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

克仑特罗治疗庞贝病的 1/2 期研究

• 批准号: 8729421
• 负责人: Dwight D Koeberl
• 金额: $ 20万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729421
• 关键词: Phase; Study; Clenbuterol; Treatment; Pompe

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.

描述（由申请人提供）： 庞贝疾病是一种肌病，类似于其晚期发作形式的肢体肌营养不良症。 它是由曲线和平滑肌中的酸α-葡萄糖苷酶（GAA）缺乏引起的，这导致溶酶体糖原的积累以及骨骼，光滑和心脏肌肉的破坏。 重组人GAA的酶替代疗法（ERT）已从肺部和运动的透视后期发作庞贝疾病中显示出疾病过程的稳定。但是，ERT的局限性已经显而易见，包括高剂量要求以及成年患者肌肉无力和肺部受累的完全逆转。 逐渐下降和死亡率的逐渐下降，强调了需要新的疗法来改善这些患者的结果。如果可以清除阳离子非依赖性甘露糖-6-磷酸受体（CI-MPR）的吸收，则可以更有效地治疗诸如蓬松疾病之类的溶酶体储存障碍。成年哺乳动物肌肉中CI-MPR的稀少凸显了CI-MPR在庞贝疾病中限制ERT的概念。 在GAA敲除小鼠的骨骼肌中，已经证明了CI-MPR的水平较低，特别是在主要由II型肌纤维组成的肌肉中。 小鼠模型的初步结果表明，β-2激动剂疗法增强了CI-MPR的表达并提高了GAA替代疗法的功效，从而确认CI-MPR在庞贝疾病中的替代疗法方面的关键作用。 该申请提出了为期52周的安慰剂对照，双盲研究，对β-2激动剂克伦布特罗（Clenbuterol）作为辅助疗法，用于20名患有晚期发作蓬松疾病的成年患者的ERT。 该研究的具体目的1是确定克伦特罗醇作为辅助治疗的安全性和功效。最初的评估将包括肌肉力量测试，步行6分钟 测试和肺功能测试。安全性评估将包括标准的血液测试和心电图，同时使用研究药物。该研究的具体目的2是确定克伦特罗疗法对患者的受体介导的重组GAA摄取的影响。将评估克伦特罗对CI-MPR表达的影响。 通过比较基线和克伦布特罗给药期间，肌肉功能和生物化学校正，将分析增强的CI-MPR介导的GAA摄取的影响。将监测尿液生物标志物四糖（GLC4）。进行这些研究是为了确定生化校正和临床终点之间是否存在任何相关性。