title: Why has therapy development for dementia failed in the last two decades?
abstract: The success rate of the pharmaceutical research and development (R&D) for dementia drugs has been abysmally low, in the last two decades. Also low has been the number of pipeline drugs in development, compared to other therapy areas. However, the rationale of early terminations has not been reported in the majority of trials. These are key findings of the recently published pharmaceutical pipeline analysis by the UK-based Office of Health Economics (OHE). Our understanding of main challenges include (1) the significant gaps of knowledge in the nosology and complexity of the underpinning biological mechanisms of the commonest, not familial, forms of late onset dementias; (2) low signal-to-noise ratio, notwithstanding the lack of validated biomarkers as entry and/or end-point criteria; (3) recruitment and retention, particularly in the asymptomatic and early disease stages. A number of current and future strategies aimed at ameliorating drug development are outlined and discussed.
authors.affiliation: Alzheimer's Disease Research Unit/Memory Clinic, McGill Centre for Studies in Aging, Montreal, Quebec, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Gauthier
authors.affiliation: Division of Cognitive Neuroscience, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Albert
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Fox
authors.affiliation: Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.affiliation: Center for Alzheimer Research and Aging Research Center (ARC), Karolinska Institutet, Department of Geriatric Medicine Clinical Trials Unit, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Miia
authors.initials: M
authors.lastname: Kivipelto
authors.affiliation: Office of Health Economics, London, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Mestre-Ferrandiz
authors.affiliation: Neuroepidemiology and Ageing Research, School of Public Health, Imperial College London, London, UK. Electronic address: l.middleton@imperial.ac.uk.
authors.forename: Lefkos T
authors.initials: LT
authors.lastname: Middleton
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D015415:Biomarkers / Q000032:analysis; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003704:Dementia / Q000188:drug therapy*; D055808:Drug Discovery; D006801:Humans; D008559:Memantine / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D008559:Memantine
keywords: Alzheimer's; Amyloid hypothesis; Attrition; Clinical trials; Dementia; Research & development