A phase 2 study of a vitamin metabolite for PKAN

项目摘要 我们广泛的长期目标是为孤儿病泛酸激酶开发合理的治疗方法- 相关神经变性（PKAN），一种先天性维生素B5代谢缺陷，由以下缺陷引起： 编码PANK 2的基因，PANK 2是辅酶A生物合成途径中的第一个调节步骤， 尽可能地节省成本。儿童和成年人受疾病发展严重的运动 脑内异常铁积累的特征性模式。PKAN造成深刻的 残疾和痛苦，特别是儿童，其中许多人死于疾病的并发症， 人生的第一个十年目前尚无经证实的疾病缓解疗法。 在这个项目中，我们将建立在实验室最近的工作，证明一个令人信服的，与疾病相关的 PKAN小鼠脑中的分子和功能特征在两种成纤维细胞培养物中重现 和人类患者的外周血中。这种生物学特征在体内和体外通过以下方式得到改善： 中间代谢产物，呈剂量依赖性。 在这项应用中，我们建议将这项工作扩展到临床，评估安全性，耐受性和 在II期、随机化、双盲、安慰剂对照、剂量- 在PKAN儿童和成人中进行的范围、平行组研究。随后将进行为期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 纵向自然史数据的建模方法，以捕获疾病改善效果，目标是 告知未来的研究设计。我们将采用一种新的方法来研究行为，旨在减少 罕见病临床研究中固有的研究参与障碍，最大限度地降低受试者的风险， 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.