What lessons can be learned from failed Alzheimer's disease trials?

Expert Review of Clinical Pharmacology

Volumn 8, Issue 3, 2015, Pages 267-269

  Toyn, Jeremy ^a  

^a Pharmaceutical and Biotechnology Consultant   (United States)

Author keywords

aducanumab; Alzheimer; amyloid; avagacestat; bapineuzumab; clinical; secretase; semagacestat; solanezumab; trial

Indexed keywords

5,6 DIHYDRO 2 IMINO 3 METHYL 6 [4 [5 (1 PROPYNYL) 3 PYRIDINYL] 2 THIENYL] 4 PYRIMIDINONE; ADUCANUMAB; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN ANTIBODY; AVAGACESTAT; BAPINEUZUMAB; BETA SECRETASE INHIBITOR; BIOLOGICAL MARKER; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; GANTENERUMAB; HOMOTAURINE; NOOTROPIC AGENT; SEMAGACESTAT; SOLANEZUMAB; TARENFLURBIL;

ALZHEIMER DISEASE; AMYLOID PLAQUE; COGNITIVE DEFECT; DISEASE ASSESSMENT; DRUG EFFICACY; DRUG MECHANISM; DRUG TREATMENT FAILURE; HUMAN; MINI MENTAL STATE EXAMINATION; NONHUMAN; PROTEIN CEREBROSPINAL FLUID LEVEL; REVIEW; BIOASSAY; CLINICAL TRIAL (TOPIC); DOSE RESPONSE; DRUG DESIGN; METABOLISM; PATHOPHYSIOLOGY; PROCEDURES;

ALZHEIMER DISEASE; BIOMARKERS; CLINICAL TRIALS AS TOPIC; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; ENDPOINT DETERMINATION; HUMANS;

EID: 84928624041     PISSN: 17512433     EISSN: 17512441     Source Type: Journal    
DOI: 10.1586/17512433.2015.1034690     Document Type: Review

References (20)

1. Toyn JH, Ahlijanian MK. Interpreting Alzheimer's disease clinical trials in light of the effects on amyloid-b. Alheimer's Res Ther 2014;6(2):14
2. Albright CF, Dockens RC, Meredith JE, et al. Pharmacodynamics of selective inhibition of g-secretase by avagacestat. J Pharmacol Exp Ther 2013;344:686-95
3. May PC, Dean RA, Lowe SL, et al. Robust central reduction of amyloid-b in humans with an orally available non-peptidic, b-secretase inhibitor. J Neurosci 2011;31: 16507-16
4. Bateman RJ, Siemers ER, Mawuenyega KG, et al. A g-secretase inhibitor decreases amyloid-b production in the central nervous system. Ann Neurol 2009;66:48-54
5. Doody RS, Raman R, Farlow M, et al. A phase III trial of semagacestat for treatment of Alzheimer's disease. New Engl J Med 2013;369:341-50
6. Green RC, Schneider LS, Amato DA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA 2009;302:2557-64
7. Yan R, Vassar R. Targeting the b secretase BACE1 for Alzheimer's disease therapy. Lancet 2014;13:319-29
8. Svedru-zic-Z , Popovic-K, S engula-Jengic-V. Modulators of g-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer's disease. PLoS One 2013;8:e50759
9. De Strooper B. Lessons from a failed g-secretase Alzheimer trial. Cell 2014;159: 721-6
10. Mitani Y, Yarimizu J, Saita K, et al. Differential effects between g-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci 2012;32:2037-50
11. Yu Y, Logovinsky V, Schuck E, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel g-secretase modulator, E2212, in healthy human subjects. J Clin Pharmacol 2014;54:528-36
12. Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Ab as a modifying therapy for Alzheimer's disease: A phase IIa, double-blind, randomized, placebo-controlled trial. Lancet Neurol 2008;7(9):779-86
13. Imagine trial of PBT2. Available from: www.anzctr.org.au/Trial/Registration/ TrialReview.aspx?id=343427
14. Salloway S, Sperling R, Keren R, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 2011;77: 1253-62
15. Aisen PS, Saumier D, Briand R, et al. A Phase II study targeting amyloid-b with 3APS in mild-to-moderate Alzheimer disease. Neurology 2006;67:1757-63
16. Saumier D, Duong A, Haine D, et al. Domain-specific cognitive effects of tramiprosate in patients with mild to moderate Alzheimer's disease: ADAS-cog subscale results from the Alphase study. J Nutrition Health Aging 2009;13:808-12
17. Aisen PS, Gauthier S, Ferris SH, et al. Tramiprosate in mild-to-moderate Alzheimer's disease-A randomized, double-blind, placebo-controlled, multi-center study (the Alphase study). Arch Med Sci 2011;7:102-11
18. Salloway S, Sperling R, Fox NC, et al. Two phase III trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014;370:322-33
19. 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;370:311-21
20. Vellas B, Carrillo MC, Sampaio C, et al. Designing drug trials for Alzheimer's disease: what have we learned from the release of phase III antibody trials: A report from the EU/US/CTAD task force. Alzheimers Dement 2013;9:438-44