Emerging Alzheimer's disease treatment paradigms: A late-stage clinical trial review

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2024-12-27 DOI:10.1002/trc2.70022

Jakub P. Hlávka, Andrew T. Kinoshita, Divya Jeyasingh, Cheng Huang, Leila Mirsafian, Mireille Jacobson

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引用次数: 0

Abstract

INTRODUCTION

Without disease-modifying interventions, Medicare and Medicaid spending on Alzheimer's disease (AD) management is expected to reach 637 billion USD annually by 2050. The recent advent of promising AD therapies after decades of a near-total failure rate in clinical trials suggests that more disease-modifying therapies are on the horizon. In this review, we assess the late-stage pipeline of disease-modifying candidates for AD and offer a novel classification of intervention candidates by treatment paradigms—groups of candidates that share an underlying biological mechanism of action and general disease target.

METHODS

We extracted data from the National Library of Medicine clinical trials database regarding Phase 2 and 3 trials of disease-modifying AD therapies. We categorized trials into eight unique treatment paradigms, which we defined by combinations of therapy (biologic, small molecule, cell and gene therapy, other) and target (amyloid, tau, other). We analyzed primary endpoints, eligibility criteria including clinical ratings of cognition, trial phase and length, and funding sources.

RESULTS

We identified 123 unique disease-modifying intervention candidates in 175 late-stage clinical trials. Biologic and small molecule drugs comprised 30% and 54% of trials, respectively. Eligibility criteria favored patients between the ages of 60 and 80 years with mild cognitive impairment. Including multi-phase trials, 81% of studies were engaged in Phase 2 and 27% in Phase 3. Notably, within the Biologic–Amyloid paradigm, 64% of trials were engaged in Phase 3.

DISCUSSION

Current studies of disease-modifying therapies for AD comprise a diverse set of approaches to treating the disease. However, effort is largely concentrated in a few treatment paradigms and a narrow patient population, causing varying rates of progress among treatment paradigms in the late-stage clinical trial pipeline. Strategies may be warranted to accelerate successes in the most promising therapeutical paradigms and nurture growth within nascent areas lacking resources but not potential.

Highlights

An analysis of Alzheimer's disease trial treatment paradigms was conducted.
From April 2021 to March 2023, 175 trials of 123 unique candidates were reviewed.
Biologic and small molecule drugs comprised 30% and 54% of trials, respectively.
Eligibility criteria favored ages 60 through 80 with mild cognitive impairment.

Abstract Image

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新出现的阿尔茨海默病治疗范例：一项晚期临床试验回顾。

导言：如果没有疾病改善干预措施，到2050年，医疗保险和医疗补助用于阿尔茨海默病（AD）管理的支出预计将达到每年6370亿美元。在数十年的临床试验几乎完全失败之后，最近出现了有希望的阿尔茨海默病治疗方法，这表明更多的疾病改善疗法即将出现。在这篇综述中，我们评估了阿尔茨海默病的晚期疾病修饰候选药物，并根据治疗模式提供了一种新的干预候选药物分类-具有潜在生物学作用机制和一般疾病靶点的候选药物组。方法：我们从美国国家医学图书馆临床试验数据库中提取有关疾病改善性AD治疗的2期和3期试验的数据。我们将试验分为八种独特的治疗模式，我们通过治疗（生物，小分子，细胞和基因治疗，其他）和靶标（淀粉样蛋白，tau蛋白，其他）的组合来定义。我们分析了主要终点、资格标准（包括临床认知评分、试验阶段和长度）和资金来源。结果：我们在175项晚期临床试验中确定了123项独特的疾病改善干预候选措施。生物和小分子药物分别占试验的30%和54%。入选标准为60 - 80岁轻度认知障碍患者。包括多期试验在内，81%的研究处于第二阶段，27%的研究处于第三阶段。值得注意的是，在生物淀粉样蛋白范式中，64%的试验处于3期。讨论：目前对阿尔茨海默病的疾病修饰疗法的研究包括多种治疗该疾病的方法。然而，努力主要集中在少数治疗模式和狭窄的患者群体上，导致在后期临床试验管道中治疗模式的进展速度不一。有必要制定战略，以加速最有希望的治疗范例的成功，并在缺乏资源但没有潜力的新兴领域培育增长。重点：对阿尔茨海默病的试验治疗模式进行了分析。从2021年4月到2023年3月，共审查了175项试验，123项独特的候选药物。生物和小分子药物分别占试验的30%和54%。年龄在60到80岁之间，有轻度认知障碍。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.