A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy of ManNAc in Subjects with GNE Myopathy

项目摘要 GNE肌病是一种缓慢进展的肌肉疾病，导致明显的残疾，包括 使用轮椅，最终需要依赖性护理。目前，没有治疗方法 可用于GNE肌病。N-乙酰-D-甘露糖胺一水合物（ManNAc），第一个 Neu 5Ac（唾液酸）生物合成的关键前体，以及GNE的底物 GNE肌病中的酶缺陷，正在开发用于这种孤儿适应症。第一次 人类1期试验已经完成，开放标签2期试验正在进行中。我们 提出一项随机、双盲、安慰剂对照试验来评估疗效， ManNAc在GNE肌病受试者中的安全性。我们希望这项研究将告知未来 试验，并最终导致FDA批准ManNAc用于GNE肌病。主 在50名GNE肌病患者中进行的多中心试验的疗效终点和设计是 基于5年来收集的知识，作为正在进行的自然历史研究的一部分， （NCT 01417533; PI：Nuria Carrillo博士），导致GNE肌病的发展 疾病进展模型。这种疾病进展模型是一种新的工具， 设计一项试验，克服在这种罕见的疾病中确定治疗效果的挑战， 并且疾病进展缓慢。疾病进展模型有助于招募 受试者在广泛的疾病谱，增加了我们的普遍性， 对患者人群的调查结果。此外，我们的策略可以慢慢地应用到其他领域， 进行性肌肉疾病最后，我们希望我们提出的试验和患者招募 这些努力将提高人们对GNE肌病的认识，并识别未确诊的患者。 1

PROJECT SUMMARY GNE myopathy is a slowly progressive muscle disease resulting in marked disability, including wheelchair use, and ultimately requiring dependent care. Currently, there is no treatment available for GNE myopathy. N-acetyl-D-mannosamine monohydrate (ManNAc), the first committed precursor for the biosynthesis of Neu5Ac (sialic acid), and a substrate of the GNE enzyme defective in GNE myopathy, is being developed for this orphan indication. A first-in- human Phase 1 trial has been completed and an Open-Label Phase 2 trial is ongoing. We propose a randomized, double-blinded, placebo-controlled trial to evaluate the efficacy and safety of ManNAc in subjects with GNE myopathy. We hope that this study will inform future trials and will eventually lead to FDA approval for ManNAc in GNE myopathy. The primary efficacy endpoint and design of our proposed multicenter trial in 50 GNE myopathy subjects is based on knowledge collected for 5 years as part of an ongoing natural history study (NCT01417533; PI: Dr. Nuria Carrillo) which led to the development of the GNE Myopathy Disease Progression Model. This disease progression model is a novel tool that has allowed the design of a trial that overcomes the challenges of determining treatment effect in this rare and slowly progressive disease. The disease progression model facililates recruitment of subjects within a wide range of the disease spectrum, increasing the generalizability of our findings to the patient population. Furthermore, our strategy could be applied to other slowly progressive muscle diseases. Finally, we hope that our proposed trial and patient recruitment efforts will increase awareness of GNE myopathy and identification of undiagnosed patients. 1