706
Views
37
CrossRef citations to date
0
Altmetric
Review

Analysis of recent failures of disease modifying therapies in Alzheimer’s disease suggesting a new methodology for future studies

, &
Pages 7-16 | Received 28 Feb 2016, Accepted 23 May 2016, Published online: 09 Jun 2016

References

  • Brookmeyer R, Johnson E, Ziegler-Graham K, et al. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 2007;3(3):186–191.
  • Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 2015;11(3):332+.
  • Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366(9503):2112–2117.
  • Du Y, Dodel R, Hampel H, et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology. 2001;57(5):801–805.
  • Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–177.
  • Morgan D, Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature. 2000;408:982–985.
  • Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46–54.
  • Gilman S, Koller M, Black RS, et al. Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–1562.
  • Dodel R, Hampel H, Depboylu C, et al. Human antibodies against amyloid β peptide: A potential treatment for Alzheimer’s disease. Ann Neurol. 2002;52:253–256.
  • Relkin NR, Szabo P, Adamiak B, et al. 18-month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009;30:1728–1736.
  • Dodel R, Rominger A, Bartenstein P, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2013;12:233–243.
  • Relkin N. Clinical trials of intravenous immunoglobulin for Alzheimer’s disease. J Clin Immunol. 2014;34(Supp 1):S74–79.
  • McLaurin J, Cecal R, Kierstead ME, et al. Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med. 2002;8:1263–1269.
  • Black Ronald S, Sperling RA, Safirestein B, et al. A single ascending dose study of Bapineuzumab in patients with Azheimer disease. Alzheimer Dis Assoc Disord. 2010;24(2):198–203.
  • Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–2070.
  • Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of Bapinezumab in Mild-to-Moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):322–333.
  • Dodart J, Bales KR, Gannon KS, et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer’s disease model. Nat Neurosci. 2002;5(5):452–456.
  • Siemers ER, Friedrich S, Dean RA, et al. Safety and changes in plasma and cerebrospinal fluid amyloid β after a single administration of an amyloid β monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol. 2010;33(2):87–73.
  • Farlow M, Arnold S, Dyck CH, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 2012;8:261–271.
  • Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of Solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):311–321.
  • Stahl SM, Muntner N. Stahl’s essential psychopharmacology, neuroscientific basis and practical applications. 4th ed. Cambridge: Cambridge University Press; 2013. p. 1973.
  • Gillman K, Starrett J, Parker M, et al. Discovery and evaluation of BMS-708163, a potent selective and orally bioavailable gama secretase inhibitor. ACD Med Chem Lett. 2010;1:120–124.
  • Dockens R, Wang J, Castaneda L, et al. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet. 2012;51:681–693.
  • Tong G, Wang J, Sverdlov O, et al. Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther. 2012;34(3):654–667.
  • Tong G, Castaneda L, Wang J, et al. Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men. Clin Drug Investig. 2012;32:761–769.
  • Coric V, Van Dyck CH, Salloway S, et al. Safety and tolerability of the gama-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer Disease. Arch Neurol. 2012;69(11):1430–1440.
  • Bachurin S, Bukatina E, Lermontova N, et al. Antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci. 2001;939:425–435.
  • Tariot P, Sabbagh M, Flitman S, et al. A safety, tolerability and pharmacokinetic study of dimebon in patients with Alzheimer’s disease already receiving donepezil. Alzheimers Dement. 2009;5(Suppl):P251.
  • Doody RS, Gavrolova SI, Thomas RG, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008;372:207–215.
  • Safety and Efficacy Study. Evaluating Dimebon in patients with mild to moderate Alzheimer’s disease on donepezil (CONCERT). ClinicalTrials.gov, Identifier: NCT00829374. 2008.
  • A safety and efficacy study of oral Dimebon in patients with mild-to-moderate Alzheimer’s disease (CONNECTION). ClinicalTrials.gov, Identifier: NCT00675623. 2008.
  • Cano-Cuenca N, Solis-Garcia del Pozo JE, Jordan J, et al. Evidence for the efficacy of latrepirdine (Dimebon) treatment for improvement of cognitive function: a meta-analysis. J Alzheimers Dis. 2014;38(1):155–164.
  • Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria”. Lancet Neurol. 2007;6(8):734–746.
  • Stahl SM, Muntner N. Stahl’s essential psychopharmacology, neuroscientific basis and practical applications. 4th ed. Cambridge: Cambridge University Press; 2013. P:10998 and then Figure 13-5 (Kindle version).
  • Hansson O, Zetterberg H, Buchhave P, et al. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5(3):228–234.
  • Morley JE, Farr SA. The role of amyloid-beta in the regulation of memory. Biochem Pharmacol. 2014;88:479–485.
  • Leinenga G, Gotz J. Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer’s disease mouse model. Sci Transl Med. 2015;7(278):1–11.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.