Emerging Drug Targets in Alzheimer's Disease

The lack of effective treatments for Alzheimer's disease (AD) and an aging population create an enormous opportunity for disease-modifying drugs. Competition to develop new drugs for AD is in fact fierce, and the efficacy bar for current AD therapies is low; market penetration will therefore hinge on safety profiles. In that regard, the use of pharmacogenomics may cause AD patients to be turned away from certain therapies- but may also lead to better dosing and reduce the possibility of side effects and adverse drug interactions. Regardless: the soaring disease prevalence, the anticipated increase in early diagnosis and treatment, and the price premium a novel agent could command ensure that an approved AD disease-modifying drug will become a blockbuster.

• The beta-amyloid peptide Aβ-42 (the main component of amyloid plaques in AD patients) is the AD target that has received the most attention from drug developers, and drugs targeting amyloid are the disease-modifying therapies furthest along in development. Which companies have promising, new drugs in development that target Aβ-42, and how do these companies' strategies and approaches differ?
• Researchers are also interested in targeting neurofibrillary tangles (NFTs) to slow cognitive decline in AD patients. However, designing drugs that target NFTs has become more feasible only relatively recently, as good animal models have finally been created. Which companies are now developing drugs that target NFTs?
• Genetic variations in drug-metabolizing enzymes can have a profound influence on the safety of a drug for any particular patient. Which allele in particular have researchers found affects the efficacy of current AD drugs?
• Diabetes is a risk factor for AD, and the high level of insulin resistance seen in AD brains has led some researchers to call AD “type three diabetes.” What hypotheses have researchers set forth to explain the effect of impaired glucose regulation in AD? Which Big Pharma company already has an FDA-approved drug for diabetes that may find a lucrative new market in treating AD patients?
• An immune-targeting vaccine against AD could become a blockbuster: as the first disease-modifying agent and the first biologic agent to launch in the AD market, such a drug could command a high price. Which companies are currently working on AD vaccines? How have newer versions of AD vaccines overcome serious side effects of earlier versions of active AD vaccines?

• Pathophysiology: neuronal death, amyloid plaques, the Aβ-42 peptide, tau protein, neurofibrillary tangles, amyloid-derived diffusible ligands
• Susceptibility factors: autosomal dominant gene mutations, allelic variation in apolipoprotein E, high cholesterol diets, diabetes
• Pharmacogenomics: the influence of metabolizing enzymes on drug safety and efficacy; the influences of genetic variation on drug efficacy
• Emerging drug targets: anti-Aβ-42 vaccine strategies, secretase inhibitors, γ-secretase modulators, anti-Aβ-42 fibrillization strategies, RAGE inhibitors, targeting beta amyloid, neurofibrillary tangles, GSK3-β inhibitors, cdk-5 modulators, targeting the tau protein, glucose metabolism, nerve growth factor, NMDA receptor, luteinizing hormone
• Outlook for emerging AD targets: emergence of the first disease-modifying drugs; the prospects of Avandia, Flurizan, and bapineuzumab vaccines; polytherapy; prospects for earlier diagnosis; the upcoming burden on third-party payers; the role of pharmacogenomics

• Abbott Laboratories
• AstraZeneca
• Ceregene
• CoMentis
• Cytos
• DeCode Genetics
• Durect
• Eisai
• Elan
• Eli Lilly
• ExonHit Therapeutics
• Forest Laboratories
• GE Healthcare
• Genentechv
• Genizon BioSciences
• GlaxoSmithKline
• Grupo Grunenthal
• Intellect Neurosciences
• Kronos Science Laboratories
• Lundbeck
• Martek Biosciences
• Medivation
• Merck
• Merz
• Mitsubishi
• Myriad Genetics
• Neurochem
• Neuropharma
• Novartis
• Perlegen Sciences
• Pfizer
• Prana Biotechnology
• Roche
• Sanofi -Aventis
• Siemens
• Takeda Pharmaceutical
• TorreyPines Therapeutics
• Toyoma Chemical
• Transition Therapeutics
• Translational Genomics
• Research Institute (Tgen)
• TransTech Pharma
• Voyager Pharmaceutical
• Wyeth

• β secretase
• γ secretase
• Amyloid-derived diffusible ligands (ADDLs)
• Amyloid fi brils
• Amyloid plaques
• Amyloid precursor protein (APP)
• Aβ-42
• beta amyloid aggregation
• cdk-5
• Cholesterol regulation
• Glucose regulation
• GSK3-β
• HMG-CoA reductase
• Immune system (via active and passive vaccines)
• Luteinizing hormone
• Metal ions
• Mitochondrial dysfunction
• Nerve growth factor
• Neurofi brillary tangles (NFTs)
• Neuron death
• Neurotransmitter dysfunction
• N-methyl-D-aspartate (NMDA) receptor
• p25
• Presenilin 1
• Presenilin 2
• Receptors for advanced glycation endproducts (RAGE)
• Tau protein