A phase 2 study of a vitamin metabolite for PKAN

项目摘要 我们广泛而长期的目标是为孤儿疾病泛酸激酶开发合理的治疗方法- 相关神经退行性变(PKAN)是维生素B5代谢的一种先天错误，由 编码PANK2的基因，辅酶A生物合成途径的第一个调节步骤，并做到这一点 尽可能具有成本效益。受这种疾病影响的儿童和成人会出现严重的运动 大脑中铁的异常积聚是一种特有的模式。PKAN引发深刻 残疾和痛苦，特别是在儿童中，他们中的许多人死于疾病的并发症 生命的第一个十年。目前还没有经过验证的疾病修正疗法。 在这个项目中，我们将以实验室最近的工作为基础，展示一种引人注目的、与疾病相关的 在两种成纤维细胞培养中重现的PKAN小鼠脑中的分子和功能特征 以及人类患者的外周血液中。这一生物学特征在体内和体外通过一种 中间代谢产物以剂量依赖的方式。 在这个应用中，我们建议将这项工作扩展到临床，评估安全性、耐受性和 该产品在2期随机、双盲、安慰剂对照、剂量- 对患有PKAN的儿童和成人进行范围平行分组研究。接下来将进行为期6个月的双盲期 为期18个月的开放标签阶段。我们还将探讨应用潜在增长曲线的可行性。 纵向自然历史数据的建模方法，以捕捉疾病改善效果，目标是 为未来的研究设计提供信息。我们将采用一种新的方法来研究行为，旨在减少 罕见病临床研究固有的研究参与障碍，最大限度地减少对受试者的风险，并减少 家庭的负担。

Project Summary Our broad, long-term goal is to develop rational therapeutics for the orphan disease pantothenate kinase- associated neurodegeneration (PKAN), an inborn error of vitamin B5 metabolism that is caused by defects in the gene that encodes PANK2, the first regulatory step in the coenzyme A biosynthetic pathway, and to do so as cost-effectively as possible. Children and adults affected by the disease develop a severe movement disorder and a characteristic pattern of abnormal iron accumulation in the brain. PKAN causes profound disability and suffering, especially in children, many of whom succumb to complications of the disease in the first decade of life. No proven disease-modifying therapy is currently available. In this project, we will build on recent work from the laboratory demonstrating a compelling, disease-relevant molecular and functional signature in the PKAN mouse brain that is recapitulated in both fibroblast cell cultures and in peripheral blood from human patients. This biological signature is ameliorated in vivo and in vitro by a product of intermediary metabolism in a dose-dependent fashion. In this application, we propose to extend this work to the clinic, evaluating the safety, tolerability and pharmacodynamic profile of the product in a phase 2, randomized, double-blind, placebo-controlled, dose- ranging, parallel-group study in children and adults with PKAN. A 6-month double-blind phase will be followed by an 18-month open-label phase. We will also explore the feasibility of applying a latent growth curve modeling approach to longitudinal natural history data to capture a disease modifying effect, with the goal of informing future study design. We will employ a novel approach to study conduct that is designed to reduce the barriers to study participation inherent in rare disease clinical research, minimize risks to subjects, and lessen the burden on families.