アンメットメディカルニーズの疾病における新しい薬剤標的

Abstract

Emerging Targets in Diseases with High Unmet Need: Alzheimer's Disease, Lung Cancer, Dyslipidemia, Type 2 Diabetes, and COPD is a survey of emerging targets in these important diseases. The report assesses the issues in target-based drug discovery and development as well as several specific issues that are common to these and other complex diseases with high unmet medical need.

Comprehensive analysis includes the following:

• Background discussion of the nature of each disease.
• Mechanistic characterization of each disease, and major issues in diagnosis, stratification, and treatment of each disease.
• Evaluation of leading emerging targets in terms of signaling pathways and therapeutic strategies.

Currently there are no mechanism-based drugs on the market for Alzheimer's disease and COPD, and only one mechanism-based therapeutic approach is available for lung cancer. While mechanism-based therapy is available for type 2 diabetes and dyslipidemia, huge gaps in the therapeutic armamentarium result in inadequate treatment. Potentially, all of the diseases discussed in this report could be treated with combination therapies (and, in some cases, possibly by multitargeted agents) of mechanism-based drugs, if such drugs were developed.

Indication-specific highlights presented in this report include the following:

Lung Cancer

The activities of several companies developing inhibitors of signaling kinases of the Raf family, which includes B-Raf, are discussed and evaluated. One such inhibitor, sorafenib (Onyx/Bayer's Nexavar) has recently been approved by the Food and Drug Administration (FDA) for renal cell carcinoma, and is also being developed for lung cancer. Companies are also developing inhibitors of MEK (mitogen-activated protein MAP kinase kinase) and of Ras

Alzheimers

The report chronicles efforts to identify and validate biomarkers of Alzheimer's, as well as recent efforts to develop agents for in vivo imaging of amyloid plaque in animal models and in human subjects. Emerging drugs, such as Targacept's selective small-molecule compounds that target the neural nicotinic receptors (NNRs), are also evaluated.

Dyslipidemia

An examination of the benefits and limitations of statins is presented, as well as new approaches to prevention and treatment of cardiovascular disease. Important activities in this area include efforts to target CETP. There are now three drug candidates in Phase II or Phase III clinical trials, including Pfizer's torcetrapib, a small-molecule CETP inhibitor delivered in a fixed combination with the company's atorvastatin.

Diabetes

Perhaps the greatest problem in discovering new drugs for type 2 diabetes is the lack of scientific understanding of the disease, and of metabolic syndrome, which usually precedes it. The report discusses the efforts of companies such as Metabolex, a biotechnology company whose mission is to discover and develop new diabetes drugs based on increased scientific understanding.

COPD

Many classes of drugs being developed for other inflammatory conditions might be applicable to COPD. However, in many cases, systemic and chronic administration of broad-spectrum anti-inflammatory drugs (such as those that target signal transduction pathways involved in inflammation) would have unacceptable side effects. Of drugs under development for COPD, PDE4 inhibitors (specifically, cilomast and roflumilast) may reach the market in 2006 or 2007, provided that they can overcome concern with potential side effects at regulatory agencies. If approved, they will be the first mechanism-specific drugs with the potential to affect the course of COPD.

Table of Contents

Chapter 1. Background: Targets and Target-Based Drug Discovery and Development

• 1.1. What Is a Drug Target?
• 1.2. The Target Validation Problem
• Sidebar: Q&A with Dr. Neil W. Gibson, Chief Scientific Officer of OSI Pharmaceuticals, on Target Validation
• 1.3. Target Validation and Falling Productivity of Pharmaceutical Research and Development
• 1.4. A More Realistic View of Target Validation
• 1.5. Approaches to Improving the Productivity of Target Evaluation and of Drug Discovery
• Dealing with Multiple Molecular "Causes" of Disease by Hitting More than One Target
• Whole-Pathway Approaches
• Biology-Driven Drug Discovery
• 1.6. Special Issues with Complex Diseases with High Unmet Medical Need
• Biomarkers, Targets, and Patient Stratification
• Animal Models and Complex Diseases

Chapter 2. Alzheimer's Disease

• 2.1. Pathobiology and Mechanistic Studies of Alzheimer's Disease
• Neurotransmitters and Alzheimer's Drugs
• The Amyloid Hypothesis
• Apolipoprotein E and Alzheimer's Disease
• Mechanistic Studies of Tau and Alpha Synuclein in Alzheimer's Disease
• 2.2. Prospects for Biomarkers in Detection of Presymptomatic and Early-Stage Alzheimer's Disease and in Monitoring Therapy
• 2.3. Selected Emerging Targets in Alzheimer's Disease
• Neural Nicotinic Receptors
• Beta-Amyloid
• Beta-Secretase and Gamma-Secretase
• Sidebar: Q&A with Dr. Adrian N. Hobden, President of Myriad Pharmaceuticals, Inc., on the Challenges of Developing the Novel-Acting Agent Flurizan for Alzheimer's Disease
• Somatostatin Receptors and Metabolism of Beta-Amyloid
• The Tau Pathway
• Apolipoprotein E
• 2.4. Outlook

Chapter 3. Lung Cancer

• 3.1. Types of Lung Cancer
• 3.2. Current Diagnosis of Lung Cancer
• 3.3. Current Therapies for Lung Cancer
• 3.4. Signaling Pathways and Strategies for Targeted Therapies in Non-Small-Cell Lung Cancer
• 3.5. Selected Emerging Targets in Lung Cancer
• Epidermal Growth Factor Receptor
• K-Ras
• B-Raf
• Mitogen-Activated Protein Kinase Kinase
• Vascular Endothelial Growth Factor Receptor
• Aromatose
• Hedgehog Signaling Pathway
• 3.6. Outlook

Chapter 4. Dyslipidemia

• 4.1. Statins: Their Benefits and Their Limitations
• 4.2. Mechanistic Issues in Atherogenic Dyslipidemia
• Anti-Atherogenic Effects of High-Density Lipoprotein
• Metabolic Syndrome, High-Density Lipoprotein, and Triglycerides
• 4.3. Selected Emerging Targets in Dyslipidemia
• Cholesteryl Ester Transfer Protein
• Targeting High-Density Lipoprotein with Mimetics
• Peroxisome Proliferator-Activated Receptors Alpha and Delta
• Liver X Receptor
• 4.4. Outlook

Chapter 5. Type 2 Diabetes

• 5.1. Current Therapies
• 5.2. Difficulties in Drug Discovery in Type 2 Diabetes
• 5.3. Selected Emerging Targets in Type 2 Diabetes
• Dipeptidyl Peptidase-IV
• Simultaneous Targeting of PPAR-Alpha and PPAR-Beta
• Cannabinoid-1 Receptor
• S6 Kinase 1
• 11 Beta-Hydroxysteroid Dehydrogenase Type 1
• Recombinant Adiponectin
• Matrix Metalloproteinases
• 5.4. Outlook

Chapter 6. Chronic Obstructive Pulmonary Disease

• 6.1. Introduction
• Chronic Bronchitis
• Emphysema
• 6.2. Current Treatments
• 6.3. Animal Models in COPD
• 6.4. Selected Emerging Targets for COPD
• Proteinases (Matrix Metalloproteinases and Neutrophil Elastase)
• Phosphodiesterase-4
• Oxidant/Antioxidant Balance
• Leukotriene B4
• CXC Chemokines
• Tumor Necrosis Factor-Alpha
• 6.5. Outlook

Chapter 7. General Conclusions

• 7.1. Biology-Driven versus Technology-Driven Drug Discovery
• 7.2. Multitargeted Drugs and Combination Therapies
• 7.3. Biomarkers, Diagnostics, and Disease Stratification

Chapter 8. Company Profiles

• 8.1. Alzheimer's Disease
• Axonyx
• Elan
• Myriad Genetics
• Neurochem
• Targacept
• 8.2. Lung Cancer
• AstraZeneca
• Curis
• Genentech
• Onyx Pharmaceuticals
• OSI Pharmaceuticals
• Pfizer
• Wyeth
• 8.3. Dyslipidemia
• Avant Immunotherapeutics, Inc.
• Exelixis
• GlaxoSmithKline
• Ligand Pharmaceuticals
• Pfizer
• 8.4. Type 2 Diabetes
• Biovitrum
• Bristol-Myers Squibb
• Merck
• Novartis
• sanofi-aventis
• 8.5. Chronic Obstructive Pulmonary Disease
• Aeolus Pharmaceuticals
• ALTANA Pharma
• Arriva
• Dompe
• Pfizer

References

Glossary

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