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

ALK-001 治疗地理萎缩的 2a 期临床试验

• 批准号: 9267153
• 负责人: Leonide Saad
• 金额: $ 103.23万
• 依托单位: ALKEUS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267153
• 关键词: 12 year old; Adolescent; Adult; Affect; Age; Age related macular degeneration; American; Animal Model; Autopsy; Award; Bioavailable; Biological Preservation; Blindness; Carbon; Chemicals; Choroidal Neovascularization; Clinical; Clinical Data; Clinical Trials; Data; Deuterium; Development; Diagnosis; Dimerization; Direct Costs; Disease; Elderly; FDA approved; Generations; Goals; Health Care Costs; Human; Hydrogen; Image; Immune response; Injection of therapeutic agent; Kilogram; Knowledge; Macular degeneration; Masks; Mission; Oral; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Photoreceptors; Prevalence; Prevention; Preventive treatment; Process; Prophylactic treatment; Public Health; Quality of life; Reporting; Research; Retina; Retinal; Retinal Degeneration; Risk; Route; Safety; Small Business Technology Transfer Research; Stargardt' s disease; Symptoms; Testing; Tissues; United States; United States National Institutes of Health; Vision; Vitamin A; Work; capsule; design; dimer; disability; geographic atrophy; immune function; improved; manufacturing process; mouse model; negative affect; placebo controlled study; prevent; public health relevance; research clinical testing; small molecule; treatment effect; visual cycle; volunteer

 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 ALK-001 is a chemically-modified vitamin A, in which 3 hydrogen atoms have been replaced by 3 deuterium atoms at carbon number 20.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.

 描述(申请人提供)：这项工作的长期目标是开发一种预防老年性黄斑变性(AMD)的口服药物。AMD是美国导致失明的主要原因，有800万美国人被诊断为或面临不可逆转的失明风险，200多万人已经患有衰弱的视力丧失。目前，没有FDA批准的AMD预防性治疗。在AMD症状之前，视网膜最早的变化之一是形成有毒的维生素A二聚体。ALK-001是一种经过化学修饰的维生素A，其中3个氢原子被碳20位的3个重氢原子取代。用ALK-001取代视网膜中的维生素A可以减缓有毒维生素A二聚体的形成。到目前为止，ALK-001是唯一一个设计用来防止维生素A二聚化的小分子，在动物模型中证明了它对视觉功能的保护作用。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。这项应用的具体目标是进一步开发ALK-001并产生临床数据，以便可以设计3或4期验证性临床试验，以评估抑制维生素A二聚化在多大程度上减缓AMD的发展和/或进展。我们计划通过完成以下具体目标来实现这一目标：目标1：确定商业规模制造ALK-001的可行性。这将通过评估我们目前合成路线的局限性来实现，以确定它是否可以用于商业规模的生产ALK-001。目的：评价ALK-001对AMD所致地理萎缩(GA)进展的影响。这将通过对80名患有地理萎缩的受试者进行为期18个月的双掩蔽、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的二聚化一直被认为是AMD发展的主要贡献因素。然而，我们缺乏临床上可行的策略来安全地防止它的二聚化。这限制了我们确定二聚化参与程度的能力。 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，也不会剥夺光感受器中的维生素A，因此可能会减缓AMD的进展。