Literature DB >> 28460541

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

Dev Mehta1, Robert Jackson1, Gaurav Paul1, Jiong Shi1, Marwan Sabbagh1.   

Abstract

INTRODUCTION: There are dozens of drugs in development for AD with billions of dollars invested. Despite the massive investment in AD drugs and a burgeoning pipeline, there have been more setbacks and failures than treatment successes. Areas covered: The classes of drugs that have failed to date include the monoclonal antibodies, the gamma secretase inhibitors, dimebon, neurochemical enhancers, and one tau drug. Data for these compounds were sought through a PubMed search and a clinicaltrials.gov search. Expert opinion: The obvious question to be posed is: Why are they failing? Is the treatment of symptomatic dementia too late? Are the therapeutic targets incorrect? Are the clinical methodologies imprecise, misleading, or inaccurate? This review summarizes the drugs that have failed during 2010-2015 and offers possible theories as to why they have failed.

Entities:  

Keywords:  Alzheimer’s; Amyloid; clinical trials; dimebon; monoclonal antibodies; secretase inhibitors

Mesh:

Substances:

Year:  2017        PMID: 28460541      PMCID: PMC5576861          DOI: 10.1080/13543784.2017.1323868

Source DB:  PubMed          Journal:  Expert Opin Investig Drugs        ISSN: 1354-3784            Impact factor:   6.206


  19 in total

Review 1.  Alzheimer's disease drug development in 2008 and beyond: problems and opportunities.

Authors:  Robert E Becker; Nigel H Greig
Journal:  Curr Alzheimer Res       Date:  2008-08       Impact factor: 3.498

2.  A phase 3 trial of semagacestat for treatment of Alzheimer's disease.

Authors:  Rachelle S Doody; Rema Raman; Martin Farlow; Takeshi Iwatsubo; Bruno Vellas; Steven Joffe; Karl Kieburtz; Feng He; Xiaoying Sun; Ronald G Thomas; Paul S Aisen; Eric Siemers; Gopalan Sethuraman; Richard Mohs
Journal:  N Engl J Med       Date:  2013-07-25       Impact factor: 91.245

3.  Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.

Authors:  Serge Gauthier; Howard H Feldman; Lon S Schneider; Gordon K Wilcock; Giovanni B Frisoni; Jiri H Hardlund; Hans J Moebius; Peter Bentham; Karin A Kook; Damon J Wischik; Bjoern O Schelter; Charles S Davis; Roger T Staff; Luc Bracoud; Kohkan Shamsi; John M D Storey; Charles R Harrington; Claude M Wischik
Journal:  Lancet       Date:  2016-11-16       Impact factor: 79.321

4.  Alzheimer's research. Stopping Alzheimer's before it starts.

Authors:  Greg Miller
Journal:  Science       Date:  2012-08-17       Impact factor: 47.728

5.  Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.

Authors:  Rachelle S Doody; Ronald G Thomas; Martin Farlow; Takeshi Iwatsubo; Bruno Vellas; Steven Joffe; Karl Kieburtz; Rema Raman; Xiaoying Sun; Paul S Aisen; Eric Siemers; Hong Liu-Seifert; Richard Mohs
Journal:  N Engl J Med       Date:  2014-01-23       Impact factor: 91.245

6.  Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

Authors:  Vladimir Coric; Christopher H van Dyck; Stephen Salloway; Niels Andreasen; Mark Brody; Ralph W Richter; Hilkka Soininen; Stephen Thein; Thomas Shiovitz; Gary Pilcher; Susan Colby; Linda Rollin; Randy Dockens; Chahin Pachai; Erik Portelius; Ulf Andreasson; Kaj Blennow; Holly Soares; Charles Albright; Howard H Feldman; Robert M Berman
Journal:  Arch Neurol       Date:  2012-11

Review 7.  Why so few drugs for Alzheimer's disease? Are methods failing drugs?

Authors:  R E Becker; N H Greig
Journal:  Curr Alzheimer Res       Date:  2010-11       Impact factor: 3.498

Review 8.  Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.

Authors:  Peter T Nelson; Irina Alafuzoff; Eileen H Bigio; Constantin Bouras; Heiko Braak; Nigel J Cairns; Rudolph J Castellani; Barbara J Crain; Peter Davies; Kelly Del Tredici; Charles Duyckaerts; Matthew P Frosch; Vahram Haroutunian; Patrick R Hof; Christine M Hulette; Bradley T Hyman; Takeshi Iwatsubo; Kurt A Jellinger; Gregory A Jicha; Enikö Kövari; Walter A Kukull; James B Leverenz; Seth Love; Ian R Mackenzie; David M Mann; Eliezer Masliah; Ann C McKee; Thomas J Montine; John C Morris; Julie A Schneider; Joshua A Sonnen; Dietmar R Thal; John Q Trojanowski; Juan C Troncoso; Thomas Wisniewski; Randall L Woltjer; Thomas G Beach
Journal:  J Neuropathol Exp Neurol       Date:  2012-05       Impact factor: 3.685

Review 9.  Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices?

Authors:  Robert E Becker; Nigel H Greig; Ezio Giacobini
Journal:  J Alzheimers Dis       Date:  2008-10       Impact factor: 4.472

10.  A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. The Tacrine Collaborative Study Group.

Authors:  K L Davis; L J Thal; E R Gamzu; C S Davis; R F Woolson; S I Gracon; D A Drachman; L S Schneider; P J Whitehouse; T M Hoover
Journal:  N Engl J Med       Date:  1992-10-29       Impact factor: 91.245

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  187 in total

1.  Intense Focus Yet Many Setbacks for Alzheimer's Disease Drug Development.

Authors:  Troy Kish
Journal:  P T       Date:  2018-04

2.  Reciprocal Predictive Relationships between Amyloid and Tau Biomarkers in Alzheimer's Disease Progression: An Empirical Model.

Authors:  Saffire H Krance; Hugo Cogo-Moreira; Jennifer S Rabin; Sandra E Black; Walter Swardfager
Journal:  J Neurosci       Date:  2019-07-26       Impact factor: 6.167

Review 3.  The effects of insulin and insulin-like growth factor I on amyloid precursor protein phosphorylation in in vitro and in vivo models of Alzheimer's disease.

Authors:  Bhumsoo Kim; Sarah E Elzinga; Rosemary E Henn; Lisa M McGinley; Eva L Feldman
Journal:  Neurobiol Dis       Date:  2019-07-23       Impact factor: 5.996

Review 4.  The vexing complexity of the amyloidogenic pathway.

Authors:  Manuel A Castro; Arina Hadziselimovic; Charles R Sanders
Journal:  Protein Sci       Date:  2019-04-11       Impact factor: 6.725

5.  β-Amyloid Accumulation Slows Earlier than Expected in Preclinical Alzheimer's Disease Patients.

Authors:  Henrique Camara; Evandro A De-Souza
Journal:  J Neurosci       Date:  2018-10-24       Impact factor: 6.167

Review 6.  Alpha7 Nicotinic Receptors as Therapeutic Targets in Schizophrenia.

Authors:  Jason R Tregellas; Korey P Wylie
Journal:  Nicotine Tob Res       Date:  2019-02-18       Impact factor: 4.244

7.  High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer's disease.

Authors:  Fengxia Zhang; Yuanyuan Qin; Lingfeng Xie; Caixia Zheng; Xiaolin Huang; Min Zhang
Journal:  J Neural Transm (Vienna)       Date:  2019-07-10       Impact factor: 3.575

8.  α2-macroglobulin in Alzheimer's disease: new roles for an old chaperone.

Authors:  Sahba Seddighi; Vijay Varma; Madhav Thambisetty
Journal:  Biomark Med       Date:  2018-03-14       Impact factor: 2.851

Review 9.  Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases.

Authors:  Jinsha Liu; Joey Paolo Ting; Shams Al-Azzam; Yun Ding; Sepideh Afshar
Journal:  Int J Mol Sci       Date:  2021-03-10       Impact factor: 5.923

10.  Physiological Aβ Concentrations Produce a More Biomimetic Representation of the Alzheimer's Disease Phenotype in iPSC Derived Human Neurons.

Authors:  Bonnie J Berry; Alec S T Smith; Christopher J Long; Candace C Martin; James J Hickman
Journal:  ACS Chem Neurosci       Date:  2018-05-22       Impact factor: 4.418

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