Alzheimer's drug‐development pipeline: 2016
Open accessAbstract
Background: Alzheimer's disease (AD) is growing in frequency and new therapies are urgently needed. Methods: We assessed clinicaltrials.gov (accessed 1‐4‐2016) to determine the number and characteristics of trials in phase I, phase II, and phase III for treatment of AD. Results: There are currently 24 agents in 36 trials in phase III of AD drug development. Seven of these 24 agents are symptomatic cognitive‐enhancing compounds, and 17 are disease‐modifying treatments (DMTs). Most DMTs address amyloid‐related targets (76%). There are 45 agents in phase II being assessed in 52 clinical trials. Phase II trials include 30 DMTs, with 26 small molecules and 4 immunotherapies. There are 24 agents in the first phase of AD drug development. Discussion: Amyloid is the principal target of late‐stage development programs. There are relatively few agents in clinical trials for AD suggesting a need to amplify the drug discovery ecosystem.
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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 [11]
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Experimental modelling of Alzheimer's disease for therapeutic screening
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Polyampholyte-Based Synthetic Chaperone Modulate Amyloid Aggregation and Lithium Delivery
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“Despite decades of research and clinical trials of potential therapies (1), no trials have been able to prove disease-modifying efficacy (2, 3, 4, 5, 6, 7).”
BackgroundParadigm shift required for translational research on the brain
Yoon, J. H., Lee, D., Lee, C., Cho, E., Lee, S., Cazenave‐Gassiot, A., Kim, K., Chae, S., Dennis, E. A., & Suh, P. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01218-x · Cited by 14 · see citing works
“For AD, 76% of agents in phase III trials in 2016 were disease-modifying therapies, including amyloid-and tau-targeted agents, whereas by 2022, only 29% of the agents in phase III trials were disease-modifying therapies 62,63 .”
Fungal Metabolites as Promising New Drug Leads for the Treatment of Alzheimer's Disease
Takahashi, J. A., Sande, D., Lima, G. D. S., Moura, M. A. F. E., & Lima, M. T. N. S. (2019) · Studies in natural products chemistry · doi:10.1016/b978-0-444-64185-4.00001-0 · Cited by 14 · see citing works
Quantitative Characterization of Metastability and Heterogeneity of Amyloid Aggregates
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“%) targeted amyloid, the current research and development landscape has pivoted towards therapies focused on inflammation and metabolism, now comprising 68% of the field [48, 49].”
BackgroundChemical-Driven Amyloid Clearance for Therapeutics and Diagnostics of Alzheimer’s Disease
Kim, H. Y., & Kim, Y. S. (2024) · Accounts of Chemical Research · doi:10.1021/acs.accounts.4c00458 · Cited by 12 · see citing works
Souchet, B., Audrain, M., Gu, Y., Lindberg, M. F., Orefice, N. S., Rey, E., Cartier, N., Janel, N., Meijer, L., & Braudeau, J. (2022) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2022.18 · Cited by 12 · see citing works
“Over the past decade, a shift in the inclusion of patients in clinical trials leads to the enrolment of patients at the prodromal and asymptomatic stages (25, 26).”
BackgroundKnodt, A. R., Burke, J. R., Welsh-Bohmer, K. A., Plassman, B. L., Burns, D. K., Brannan, S. K., Kukulka, M. J., Wu, J., & Hariri, A. R. (2019) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.05.004 · Cited by 11 · see citing works
“There is widespread recognition that Alzheimer’s disease (AD) is a looming global public health crisis, and new interventions are urgently needed [1,2].”
BackgroundPirolla, N. F. F., Batista, V. S., Viegas, F. P. D., Gontijo, V. S., McCarthy, C. R., Viegas, C., & Nascimento-Júnior, N. M. (2020) · Current Drug Targets · doi:10.2174/1389450121999200819144544 · Cited by 11 · see citing works
Who funds Alzheimer's disease drug development?
Cummings, J. L., Bauzon, J. S., & Lee, G. (2021) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12185 · Cited by 10 · see citing works
Self-citationImpact of non‐binding FDA guidances on primary endpoint selection in Alzheimer's disease trials
Yu, J. C., Hlávka, J. P., Joe, E., RICHMOND, F. J. R., & Lakdawalla, D. N. (2022) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12280 · Cited by 10 · see citing works
Wang, Z., Zhang, Y., Dong, L., Zheng, Z., Zhong, D., Long, X., Cai, Q., Jian, W., Zhang, S., Wu, W., et al. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201560 · Cited by 11 · see citing works
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“In fact, human clinical trials have been conducted to test some of the potential targets including antioxidants, PPAR-γ agonists, and phosphodiesterase [120,121].”
BackgroundEvaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer's Disease Predementia
Souchet, B., Audrain, M., Alves, S., Fol, R. R., Tada, S., Orefice, N. S., Potier, B., Dutar, P., Billard, J., Cartier, N., et al. (2022) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2021.67 · Cited by 9 · see citing works
“Thus, if 60% of the drugs were tested in 2016 in patients with mild to severe dementia, it decreased to 43% in 2020 (14, 15).”
BackgroundTranslational Scoring of Candidate Treatments for Alzheimer’s Disease: A Systematic Approach
Cummings, J. L. (2020) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000507569 · Cited by 9 · see citing works
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Pharmacology of Acetylcholine and Cholinergic Receptors
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“There were 13 anti-Aβ trials among the total 24 ongoing phase III clinical trials in 2016 [26], and 6 among 29 in 2020 [25].”
BackgroundTolomeu, H. V., & Fraga, C. A. M. (2021) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527320666210820092220 · Cited by 5 · see citing works
Alzheimer’s Disease Therapy: Present and Future Molecules
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“[2] Each year thousands of articles are indexed in PubMed when searching for keyword combination Alzheimer’s disease and treatment (Figure 1).”
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“In the absence of a cure for the disease or treatment, reducing the risk of dementia is doubly important (Cummings et al., 2016).”
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RetractedDegenerative or Debilitative Neurologic Syndromes
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Selective HLA Class II Allele-Restricted Activation of Atabecestat Metabolite-Specific Human T-Cells
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Cognitive Training and Rehabilitation in Aging and Dementia
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Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem
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Therapeutic Potential of PPARs in Alzheimer’s Disease
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Beyond the streetlight: a TREAT‐AD perspective on where to find new Alzheimer's targets
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Die Entwicklung von Anti-Alzheimer-Medikamenten in der Sackgasse
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Therapie der Alzheimer-Demenz — was kommt?
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“auf etwa 5,7 Milliarden US-Dollar geschätzt [23].”
BackgroundInfluentialA New Era Has Begun in Neurology Thanks to Gene and Biotechnologies
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The Importance of Phase 2 in Drug Development for Alzheimer’s Disease
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Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem
Tzioras, M., Henstridge, C. M., & Spires‐Jones, T. L. (2018) · doi:10.26226/morressier.5b31ec592afeeb001345aa88
Transforming Alzheimer's Treatment: Unveiling New Potential with Drug Repurposing Strategies
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- Authors
- Cummings, J., Morstorf, T., & Lee, G.
- Affiliations
- Cleveland Clinic (US)
- Touro University Nevada (US)
- Corresponding author
- Cummings, Jeffrey
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2016-08-18
- Volume
- 2
- Issue
- 4
- Pages
- 222-232
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC5651348
- OpenAlex
- W2517281879
- Cited by
- 108
- References
- 25
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 3 · 2022: 17 · 2021: 5 · 2020: 13 · 2019: 15 · 2018: 19 · 2017: 20 · 2016: 1
- FWCI
- 14.76
- 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)
- Funders
- Avid Pharmaceuticals
- Teva Pharmaceuticals
- CogState
- 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, amyloid, immunotherapy, small molecules
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