Report number:66
  Print:$2,750.00
  Single-site or operational unit license:$3,500.00
  Length:est. 125 pages
  Date published:June 2006  
 
Overview
 
 
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.

About the Author

Allan B. Haberman, Ph.D., is Principal of Haberman Assoc iates (http://www.biopharmconsortium.com), a consulting firm specializing in science and technology strategy for pharmaceutical, biotechnology, and other life science companies. He is also a Principal and Founder of the Biopharmaceutical Consortium, an expert team formed to assist life science companies, research groups, and emerging enterprises to identify and exploit promising, breakthrough technologies. Dr. Haberman’s consulting activities include work in new product development and technology strategy, opportunity assessment, assessment of drug pipelines, and due diligence on established and emerging biotechnology companies. He is also the author of numerous publications on the pharmaceutical and biotechnology industries, their technologies and products, and on the major therapeutic areas for drug discovery and development. Prior to forming Haberman Associates, Dr. Haberman was the Associate Director of the Biotechnology Engineering Center at Tufts University. He received his Ph.D. in biochemistry and mo lecular biology from Harvard University.
 
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
Dompé
Pfizer

References

Glossary

Company Index with Web Sites
 
Tables and Figures
 
Figure 3.1. The Ras Pathway and Tumor Drug Sensitivity

Figure 4.1. High-Density Lipoprotein and Cholesterol Efflux from the Arterial Wall

Figure 5.1. S6 Kinase 1 and Feedback Regulation of Insulin Signaling

Table 1.1. Major Types of Target Evaluation Technologies

Table 2.1. Selected Emerging Targets in Alzheimer’s Disease

Table 3.1. Types of Lung Cancer

Table 3.2. Selected Emerging Targets in Lung Cancer

Table 4.1. Accepted Modifiable Risk Factors for Coronary Heart Disease

Table 4.2. Selected Emerging Targets in Dyslipidemia

Table 5.1. Major Current Therapies for Type 2 Diabetes

Table 5.2. Selected Emerging Targets in Type 2 Diabetes

Table 6.1. Selected Emerging Targets in COPD