Clinical trials of new drugs for Alzheimer disease

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Abstract

Alzheimer disease (AD) accounts for 60–70% of dementia cases. Given the seriousness of the disease and continual increase in patient numbers, developing effective therapies to treat AD has become urgent. Presently, the drugs available for AD treatment, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate receptor, can only inhibit dementia symptoms for a limited period of time but cannot stop or reverse disease progression. On the basis of the amyloid hypothesis, many global drug companies have conducted many clinical trials on amyloid clearing therapy but without success. Thus, the amyloid hypothesis may not be completely feasible. The number of anti-amyloid trials decreased in 2019, which might be a turning point. An in-depth and comprehensive understanding of the contribution of amyloid beta and other factors of AD is crucial for developing novel pharmacotherapies.

In ongoing clinical trials, researchers have developed and are testing several possible interventions aimed at various targets, including anti-amyloid and anti-tau interventions, neurotransmitter modification, anti-neuroinflammation and neuroprotection interventions, and cognitive enhancement, and interventions to relieve behavioral psychological symptoms. In this article, we present the current state of clinical trials for AD at clinicaltrials.gov. We reviewed the underlying mechanisms of these trials, tried to understand the reason why prior clinical trials failed, and analyzed the future trend of AD clinical trials.

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NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

Clifford R. Jack, David Bennett, Kaj Blennow … (2018)

In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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The amyloid hypothesis of Alzheimer's disease at 25 years

Dennis Selkoe, John Hardy (2016)

Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.

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The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

Jeff Sevigny, Ping Chiao, Thierry Bussière … (2016)

Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

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Author and article information

Contributors

Chaur-Jong Hu: chaurjongh@tmu.edu.tw

Journal

Journal ID (nlm-ta): J Biomed Sci

Journal ID (iso-abbrev): J. Biomed. Sci

Title: Journal of Biomedical Science

Publisher: BioMed Central (London )

ISSN (Print): 1021-7770

ISSN (Electronic): 1423-0127

Publication date (Electronic): 6 January 2020

Publication date PMC-release: 6 January 2020

Publication date Collection: 2020

Volume: 27

Electronic Location Identifier: 18

Affiliations

[1 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, Dementia Center, Department of Neurology, Shuang Ho Hospital, , Taipei Medical University, ; New Taipei City, Taiwan

[2 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, The PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, , Taipei Medical University, National Health Research Institute, ; Taipei, Taiwan

[3 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, , Taipei Medical University, ; Taipei, Taiwan

[4 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, Neurology, School of Medicine, College of Medicine, , Taipei Medical University, ; Taipei, Taiwan

[5 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, Taipei Neuroscience Institute, , Taipei Medical University, ; Taipei, Taiwan

Article

Publisher ID: 609

DOI: 10.1186/s12929-019-0609-7

PMC ID: 6943903

PubMed ID: 31906949

SO-VID: e219a138-5ba8-41b5-9f8e-cc2055465020

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 4 October 2019

Date accepted : 19 December 2019

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ScienceOpen disciplines: Molecular medicine

Keywords: alzheimer disease,clinical trials of drugs,neuroinflammation,neuroprotection,anti-amyloid,anti-tau,cognitive enhancement

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ScienceOpen disciplines: Molecular medicine

Keywords: alzheimer disease, clinical trials of drugs, neuroinflammation, neuroprotection, anti-amyloid, anti-tau, cognitive enhancement

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Clinical trials of new drugs for Alzheimer disease

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Alternative approaches to Alzheimer's Disease

Most cited references 82

NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

The amyloid hypothesis of Alzheimer's disease at 25 years

The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

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