Pre-clinical Development of a Therapeutic for Alzheimer's Disease

描述(由申请人提供)： A2多肽被广泛认为与阿尔茨海默病(AD)的发病机制有关，大多数主要制药公司都在寻求降低A2的策略。Archer制药公司(Archer)和Roskamp研究所联合开发了降低A2的药物，这种药物间接抑制BACE，减少淀粉样蛋白积累，同时在转基因疾病模型中保留认知功能。铅系列是基于钙通道阻断药物尼伐地平，初步数据表明，该药物在延缓认知衰退和防止从轻度认知障碍向阿尔茨海默病的过渡方面有效。尼伐地平的潜在疗效已经在由Archer在欧洲完成的I/11a期试验中得到证实，并支持来自独立研究的临床数据。尽管如此，以及大量的临床前和安全性数据，人们担心增加尼伐地平的剂量以提高疗效将受到其降压作用的限制。因此，我们在临床前模型中检测了非降压(-)-尼伐地平对映体，并表明在转基因疾病模型中，它也降低了急性发作中的A2/淀粉样蛋白水平。在推动这种形式的尼伐地平作为先导化合物的过程中，有临床试验发展所需的关键数据。虽然已知消旋尼尔伐地平在人的大脑中集中，但将决定(-)-尼尔伐地平在人的大脑中的相对浓度的关键因素是：a)(-)-尼尔伐地平在人中的代谢比(+)-尼尔伐地平大[3倍]；b)啮齿类动物的(-)-尼尔伐地平与外消旋尼尔伐地平的AUC大脑/AUC血浆比率增加[3：1]；c)(-)-尼尔伐地平与(+)-尼尔伐地平的血管扩张作用要低得多[100倍]。这项第一阶段的提案将解决以下问题：Aim 1将把(-)-尼伐地平的血浆水平(PK)与脑PK以及对转基因AD小鼠模型A2水平(PD)的影响联系起来。在相同的模型中，它还将比较急性和慢性分娩对大脑PK和PD的影响。最后，将增加剂量的(-)-尼伐地平对脑PK/PD的影响与外消旋尼伐地平进行比较，并确定最高无毒剂量并收集基本毒理学数据。目的探讨(I)(-)-尼伐地平与外消旋尼伐地平在(I)(-)-尼伐地平最高无毒剂量和(Ii)最高无毒(-)-尼伐地平剂量下治疗6个月对AD转基因动物模型的影响。该第一阶段提案旨在作为第二阶段计划的前奏，该计划描述毒理学参数、合成和制剂战略(这两项都已由Archer开发到非GMP水平)，以期就(-)-尼伐地平提交IND申请，用于AD的临床试验。 公共卫生相关性： 阿尔茨海默病(AD)是痴呆症最常见的形式，全世界有超过2700万人受到影响，预计到2050年，这一比例将翻一番。在美国，老年痴呆的医疗保险和医疗补助费用每年超过1400亿美元，随着人口老龄化，公共卫生的负担预计将急剧增加。目前，还没有有效的治疗AD的疾病修饰疗法，我们希望开发一种新的尼伐地平衍生物，在疾病模型中展示令人鼓舞的临床前数据。

DESCRIPTION (provided by applicant): The A2 peptide is widely thought to be implicated in the pathogenesis of Alzheimer's Disease (AD) and A2-lowering strategies are being pursued by most major pharmaceutical companies. Archer Pharmaceuticals Inc. (Archer) and the Roskamp Institute have jointly developed A2-lowering drugs which indirectly inhibit BACE and reduce amyloid accumulation whilst preserving cognitive function in transgenic models of the disease. The lead series is based on a calcium channel blocking drug, nilvadipine, for which preliminary data suggests efficacy in delaying cognitive decline and in preventing the transition from mild cognitive impairment to AD. The potential efficacy of nilvadipine has been demonstrated in a Phase I/lla trial completed by Archer in Europe and supporting clinical data from independent studies. Despite this, and a wealth of preclinical and safety data, there are concerns that increasing doses of nilvadipine to improve efficacy will be limited by its anti-hypertensive effects. Therefore, we have examined the non anti-hypertensive (-)-nilvadipine enantiomer in preclinical models and have shown that it also lowers A2/amyloid levels in acute paradigms in transgenic models of the disease. In advancing this form of nilvadipine as a lead compound there are critical data required for the development of clinical trials. Although racemic nilvadipine is known to concentrate in the brain in man, key factors that will determine the relative brain concentrations of (-)-nilvadipine that can be achieved in man are: a) Greater [times three] metabolism of (-)-nilvadipine vs. (+)-nilvadipine in man; b) Increased AUCbrain/ AUCplasma ratios for (-)-nilvadipine vs. racemic nilvadipine [3:1] in rodents and; c) Much lower [100 fold reduced] vasodilatory effects of (-)-nilvadipine vs. (+)-nilvadipine. This phase I proposal will address the following issues: Aim 1 will correlate plasma levels (PK) of (-)- nilvadipine with brain PK and the impact on A2 levels (PD) in transgenic mouse models of AD. It will also compare the impact of acute vs. chronic delivery profiles on brain PK and PD in the same models. Finally, the impact of increasing doses of (-)-nilvadipine on brain PK/PD will be compared to racemic nilvadipine and the highest non-toxic dose determined and basic toxicology data gathered. Aim 2 will explore the impact of 6 months of treatment with (i) (-)-nilvadipine compared to racemic nilvadipine at the highest non-toxic dose of the latter, and (ii) the highest non-toxic (-)-nilvadipine dose, in a transgenic model of AD with pathological and behavioral outcomes. This phase I proposal is intended as a prelude to a phase II plan to delineate toxicology parameters, synthetic and formulation strategies (both of which are already developed to non-GMP levels by Archer) with a view to an IND filing on (-)-nilvadipine for clinical trials for use in AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD), the most common form of dementia, affects over 27 million people worldwide and this rate is expected to double by year 2050. In the United States, Medicare and Medicaid costs for AD amount to over $140 billion dollars per year and the burden on Public Health is anticipated to increase sharply as the population ages. Currently, there are no effective disease modifying therapeutics for AD and we wish to develop a novel derivative of nilvadipine which demonstrates encouraging preclinical data in models of the disease.