ALK-001 Phase 2 Treatment of Stargardt Disease IND 108,353 (09/08/2015)

项目总结/摘要 这项临床研究的长期目标是开发一种口服治疗方法，以预防或减缓 Stargardt病（STGD）的进展，这是一种主要但罕见的青少年失明形式，患病率为1 每10，000人中有一个。没有FDA批准的STGD的治愈或预防性治疗。视力丧失 STGD是由ABCA 4基因突变引起的。这些突变导致加速形成 有毒的维生素A聚集体称为“维生素A二聚体”。核心假设是， 这些二聚体将减缓STGD的发展和/或进展。本研究将调查一种 称为ALK-001的分子，其抑制维生素A的二聚化，对STGD的进展。 在STGD的啮齿动物模型中，ALK-001给药超过一年，导致显著的、持续的STGD。 减缓维生素A二聚化，并保护视觉功能。在为期4周的多次给药的1a期研究中， 在健康志愿者中进行的临床研究，以及在Stargardt病、ALK- 001达到“生物活性水平”，所有受试者耐受良好，并且没有显示出副作用或毒性。为 然而，ALK-001要成为FDA批准的治疗药物，必须首先在II期然后在III期进行评估 临床试验本申请的具体目的是收集关于安全性和 ALK-001的作用，以便设计和进行III期验证性试验。完成这项工作的方法是 通过完成以下具体目标：进行一项为期24个月的随机、双盲、安慰剂对照 在多达110例STGD受试者中进行的交叉组研究，以评价 ALK-001对STGD进展的影响。本研究将在美国的多个临床研究中心进行 States.安全性结局指标包括：不良事件（AE）、严重不良事件（SAE）、12导联 心电图、生命体征、体格检查、眼部检查、血液检查（肝酶，血液化学， 血液学和脂质组）。疗效结局指标包括眼底萎缩性病变的大小 自体荧光（FAF），最佳矫正视力，微视野，光学相干断层扫描（SD- OCT）、视功能问卷、阅读速度和暗适应。 完成拟议工作将产生临床数据，以：（a）评估 （B）在STGD患者中测定ALK-001的量及其在24个月的每日给药; 血浆中的代谢物，响应每日给药长达24个月;（c）获得 ALK-001对STGD进展的影响，通过以下方面的变化测量：FAF显著降低的面积， 微视野、视力、阅读速度、视网膜厚度和/或OCT体积;（d）比较安全性 和ALK-001在不同年龄或不同表型患者中的作用;（e）探索剂量反应 使用上述疗效和安全性参数的依赖性;以及（f）收集数据，以更好地了解 STGD进展。上述数据将用于支持III期安全性和疗效研究，以评估 抑制视网膜中维生素A的二聚化防止由于STGD引起的视力丧失的程度，以及 完成STGD可能治疗方法的临床开发。一种预防或减缓 STGD的恶化将对STGD患者的生活质量产生巨大影响。

PROJECT SUMMARY / ABSTRACT The long-term goal of this clinical research is to develop an oral treatment to prevent or slow the progression of Stargardt disease (STGD), a leading, but rare form of juvenile blindness with a prevalence of 1 in 10,000 in the United States. There is no FDA-approved cure or preventative treatment for STGD. Vision loss in STGD is caused by mutations on the ABCA4 gene. These mutations lead to the accelerated formation of toxic vitamin A aggregates called “vitamin A dimers”. The central hypothesis is that retarding the formation of these dimers will slow the development and/or progression of STGD. This study will investigate the effects of a molecule called ALK-001, which inhibits the dimerization of vitamin A, on the progression of STGD. In rodent models of STGD, administration of ALK-001 for over one year, led to significant, sustained slowing of vitamin A dimerization, and to preservation of visual function. In a 4-week long, multi-dose, phase 1a clinical study in healthy volunteers, and in an 8-week long phase 1b in patients with Stargardt disease, ALK- 001 reached “bioactive levels”, was well-tolerated by all subjects, and showed no side effects or toxicity. For ALK-001 to become a FDA-approved therapeutic however, it must first be evaluated in Phase 2 then Phase 3 clinical trials. The specific objective of this application is to collect additional data regarding the safety and effects of ALK-001 so that Phase 3, confirmatory trials can be designed and performed. This will be achieved by completing the following specific aim: Perform a 24-month, randomized, double-masked, placebo-controlled study with a cross-over arm, in up to 110 subjects with STGD, to evaluate the safety, tolerability and effects of ALK-001 on the progression of STGD. This study will be performed at multiple clinical sites across the United States. Safety outcome measures include: adverse events (AE), serious adverse events (SAE), 12-lead electrocardiograms, vital signs, physical exam, ocular exam, blood tests (liver enzymes, blood chemistry, hematology, and lipid panels). Efficacy outcome measures include size of atrophic lesions by fundus autofluorescence (FAF), best-corrected visual acuity, microperimetry, optical coherence tomography (SD- OCT), visual function questionnaire, reading speed, and dark adaptation. Completion of the proposed work will generate clinical data to: (a) assess the safety and tolerability of 24 months of daily dosing of ALK-001 in STGD patients; (b) determine the quantity of ALK-001 and its metabolites in plasma, in response to daily dosing for up to 24 months; (c) obtain estimates of the effect size of ALK-001 on the progression of STGD, as measured by changes in: areas of significantly decreased FAF, microperimetry, visual acuity, reading speed, retinal thickness and/or volume by OCT; (d) compare the safety and effects of ALK-001 in patients of different age or varying phenotypes; (e) explore dose-response dependencies using the above efficacy and safety parameters; and (f) gather data to better understand how STGD progresses. The above data will be used to power a Phase 3 safety and efficacy study to evaluate the extent to which inhibiting the dimerization of vitamin A in the retina prevents vision loss due to STGD, and to finalize the clinical development of a possible treatment for STGD. An oral drug to prevent or slow the worsening of STGD would have tremendous impact on the quality of life of people with STGD.