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

一项随机、双盲、安慰剂对照、多中心研究，旨在评估 ManNAc 对 GNE 肌病受试者的疗效

• 批准号: 10456024
• 负责人: ANTHONY Arnold AMATO
• 金额: $ 136.46万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456024
• 关键词: Age; Anabolism; Awareness; Biological Markers; Caring; Clinical; Clinical Trials; Data; Development; Disease; Disease Progression; Disease model; Double-Blind Method; Enzymes; Future; Glycolipids; Glycoproteins; In Vitro; Infrastructure; Knowledge; Lead; Measures; Medical; Modeling; Monosaccharides; Multicenter Studies; Multicenter Trials; Muscle; Muscle Weakness; Muscle function; Myopathy; Natural History; Orphan; Outcome Measure; Patient Outcomes Assessments; Patient Recruitments; Patients; Placebo Control; Placebos; Polysaccharides; Production; Progressive Disease; Randomized; Safety; Sialic Acids; Standardization; Structure; Therapeutic; Time; Wheelchairs; base; cost; design; disability; double-blind placebo controlled trial; efficacy evaluation; first-in-human; functional loss; functional outcomes; improved; in vivo; mannosamine; mathematical model; muscle strength; novel; open label; patient oriented; patient population; phase I trial; phase II trial; pragmatic implementation; prevent; prophylactic; prospective; randomized placebo-controlled clinical trial; recruit; reduced muscle strength; restoration; secondary outcome; sialylation; simulation; therapeutic development; tool; treatment effect; Age; Anabolism; Awareness; Biological Markers; Caring; Clinical; Clinical Trials; Data; Development; Disease; Disease Progression; Disease model; Double-Blind Method; Enzymes; Future; Glycolipids; Glycoproteins; In Vitro; Infrastructure; Knowledge; Lead; Measures; Medical; Modeling; Monosaccharides; Multicenter Studies; Multicenter Trials; Muscle; Muscle Weakness; Muscle function; Myopathy; Natural History; Orphan; Outcome Measure; Patient Outcomes Assessments; Patient Recruitments; Patients; Placebo Control; Placebos; Polysaccharides; Production; Progressive Disease; Randomized; Safety; Sialic Acids; Standardization; Structure; Therapeutic; Time; Wheelchairs; base; cost; design; disability; double-blind placebo controlled trial; efficacy evaluation; first-in-human; functional loss; functional outcomes; improved; in vivo; mannosamine; mathematical model; muscle strength; novel; open label; patient oriented; patient population; phase I trial; phase II trial; pragmatic implementation; prevent; prophylactic; prospective; randomized placebo-controlled clinical trial; recruit; reduced muscle strength; restoration; secondary outcome; sialylation; simulation; therapeutic development; tool; treatment effect

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

项目摘要 嗅觉肌病是一种缓慢进行性肌肉疾病，导致了明显的残疾，包括 轮椅使用，最终需要依赖护理。目前，没有治疗 可用于GNE肌病。 N-乙酰基-D-甘露胺一水合物（MANNAC），第一个 用于neu5ac（唾液酸）生物合成的前体和gne的底物 为此孤儿的指示，正在开发gne肌病中的酶缺陷。第一个 人类1期试验已经完成，并且正在进行开放标签2期试验。我们 提出一项随机，双盲，安慰剂对照试验，以评估功效和 Mannac在患有局势肌病的受试者中的安全。我们希望这项研究能为未来提供信息 试验，最终将导致FDA批准MANNAC在GNE肌病中。主要 在50个GNE肌病学科中，我们提出的多中心试验的功效终点和设计是 作为一项正在进行的自然历史研究的一部分，基于收集了5年的知识 （NCT01417533; PI：Nuria Carrillo博士），导致了GNE肌病的发展 疾病进展模型。这种疾病进展模型是一种新颖的工具，已允许 在这种罕见的情况下克服了确定治疗效果的挑战的试验的设计 并缓慢进行性疾病。疾病进展模型促进了 在广泛的疾病范围内的受试者，提高了我们的普遍性 对患者人群的发现。此外，我们的策略可以缓慢地应用于其他 进行性肌肉疾病。最后，我们希望我们提议的审判和招募患者 努力将提高人们对局势肌病的认识和对未诊断患者的识别。 1