Emerging Drug Targets in Alzheimer’s Disease

Published by: Decision Resources

Published: Dec. 12, 2007 - 31 Pages

Table of Contents

Executive Summary

Strategic Considerations

Stakeholder Implications

Introduction

The Pathophysiology of Alzheimer’s Disease

Susceptibility Factors in AD

Apolipoprotein E

The ApoE å4 Allele and Other AD Risk Factors

The Pharmacogenomics of AD

The Influence of Metabolizing Enzymes on Drug Safety and Effi cacy in Alzheimer’s Disease

The Influence of Genetic Variation on Drug Effi cacy in Alzheimer’s Disease

Emerging Drug Targets in AD

Amyloid Plaques

Anti-Aâ-42 Vaccine Strategies

Secretase Inhibitors

ã-Secretase Modulators

Anti-Aâ-42 Fibrillization Strategies

RAGE Inhibitors

Targeting Beta Amyloid

Neurofi brillary Tangles

GSK3-â Inhibitors

Cdk-5 Modulators

Targeting the Tau Protein

Glucose Metabolism

Other Targets

NMDA Receptor

Luteinizing Hormone

Nerve Growth Factor

Outlook for Emerging AD Targets

Bibliography

Tables

1. Genes Associated with Familial Alzheimer’s Disease

2. Select Susceptibility Genes in Late Onset Alzheimer’s Disease

3. Select Collaborations in Alzheimer’s Disease Pharmacogenomic Projects

4. Select Mutations in the CYP2D6 Gene

5. Select Drugs in Development Target Beta-amyloid Plaques

6. Advantages and Disadvantages of Active and Passive Vaccination

7. Select GSK3-â Inhibitors in Development Targeting Neurofi brillary Tangles

8. Select Drugs in Development Against Other AD Targets

Figures

1. Amyloid Plaques and Neurofi brillary Tangles in Alzheimer’s Disease

2. Normal and Pathogenic Cleavage of Amyloid Precursor Protein

3. Susceptibility Factors in Alzheimer’s Disease

4. Sites of Action of Select Alzheimer’s Disease Drugs

Abstract

• The beta-amyloid peptide Aâ-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 Aâ-42, and how do these companies’ strategies and approaches differ?
• Researchers are also interested in targeting neurofi brillary tangles (NFTs) to slow cognitive decline in AD pa- • tients. However, designing drugs that target NFTs has become more feasible only relatively recently, as good animal models have fi nally been created. Which companies are now developing drugs that target NFTs?
• Genetic variations in drug-metabolizing enzymes can have a profound infl uence on the safety of a drug for • any particular patient. Which allele in particular have researchers found affects the effi cacy 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 fi nd a lucrative new market in treating AD patients?
• An immune-targeting vaccine against AD could become a blockbuster: as the fi rst disease-modifying agent • and the fi rst 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 Aâ-42 peptide, tau protein, neurofi brillary tangles, amyloid-derived diffusible ligands
• Susceptibility factors: • autosomal dominant gene mutations, allelic variation in apolipoprotein E, high cholesterol diets, diabetes
• Pharmacogenomics: • the infl uence of metabolizing enzymes on drug safety and effi cacy; the infl uences of genetic variation on drug effi cacy
• Emerging drug targets: • anti-Aâ-42 vaccine strategies, secretase inhibitors, ã-secretase modulators, anti-Aâ-42 fi brillization strategies, RAGE inhibitors, targeting beta amyloid, neurofi brillary tangles, GSK3-â 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 fi rst 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

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