Presently, there are no cures, nevertheless, accelerating insights into the biology of the disease and intensive research studies are promising new treatments. However, it may be many years before cures emerge.
Current FDA-approved drugs for Alzheimer’s disease do not prevent or reverse the disease, and provide only modest symptomatic benefits. The growing understanding of the patophysiology of Alzheimer’s disease has led to an increase in the development of agents. Disease-modifying therapies targeting the underlying mechanisms of Alzheimer’s disease are now in late stages of human clinical trials.
The primary targets include beta-amyloid, the aggregation of which contributes to the pathogenesis of Alzheimer’s disease and tau proteins, the hyperphosphorylation of which leads to the development of neurofibrillary tangles, central to the pathogenesis of Alzheimer’s disease.
Most of the biotech and pharmaceutical industry is focusing on the amyloid hypothesis (Selkoe DJ. and Hardy J.).
Therapeutic approaches aim at preventing Aβ formation, blocking its aggregation into plaques, lowering its soluble levels in the brain and disassembling existing amyloid plaques. Concerning neurofibrillary tangles, therapeutic approaches aim at reducing tau phosphorylation and/or aggregation.
Other aspects include mitochondrial dysfunction, failure of molecular transport mechanisms, oxidative damage, inflammation and cell cycle dysregulation.
The following table shows selected Alzheimer’s disease drug developments.
|
Drug |
Mechanism of Action |
Stage of development |
|
Tramiprosate |
Direct Aβ binding to prevent Aβ aggregation |
Completed phase III/ discontinued |
|
ACC-001 |
Active Aβ vaccination |
Phase II (safety, proof of concept) |
|
Bapineuzumab |
Anti-Aβ monoclonal antibodies |
Phase III (efficacy in AD) |
|
IgIV |
Anti-Aβ polyclonal antibodies |
Phase III (efficacy in AD) |
|
PF-04494700 |
RAGE inhibitor |
Phase II (safety, proof of concept) |
|
Tarenflurbil |
γ-secretase inhibitor |
Completed Phase III/discontinued |
|
Semagacestat |
γ-secretase inhibitor |
Phase III (efficacy in AD) |
|
Rember |
Tau aggregation inhibitor |
Entering Phase III (efficacy in AD) |
|
NAP (AL-108) |
Microtubule stabilizer |
Phase II (safety, cognitive enhancement) |
|
Dimebon |
Microtubule stabilizer |
Phase III(efficacy in AD) |
Currently, the greatest numbers of studies are focusing on anti-amyloid strategies. Other disease-modifying therapies that underly the pathogenic mechanisms of Alzheimer’s disease are currently in clinical trials.
The four Alzheimer’s drugs already on the market are the following, along with their dosage forms, chemical name, manufacturer and 2009 sales:
- Aricept: tablets; donepezil; Pfizer Inc.; $432 million (partner Esai Inc. got about $3.3 billion in revenue)
- Namenda: tablets or liquid; memantine; Forest Laboratories Inc.; $1.06 billion
- Exelon: patch, liquid or capsules; rivastigmine; Novartis AG; $954 million
- Razadyne: tablets, capsules or liquid; galantamine; Johnson & Johnson; $415 million
Source: Physicians’ Desk Reference, the companies
References
Gervais F: GAG mimetics: potential to modify underlying disease process in AD. Neurobiol Aging 2004, 25:S11-12.
Hardy J., Selkoy DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297: 353-356.
Rafii S. Michael and Aissen S. Paul. Recent Developments in Alzheimer’s disease therapeutics. Miniriview. BMC Medicine 2009, 7:7
