title: Therapeutic strategies for Alzheimer's disease in clinical trials.
abstract: Alzheimer's disease (AD) is considered to be the most common cause of dementia and is an incurable, progressive neurodegenerative disorder. Current treatment of the disease, essentially symptomatic, is based on three cholinesterase inhibitors and memantine, affecting the glutamatergic system. Since 2003, no new drugs have been approved for treatment of AD. This article presents current directions in the search for novel, potentially effective agents for the treatment of AD, as well as selected promising treatment strategies. These include agents acting upon the beta-amyloid, such as vaccines, antibodies and inhibitors or modulators of γ- and β-secretase; agents directed against the tau protein as well as compounds acting as antagonists of neurotransmitter systems (serotoninergic 5-HT6 and histaminergic H3). Ongoing clinical trials with Aβ antibodies (solanezumab, gantenerumab, crenezumab) seem to be promising, while vaccines against the tau protein (AADvac1 and ACI-35) are now in early-stage trials. Interesting results have also been achieved in trials involving small molecules such as inhibitors of β-secretase (MK-8931, E2609), a combination of 5-HT6 antagonist (idalopirdine) with donepezil, inhibition of advanced glycation end product receptors by azeliragon or modulation of the acetylcholine response of α-7 nicotinic acetylcholine receptors by encenicline. Development of new effective drugs acting upon the central nervous system is usually a difficult and time-consuming process, and in the case of AD to-date clinical trials have had a very high failure rate. Most phase II clinical trials ending with a positive outcome do not succeed in phase III, often due to serious adverse effects or lack of therapeutic efficacy.
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Godyń
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Jończyk
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Panek
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland. Electronic address: mfmalaws@cyf-kr.edu.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods*; D006801:Humans; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; Anti-amyloid β immunotherapy; Anti-tau immunotherapy; Clinical trials; β-Secretase inhibitors