A Phase 2a clinical trial of ALK-001 in geographic atrophy

 描述（由申请人提供）：这项工作的长期目标是开发一种预防年龄相关性黄斑变性（AMD）的口服药物。AMD是美国致盲的主要原因，有800万美国人被诊断或面临不可逆的视力丧失风险，超过200万人已经患有视力丧失。目前，没有FDA批准的AMD预防性治疗。在AMD症状之前的视网膜中的最早变化之一是毒性维生素A二聚体的形成。ALK-001是一种化学修饰的维生素A，其中3个氢原子在20号碳原子处被3个氘原子取代。用ALK-001替代视网膜的维生素A可以减缓有毒维生素A二聚体的形成。迄今为止，ALK-001是唯一一种设计用于防止维生素A二聚化的小分子，已在动物模型中证明了视觉功能的功能性保护。这项工作的中心假设是，延缓维生素A二聚化将减缓AMD的发展和/或进展。本申请的具体目的是进一步开发ALK-001并生成临床数据，以便可以设计3期或4期验证性临床试验来评估抑制维生素A二聚化减缓AMD发展和/或进展的程度。我们计划通过完成以下具体目标来实现这一目标：目的1：确定商业规模生产ALK-001的可行性。这将通过评估我们当前合成路线的局限性来实现，以确定其是否可用于商业规模生产ALK-001。目的2：评价ALK-001对AMD所致地图状萎缩（GA）进展的效应量。这将通过在80例地图状萎缩受试者中进行一项为期18个月的双盲、安慰剂对照研究来实现。预防AMD发展和/或恶化的口服药物将对数百万美国人的生活质量产生巨大影响。长期以来，维生素A的二聚化一直被假设为AMD发展的主要贡献者。然而，我们缺乏临床上友好的策略来安全地防止其二聚化。这限制了我们确定二聚化参与的程度的能力。 AMD的进展。ALK-001是一种新的化合物，已被证明可以防止维生素A的二聚化，而不会对视觉周期产生负面影响或剥夺维生素A的光感受器，因此可能会减缓AMD的进展。

 DESCRIPTION (provided by applicant): The long-term goal of this work is to develop an oral drug for the prevention of age-related macular degeneration (AMD). AMD is the leading cause of blindness in the United States, with 8 million Americans diagnosed or at risk of irreversibly losing vision, and over 2 million people who already have debilitating vision loss. Currently, there is no FDA-approved preventative treatment for AMD. One of the earliest changes in the retina that precede symptoms of AMD is the formation of toxic vitamin A dimers. ALK-001 is a chemically-modified vitamin A, in which 3 hydrogen atoms have been replaced by 3 deuterium atoms at carbon number 20. Replacing the retina's vitamin A with ALK-001 slows the formation of toxic vitamin A dimers. To date, ALK-001 is the only small molecule designed to prevent the dimerization of vitamin A that has demonstrated functional preservation of visual function in animal models. The central hypothesis of this work is that retarding vitamin A dimerization will slow the development and/or progression of AMD. The specific objective of this application is to further develop ALK-001 and generate clinical data so that phase 3 or 4 confirmatory clinical trials can be designed to assess the extent to which inhibiting the dimerization of vitamin A slows the development and/or progression of AMD. We plan to achieve this goal by completing the following specific aims: AIM 1: Determine the feasibility of manufacturing ALK-001 on a commercial scale. This will be achieved by assessing the limitations of our current synthetic route to determine if it can be used to manufacture ALK- 001 on a commercial scale. AIM 2: Evaluate the effect size of ALK-001 on the progression of geographic atrophy (GA) due to AMD. This will be achieved by performing an 18-month double-masked, placebo-controlled study in 80 subjects with geographic atrophy. An oral drug to prevent the development and/or worsening of AMD would have a tremendous impact on the quality of life of millions of Americans. The dimerization of vitamin A has long been hypothesized to be a major contributor of the development of AMD. However, we lack clinically-amiable strategies to safely prevent its dimerization. This limits our ability to determine the extent to which dimerization participates in the progression of AMD. ALK-001 is a new compound that has been shown to prevent the dimerization of vitamin A without negatively affecting the visual cycle or depriving the photoreceptors of vitamin A, and thus could possibly slow the progression of AMD.