Janssen Alzheimer Immunotherapy, Dublin, Ireland.
Curr Alzheimer Res. 2011 Nov;8(7):798-807. doi: 10.2174/156720511797633250.
While much uncertainty exists in the estimates of the global burden of Alzheimer's disease and about the potential impact of various interventions, there is a widespread acceptance of the fact that the steady increase in the incidence and prevalence of the condition worldwide is becoming a massive public health problem as well as a huge economic burden for all healthcare systems and societies. These heavy demands are further compounded by the poor quality of life of the affected individuals, of their families and of their caregivers. The epidemic proportion of Alzheimer's disease has triggered relentless attempts for development of treatment approaches during the past two decades by a multitude of pharmaceuticals and biotech companies. Commercial development of the acetylcholinesterase inhibitors has, until recently, virtually dominated the field and, although efficacy has been demonstrated for five different products, the longterm clinical results suggested that alternate approaches were warranted. Disease modifying strategies targeting the β- amyloid plaques (e.g., decreasing β-amyloid formation through β- and γ-secretase inhibition, diminishing β-amyloid aggregation through anti-aggregants or enhancement of β-amyloid clearance through active/passive immunization), targeting the neurofibrillary tangles through inhibition of tau protein hyperphosphorilation or, more recently, by increasing mitochondrial permeability, all these potential treatment modalities are facing major methodological challenges during the conduct of a myriad of clinical trials meant to bring the novel therapies to the market. Failure of more than 400 products tested in more than 800 clinical trials to date, with many of these failures occurring in late stage development (phase III) have triggered a paradigm shift toward targeting of the early stages of cognitive deficiencies (mild cognitive impairment- MCI) and a refinement of the investigative methodologies. The great heterogeneity of the disease entity itself (MCI) coupled with inadequate sensitivity, specificity and positive/negative predictive values of the many common diagnostic outcome scales, outcome measures, and of many of the currently used biomarkers expose the drug development professionals to the risk of methodological flaws rendering the products explored ineffective, while very expensive.
虽然阿尔茨海默病的全球负担的估计存在很大的不确定性，并且对于各种干预措施的潜在影响也存在很大的不确定性，但人们普遍认为，这种疾病在全球范围内的发病率和患病率的稳步上升正在成为一个巨大的公共卫生问题，也是所有医疗保健系统和社会的巨大经济负担。这种巨大的需求进一步加剧了受影响个体、他们的家庭和照顾者的生活质量较差的问题。阿尔茨海默病的流行程度引发了过去二十年来众多制药和生物技术公司不断尝试开发治疗方法。乙酰胆碱酯酶抑制剂的商业开发直到最近才几乎主导了这一领域，尽管已经证明了五种不同产品的疗效，但长期的临床结果表明需要采取替代方法。针对β-淀粉样斑块的疾病修饰策略（例如，通过β-和γ-分泌酶抑制减少β-淀粉样蛋白的形成，通过抗聚集剂减少β-淀粉样蛋白的聚集，或通过主动/被动免疫增强β-淀粉样蛋白的清除），通过抑制tau 蛋白过度磷酸化靶向神经原纤维缠结，或者最近通过增加线粒体通透性，所有这些潜在的治疗方法在进行无数旨在将新疗法推向市场的临床试验时都面临着重大的方法学挑战。迄今为止，已有 400 多种产品在 800 多项临床试验中失败，其中许多失败发生在后期开发（III 期）阶段，这引发了向针对认知缺陷早期阶段（轻度认知障碍-MCI）的治疗方法转变，并改进了研究方法。该疾病实体本身（MCI）的巨大异质性，加上许多常见诊断结果量表、结果测量和目前使用的许多生物标志物的敏感性、特异性和阳性/阴性预测值不足，使药物开发专业人员面临方法学缺陷的风险，使所研究的产品无效，而费用却非常昂贵。
