患者受体介导的重组GAA摄取的影响。将评估克伦特罗对CI-MPR表达的影响。增强CI-MPR介导的GAA摄取的影响将通过比较肌肉功能和基线和克伦特罗给药期间肌肉中糖原积累的生化校正来分析。将监测尿液生物标记物葡萄糖四糖(Glc4)。正在进行这些研究，以确定生化校正和临床终点之间是否存在任何相关性。

DESCRIPTION (provided by applicant): Pompe disease is a myopathy, similar to limb-girdle muscular dystrophy in its late-onset form. It results from acid alpha-glucosidase (GAA) deficiency in striated and smooth muscle, which leads to the accumulation of lysosomal glycogen and destruction of skeletal, smooth and cardiac muscle. Enzyme replacement therapy (ERT) with recombinant human GAA has shown stabilization of the disease process from a pulmonary and motor perspective in late onset Pompe disease. However, the limitations of ERT have become apparent, including high dosage requirements and the lack of complete reversal of muscle weakness and pulmonary involvement in adult patients. A gradual clinical decline and increased mortality has emphasized the need for new therapy to improve the outcome of these patients. Lysosomal storage disorders such as Pompe disease may be more effectively treated, if the hurdle of cation-independent mannose-6-phosphate receptor (CI-MPR) uptake can be cleared. The paucity of CI-MPR in adult mammals' muscle has underscored the concept that CI-MPR is limiting for ERT in Pompe disease. Low levels of CI-MPR have been demonstrated in skeletal muscle of GAA knockout mice, specifically in muscles comprised primarily of type II myofibers. Preliminary results in a mouse model revealed that beta-2 agonist therapy enhanced CI-MPR expression and increased efficacy from GAA replacement therapy, thereby confirming the key role of CI-MPR with regard to replacement therapy in Pompe disease. This application proposes a 52 week placebo-controlled, double-blind study of the beta-2 agonist clenbuterol as an adjunctive therapy to ERT in 20 adult patients with late onset Pompe disease. Specific Aim 1 of the study is to determine the safety and efficacy of clenbuterol as adjunctive therapy. This initial evaluation will include muscle strength testing, the 6 minute walk test, and pulmonary function testing. Evaluation of safety will include standard blood testing and electrocardiograms, while on study drug. Specific Aim 2 of the study is to determine the effect of clenbuterol therapy upon receptor-mediated uptake of recombinant GAA in patients. The effects of clenbuterol upon CI-MPR expression will be evaluated. The impact of enhanced CI-MPR mediated uptake of GAA will be analyzed by comparing muscle function and biochemical correction of glycogen accumulation in muscle at baseline and during clenbuterol administration. The urinary biomarker glucose tetrasaccharidde (Glc4), will be monitored. These studies are being done to determine if there are any correlations between biochemical correction and clinical endpoints.