Reasons for failed trials of disease-modifying treatments for alzheimer disease and their contribution in recent research

Yiannopoulou, Konstantina G.; Anastasiou, Aikaterini I.; Zachariou, Venetia; Pelidou, Sygkliti-Henrietta

doi:10.3390/biomedicines7040097

Cited by 330Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Reasons for failed trials of disease-modifying treatments for alzheimer disease and their contribution in recent research

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Yiannopoulou, Konstantina G., Anastasiou, Aikaterini I., Zachariou, Venetia, Pelidou, Sygkliti-Henrietta·2019·Biomedicines

DOI 10.3390/biomedicines7040097PMC PMC6966425

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Abstract

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

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New AD drug development has faced many obstacles, including high monetary and time costs and high failure rates in preclinical and clinical trials.
“New AD drug development has faced many obstacles, including high monetary and time costs and high failure rates in preclinical and clinical trials (Cummings et al., 2014;Yiannopoulou et al., 2019).”
From Drug repurposing for Alzheimer’s disease from 2012–2022—a 10-year literature review (2023) · cites this paper as Yiannopoulou et al., 2019
The Introduction reports more than 200 failed or abandoned AD investigational programs, and the Discussion describes a high failure rate for disease-modifying treatments. The reviewed failures are clinical trials; the Introduction says animal studies were included only for additional information. The body of our copy does not establish high failure rates in preclinical trials or directly document monetary costs, though it discusses reducing trial duration. (LLM, conf=0.83)
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Background
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Authors: Yiannopoulou, K. G., Anastasiou, A. I., Zachariou, V., & Pelidou, S.-H.
Affiliations: Henry Dunant Hospital (GR)
National and Kapodistrian University of Athens (GR)
Icahn School of Medicine at Mount Sinai (US)
Department of Neurology, University of Ioannina, University Hospital of Ioannina, 45500 Ioannina, Greece
Corresponding author: Yiannopoulou, Konstantina G.
ORCID: Yiannopoulou, Konstantina G.
Anastasiou, Aikaterini I.
Zachariou, Venetia
Pelidou, Sygkliti-Henrietta
Venue: Biomedicines
Publisher: MDPI AG
Published: 2019-12-09
Volume: 7
Issue: 4
Pages: 97
ISSN: 2227-9059 (ISSN-L)
DOI: 10.3390/biomedicines7040097
PMC: PMC6966425
OpenAlex: W2976060980
Cited by: 330
References: 21
Citations by year: 2026: 46 · 2025: 47 · 2024: 59 · 2023: 47 · 2022: 79 · 2021: 42 · 2020: 9 · 2019: 1
FWCI: 3.89
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Biomedicines (publishedVersion, cc-by)
Preprints.org (acceptedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords: Alzheimer's disease, disease-modifying therapy, clinical trial failure, drug development, prodromal Alzheimer's disease, preclinical Alzheimer's disease, biomarkers, amyloid, tau protein, neurofilament light chain, neurogranin, treatment goals, combination therapy, Bayesian analysis, clinical trial design, trial simulation

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Reasons for failed trials of disease-modifying treatments for alzheimer disease and their contribution in recent research

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