Drug repositioning and repurposing for Alzheimer disease

Abstract

Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.

Key points

  • Drug repositioning and repurposing offers a valuable alternative route for the identification of effective disease-modifying treatments for Alzheimer disease (AD).

  • The Delphi method can be used to bring together the opinion of multiple experts to suggest candidates for repurposing.

  • An expert Delphi consensus published in 2012 prioritized five compounds for repurposing as treatments for AD, of which glucagon-like peptide analogues remain high priority candidates.

  • A Delphi consensus involving the authors of this Review was conducted in 2018–2019 and identified the ROCK inhibitor fasudil, the cholinesterase inhibitor phenserine and antiviral treatments such as valaciclovir as high priority candidates for trials in individuals with AD.

  • The prioritization of these compounds was supported by strong packages of preclinical data, most of which include evidence from a number of different preclinical models.

  • Transcriptional screening approaches offer a novel means of identifying potential treatment candidates by targeting AD-associated transcriptional profiles.

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Acknowledgements

The authors thank J. Pickett from the Alzheimer’s Society (UK), C. Routledge from Alzheimer Research UK and H. Fillit from the Alzheimer’s Drug Discovery Foundation for their invaluable contributions to the 2018–2019 Delphi consensus. We also thank the Wellcome Trust for supporting much of the work pertaining to transcript signatures presented in the current paper. J.C. is supported by KMA, NIGMS grant P20GM109025, NINDS grant U01NS093334, and NIA grant R01AG053798.

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Searches were performed in EMBASE, PsycINFO, MEDLINE and Cochrane databases for papers published after 1960. Search terms were as follows: generic class OR specific drug names OR any known alternative name (obtained from the electronic Medicines Compendium and the British National Formulary) AND dement* OR Alzheim* OR mild cognitive impairmen* OR neuropsych* test* OR cognitive func*.

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Correspondence to Clive Ballard.

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C.B. reports grants and personal fees from Acadia Pharmaceutical Company and H. Lundbeck, as well as personal fees from AARP, Biogen, Eli Lilly, Novo Nordisk, Otsuka, Roche and Synexus, outside the submitted work. D.A. has received research support and/or honoraria from Astra-Zeneca, GE Health, H. Lundbeck and Novartis Pharmaceuticals, and served as a paid consultant for Biogen, Eisai, H. Lundbeck, Heptares and Mentis Cura. J.C. reports grants from National Institute of General Medical Sciences Centers of Biomedical Research Excellence (grant no. P20GM109025), during the conduct of the study; personal fees from Acadia, Actinogen, AgeneBio, Alkahest, Alzheimer Drug Discovery Foundation, Alzheon, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cognoptix, Cortexyme, EIP Pharma, Eisai, Foresight, Green Valley, Grifols, Hisun, Karuna, Nutricia, Otsuka, reMYND, Resverlogix, Roche, Samumed, Samus Therapeutics, Third Rock, Signant Health, Sunovion, Suven, and United Neuroscience pharmaceutical and assessment companies; other from ADAMAS, BioAsis, MedAvante, QR Pharma, United Neuroscience, other from Keep Memory Alive; outside the submitted work. J.C. has copyright for the Neuropsychiatric Inventory with royalties paid. J.O’B. reports personal fees from Axon, Eisai, GE Healthcare, Roche and TauRx; grants and personal fees from Avid Technology and Eli Lilly; grants from Alliance Medical and Merck, outside the submitted work. J.L.M. reports personal fees from Alector, Alergan, Eisai, Genentech, Oryzon, Green Valley, H. Lundbeck, Janssen, Eli Lilly, MSD, Novartis and Raman Health; personal fees and other from Biogen, outside the submitted work. All other authors declare no competing interests.

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Ballard, C., Aarsland, D., Cummings, J. et al. Drug repositioning and repurposing for Alzheimer disease. Nat Rev Neurol (2020). https://doi.org/10.1038/s41582-020-0397-4

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