Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015

Expert Opinion on Investigational Drugs

Volumn 26, Issue 6, 2017, Pages 735-739

  Mehta, Dev ^a   Jackson, Robert ^a   Paul, Gaurav ^a   Shi, Jiong ^a   Sabbagh, Marwan ^a  

^a BARROW NEUROLOGICAL INSTITUTE   (United States)

Author keywords

Alzheimer s; Amyloid; clinical trials; dimebon; monoclonal antibodies; secretase inhibitors

Indexed keywords

AVAGACESTAT; BAPINEUZUMAB; CRENEZUMAB; DIMEBON; ENCENICLINE; GANTENERUMAB; IDALOPIRDINE; SEMAGACESTAT; SOLANEZUMAB; TAU PROTEIN; NEW DRUG;

ALZHEIMER DISEASE; ARTICLE; DRUG TREATMENT FAILURE; DRUG WITHDRAWAL; HUMAN; METHODOLOGY; PALLIATIVE THERAPY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN TARGETING; THERAPY DELAY; CLINICAL TRIAL (TOPIC); DRUG DESIGN; TREATMENT FAILURE;

ALZHEIMER DISEASE; CLINICAL TRIALS AS TOPIC; DRUG DESIGN; DRUGS, INVESTIGATIONAL; HUMANS; TREATMENT FAILURE;

EID: 85019839165     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1080/13543784.2017.1323868     Document Type: Article

References (25)

1. Becker RE, Greig NH, Giacobini E., Why do so many drugs for Alzheimer’s disease fail in development? Time for new methods and new practices? J Alzheimer’s Dis. 2008;15:303–325.
2. Giacobini E, Becker RE, Mecocci P. One hundred years after the discovery of Alzheimer’s disease:a turning point for therapy? J Alzheimers Dis. 2007;12:37–52.
3. Becker RE, Greig NH. Alzheimer’s disease drug development in 2008 and beyond:problems and opportunities. Curr Alzheimer Res. 2008;5:346–357.
4. Becker RE. Lessons from Darwin:21st century designs for clinical trials. Curr Alzheimer Res. 2007;4:458–467.
5. Vandenberghe R, Rinne JO, Boada M, et al. Bapineuzamab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimer’s Res Ther. 2016;8(1):18.• Analysis of why bapineuzamab failed.
6. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014;370:322–333.
7. Doody R, Thomas R, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014 Jan 23;370:311–321.•• Primary report of solanezumab in two RCTs.
8. Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials:secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2016;12(2):110–120.•• Primary report of a clinical trial.
9. Miller G. Alzheimer's research:stopping Alzheimer’s before it starts. Science. 2012 Aug;337:790–792.
10. Available from: https://clinicaltrials.gov/ct2/show/NCT01343966?term=ABBY&rank=1
11. Available from: https://clinicaltrials.gov/ct2/show/NCT01397578?term=MABT5102A&rank=3
12. Bezprozvanny I. The rise and fall of dimebon. Drug News Perspect. 2010;23(8):518–523.
13. Scheltens P, Nikolcheva T, Lasser R, et al. Biomarker data fromSCarlet RoAD:a global phase 3 study of gantenerumab in patients with prodromal Alzheimer’s disease (Developing Topics Session:Clinical Trial Results [DT-01-02]). Alzheimers Dement. 2015;11(7):P331.• Primary report of gantenerumab RCT.
14. Lasser R, Ostrowitzki S, Scheltens P, et al. Efficacy and safety of gantenerumab in prodromal Alzheimer’s disease:results from SCarlet RoAD—a global, multicenter trial (Developing Topics Session:Clinical Trial Results [DT-01-03]). Alzheimers Dement. 2015;11(7):P331–P332.
15. Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69(11):1430–1440.• Primary report of avagecestat RCT.
16. Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–350.•• Primary report of gamma secretase inhibtor.
17. Mullane K, Williams M. Alzheimer’s therapeutics:continued clinical failures question the validity of the amyloid hypothesis—but what lies beyond? Biochem Pharmacol. 2013;85:289–305.
18. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status:a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362–381.
19. Cummings J, Cho W, Ward M, et al. A randomized, double-blind, placebo-controlled phase 2 study to evaluate the efficacy and safety of crenezumab in patients with mild to moderate Alzheimer’s disease. (abstract O4-11-06). Alzheimers Dement. 2014;10(4):275.
20. Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69(2):198–207.
21. Connor DJ, Sabbagh MN. Administration and scoring variance on the ADAS-Cog. J Alzheimers Dis. 2008;15:461–464.•• An important report on why RCTs might be failing from a methodology standpoint.
22. Davis KL, Thal LJ, Gamzu ER, et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease. The Tacrine Collaborative Study Group. N Engl J Med. 1992;29;327(18):1253–1259.
23. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984;141(11):1356–1364.
24. Connor DJ, Schafer K. Administration Manual for the Alzheimer’s Disease Assessment Scale. San Diego:Alzheimer’s Disease Cooperative Study; 1998.
25. Becker RE, Greig NH. Why so few drugs for Alzheimers disease? Are methods failing drugs? Curr Alzheimer Res. 2010; 7(7):642–651.•• An important analysis on why methods are imprecise for AD assessments.