Alzheimer's disease drug development pipeline: 2017
Open accessAbstract
Introduction: There is an urgent need to develop new treatments for Alzheimer's disease (AD) and to understand the drug development process for new AD therapies. Methods: We assessed the agents in the AD pipeline as documented in clinicaltrials.gov for phase I, phase II, and phase III, accessed 1/5/2017. Results: There are 105 agents in the AD treatment development pipeline, of which 25 agents are in 29 trials in phase I, 52 agents are in 68 trials in phase II, and 28 agents are in 42 trials in phase III. Seventy percent of drugs in the AD pipeline are disease‐modifying therapies (DMTs). Fourteen percent are symptomatic cognitive enhancers, and 13% are symptomatic agents addressing neuropsychiatric and behavioral changes (2% have undisclosed mechanisms). Most trials are sponsored by the biopharmaceutical industry. Trials include patients with preclinical AD (cognitively normal with biomarker evidence of AD), prodromal AD (mild cognitive symptoms and biomarker evidence of AD), and AD dementia. Biomarkers are included in many drug development programs particularly those for DMTs. Thirteen of 46 phase II DMT trials have amyloid imaging as an entry criterion, and 10 of 28 phase III trials incorporate amyloid imaging for diagnosis and entry. A large number of participants are needed for AD clinical trials; in total, 54,073 participants are required for trials spanning preclinical AD to AD dementia. When compared with the 2016 pipeline, there are eight new agents in phase I, 16 in phase II, and five in phase III. Discussion: The AD drug development pipeline has 105 agents divided among phase I, phase II, and phase III. The trials include a wide range of clinical trial populations, many mechanisms of action, and require a substantial number of clinical trial participants. Biomarkers are increasingly used in patient identification and as outcome measures, particularly in trials of DMTs.
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Additional pathogenic mechanisms possibly overlapping with Aβ plaques and NFT formation include inflammation, oxidative damage, iron deregulation, cholesterol metabolism, blood-brain barrier dysfunction, or α-synuclein toxicity.
“A number of additional pathogenic mechanisms have been described, possibly overlapping with Aβ plaques and NFT formation or induced by them, including inflammation, oxidative damage, iron deregulation, and cholesterol metabolism blood-brain barrier (BBB) dysfunction or α-synuclein toxicity.9-13”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [12]
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“small molecule agents administered orally [7, 8].”
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Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment
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“Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for 50–70% of the cases of dementia [1].”
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“AD is particularly difficult to treat, which is exemplified by a high number of approaches, studies and trials which unfortunately failed to develop an effective therapy (Cummings et al., 2017).”
The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update
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“Clinical trials of disease-modifying therapies (DMTs) have been the top priority in AD research in an attempt to find a definite treatment: 70% of drugs in the pipeline are DMTs aiming at halting or reversing AD’s progression, while only 14% are symptomatic cognitive enhancers [5].”
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“85), we created High and Low self-reported MedDiet adherence groups based on the median split [dummy-coded high (1) and low (0)].”
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“Several protein kinase inhibitors are in Phase II trials for AD in 2017 (Cummings et al., 2017).”
BackgroundThe costs of developing treatments for Alzheimer's disease: A retrospective exploration
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“All drug development programs aimed at developing disease-modifying treatments for AD or any other neurodegenerative disorder have failed [206].”
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Present Algorithms and Future Treatments for Alzheimer’s Disease
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“, tyrosine kinase inhibitor, receptor for advanced glycation end-products inhibitor) are being investigated [103, 107].”
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“The failure of trials directed against symptomatic AD over the last few years has led to an increased interest among researchers and drug developers to study preclinical AD.(1,2) The hope is that early interventions, initiated before widespread neuronal damage, may be more likely to modify the disease course.”
BackgroundInfluentialBacterial DNA promotes Tau aggregation
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“Intervention strategies based on the amyloid cascade hypothesis had, up to date, limited success despite their being the primary target of clinical assays 2 .”
Repurposed agents in the Alzheimer’s disease drug development pipeline
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The Global Economic Impact of Neurodegenerative Diseases: Opportunities and Challenges
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“disease-modifying treatments for Alzheimer’s disease and other major neurodegenerative diseases [15].”
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“These definitions are widely used nowadays in clinical trials of disease-modifying drugs (Cummings et al., 2017).”
BackgroundThe Role of Genetics in Advancing Precision Medicine for Alzheimer’s Disease—A Narrative Review
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“Ongoing drug trials include targeting anti-amyloid, anti-tau, anti-inflammatory, neuroprotection, stem cell therapy, and metabolism (136).”
BackgroundAmyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges
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“However, the clinical trials of drugs targeting Aβ are challenging with a 99% failure rate [13-15].”
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“Nevertheless, amyloid PET is already incorporated in anti-amyloid trials (> 15) as a screening instrument to identify individuals with Alzheimer’s pathology, either cognitively normal (CN) or with MCI, and result disclosure is a necessity of design [24, 25].”
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“(3) Wider applicationof our newmethod inother neurodegenerativediseases and beyond neuropsychological test scores, including data-driven subtypingof diseases.”
BackgroundTau and atrophy: domain-specific relationships with cognition
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Recent Progress in the Pharmacotherapy of Alzheimer’s Disease
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“Ad is characterized by neurofibrillary tangles, synaptic dysfunction and neurodegeneration; its incidence is increasing rapidly with the aging of the population as an increasing number of individuals approach the key risk period for this age-related disease (26,27).”
Advances on Therapeutic Strategies for Alzheimer’s Disease: From Medicinal Plant to Nanotechnology
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“Clinical trials are being conducted using a variety of anti-Aβ monoclonal antibodies and other medicines, including nutraceuticals [12,13].”
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“However, despite gene discoveries from ever-larger sequencing studies, most clinical trials (Cummings et al., 2017) remain focused on the beta-amyloid pathway identified in familial Alzheimer’s disease (AD) in the early 1990’s (Goate et al.”
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“According to a study of the drug development pipeline for AD in 2017, current efforts focus mainly on disease-modifying therapies (DMTs) (3), and most of DMT agents in phase III AD trials (as reported on https://clinicaltrials.”
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- Authors
- Cummings, J., Lee, G., Mortsdorf, T., Ritter, A., & Zhong, K.
- Affiliations
- Cleveland Clinic (US)
- Cleveland Clinic Lou Ruvo Center for Brain Health Las Vegas NV USA
- Touro University Nevada Henderson NV USA
- Corresponding author
- Cummings, Jeffrey
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2017-05-24
- Volume
- 3
- Issue
- 3
- Pages
- 367-384
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC5651419
- OpenAlex
- W2617072792
- Cited by
- 549
- References
- 47
- Citations by year
- 2026: 14 · 2025: 53 · 2024: 48 · 2023: 52 · 2022: 67 · 2021: 59 · 2020: 53 · 2019: 91 · 2018: 103 · 2017: 7 · 2016: 1 · 2015: 1
- FWCI
- 52.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Scholarship - UNLV (University of Nevada Reno) (submittedVersion, cc-by-nc)
- Funders
- National Institute on Aging (R01AG084250 R56AG074001 U01AG073323 R01AG066707 R01AG076448 R01AG082118 RF1AG082211 R21AG083003 R35AG71476)
- National Institute of General Medical Sciences (NIA R25AG083721, NIA R35AG71476, P20GM109025)
- National Institute of Neurological Disorders and Stroke (RF1NS133812)
- 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, drug development pipeline, clinical trials, disease-modifying therapy, prodromal Alzheimer's disease, preclinical Alzheimer's disease, amyloid imaging, biomarkers, clinical trial participants
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