A TRIAL OF TTP488 TO SLOW THE RATE OF CLINICAL PROGRESSION OF PATIENTS WITH AD

项目3：TTP488延缓AD患者临床进展的试验 目前FDA批准的治疗阿尔茨海默病(AD)的药物主要是有症状的，没有针对性 致病途径。淀粉样β蛋白(ALI)在斑块中的沉积和炎症可能 治疗靶点。晚期糖基化终产物受体(RAGE)在神经元和 星形胶质细胞，并在AD中上调。RAGE与包括AIJ在内的多个配体相互作用，并可能与 炎症和神经元功能障碍。抑制RAGE/配体相互作用可能会减缓 急性脑出血所致的神经病理改变和认知功能改变。TTP488是一种小分子，由一个 筛选过程，在体外与RAGE结合，并抑制RAGE与其配体的相互作用。在体内， TTP488跨越血脑屏障，在转基因小鼠AD模型中降低脑淀粉样蛋白负荷 和行为障碍。该化合物在健康受试者中耐受性良好，包括日常口服 老年受试者服药1个月，AD患者进行更长时间的安全性研究(数据 2006年2月提供)。我们建议在350名患者中进行一项随机、双盲、多中心试验 轻至中度AD患者接受一剂TTP488或安慰剂治疗18个月。研究对象将 随机分为60：40接受活性药物或安慰剂治疗。假设是用TTP488治疗， 相对于安慰剂，会导致较慢的临床下降。将定期跟踪受试者以评估 认知、功能、行为、安全性和耐受性。主要结果指标是ADAS-COG和CDR 箱数(CDR-SOB)。次要结果测量是ADCS-ADL和神经精神病学 库存(NPI)。药物水平和生物标志物将在血浆中进行测量。AD的标准治疗方法将是 允许的。这项研究有90%的能力来检测ADAS-COG上41%或更大的变化，假设是3.8 在安慰剂组中，点数平均每年变化，并有80%的能力检测35%的变化。

Project 3: A Trial of TTP488 to Slow the Rate of Clinical Progression of Patients with AD Currently FDA-approved drugs for Alzheimer's disease (AD) are primarily symptomatic and do not target pathogenic pathways. Deposition of amyloid beta protein (Ali) in plaques and inflammation may offer therapeutic targets. The receptor for advanced glycation endproducts (RAGE) is expressed in neurons and astrocytes and is upregulated in AD. RAGE interacts with multiple ligands, including AIJ, and may link AS to inflammation and neuronal dysfunction. Inhibition of RAGE/ligand interactions may slow the progression of neuropathological defects and cognitive changes induced by AH. TTP488 is a small molecule identified by a screening process, that binds to RAGE in vitro, and inhibits the interaction of RAGE with its ligands. In vivo, TTP488 crosses the blood brain barrier and, in transgenic mouse AD models, reduces brain amyloid load and behavioral dysfunction. The compound is well tolerated in healthy human subjects, including daily oral dosing for 1 month in elderly subjects, and longer safety studies in patients with AD are ongoing (data available in February 2006). We propose to carry out a randomized, double blind, multicenter trial in 350 patients with mild to moderate AD treated with one dose of TTP488 or placebo for 18 months. Subjects will be randomized 60:40 to receive active drug or placebo. The hypothesis is that treatment with TTP488, relative to placebo, will lead to slower clinical decline. Subjects will be followed at regular intervals to assess cognition, function, behavior, safety and tolerability. Primary outcome measures are the ADAS-cog and CDR Sum of Boxes (CDR-SOB). Secondary outcome measures are the ADCS-ADL and Neuropsychiatric Inventory (NPI). Drug levels and biomarkers will be measured in plasma. Standard therapy for AD will be permitted. The study has 90% power to detect a 41% or larger change on the ADAS-cog assuming a 3.8 point mean annual change in the placebo group, and has 80% power to detect a 35% change.