Metabolic and Inflammatory Disease R&D: An Assessment of 5 Highly Promising Therapeutic Classes

Published by: CHI Insight Pharma Reports

Published: Apr. 1, 2007 - 170 Pages

Table of Contents

Chapter 1

INTRODUCTION

1.1 Target-Based Approaches to Drug Discovery

1.2 Identification of Current High-Profile Targeted Approaches

Inflammatory and Immune Diseases

Metabolic Diseases

1.3 Does Extensive Activity Predict Success?

Success from High Activity

Leukotriene CysLT1 Receptor Antagonists

PDE5 Inhibitors

COX-2 Inhibitors

Failures Despite Intense Efforts

5-Lipoxygenase Inhibitors

Renin Inhibitors

Thromboxane Antagonists

Long-lived Efforts

p38 MAP Kinase

PDE4 Inhibitors

1.4 Reasons for Failures

Chapter 2

METHODOLOGY: IDENTIFYING HIGH-PROFILE AREAS OF EFFORT

2.1. Medical Advances

2.2. Literature Activity

2.3. Meetings

2.4. Patenting Activity

2.5. Commercial Deals

Chapter 3

HIGH-PROFILE TOPICS IN INFLAMMATORY AND METABOLIC DISEASES

3.1. Inflammatory Diseases

Respiratory Diseases

Arthritis

3.2. Metabolic Diseases

Diabetes

Obesity

Metabolic Syndrome

Lipid Disorders

Chapter 4

CHEMOKINE ANTAGONISTS

4.1. Chemokines

4.2. Targets

CCR Receptors

CXCR Receptors

4.3. Pathophysiological Role(s)

Inflammatory Processes

HIV Infection

4.4. Potential Therapeutic Indications

Atherosclerosis

Allergic Rhinitis

Asthma

Chronic Obstructive Pulmonary Disease

Multiple Sclerosis

Rheumatoid Arthritis

Cancer

4.5. Possible Pitfalls

CCR Receptors

CXCR Receptors

CCR1 Antagonists

SH-T-04268-H

CCR2 Antagonists

Chemokine Antagonists: Strong Evidence ¡- Well Validated. Q&A with Dr. Kris Vaddi, vice president, Preclinical Biology, Incyte, and Dr. Robert Newton, Drug Discovery Biology, Incyte

CCR3 Antagonists

CCX-282

CXCR2 Antagonists

SCH-527123

GSK-656933

DF-1681

CTCE-9908

Preclinical Efforts

4.6. Active Major Companies

Amgen

Astellas

AstraZeneca

Bayer Schering

Boehringer Ingelheim

Bristol-Meyers Squibb

Daiichi Sankyo

GlaxoSmithKline

Hoffmann-La Roche

Janssen

Merck

Novartis

Pfizer

sanofi-aventis

Schering-Plough

Takeda

Wyeth

4.7. Other Active Companies

AnorMED

ChemoCentryx

Chemokine Therapeutics

Domp¨¦

Incyte

Millennium Pharmaceuticals

Ono Pharmaceutical

Pharmacopeia Drug Discovery

UCB SA

4.8. Significant Commercial Deals

4.9. Current Outlook

Chapter 5

TOLL-LIKE RECEPTOR MODULATORS

5.1. Pathophysiological Role(s)

5.2. Potential Therapeutic Indications

5.3. Possible Pitfalls

5.4. Level of Activity, 2000 to 2006

5.5. Development Compounds

TLR-3 Agonists

Ampligen

TLR-4 Modulators

Eritoran

TAK-242

CRX-675

TLR-7 Agonists

852A

Isatoribine and ANA-975

ANA-773

Toll-like Receptors: Opportunities in Numerous Disease States. Q&A with Professor Luke O¡¯Neill, Opsana Therapeutics

TLR-9 Agonists

PF-3512676

Tolamba, Heplisav, and ISS-1018

CpG-10101

IMO-2055

Preclinical Agents

5.6. Active Major Companies

AstraZeneca

Eisai

GlaxoSmithKline

Novartis

Pfizer

sanofi-aventis

Takeda

5.7. Other Active Companies

3M Pharmaceuticals

Anadys

Coley Pharmaceuticals

Dynavax Technologies

Hemispherx Biopharma

Idera Pharmaceuticals

Innate Pharma

Opsona Therapeutics

5.8. Significant Commercial Deals

5.9. Current Outlook

Chapter 6

11¦Â-HYDROXYSTEROID DEHYDROGENASE INHIBITORS

6.1. 11¦Â-Hydroxysteroid Dehydrogenase

11¦Â-HSD1

11¦Â-HSD2

6.2. Pathophysiological Role(s)

6.3. Potential Therapeutic Indications

Type 2 Diabetes

11¦Â-HSD Inhibitors: Broad Applications in Metabolic Disease. Q&A with Dr. Greg Hollis, vice president, Advanced Technology, Incyte; Dr. Deborah Hunter, leader, Incyte; and Dr. Nigel Vicker, group leader, Discovery Chemistry, Ipsen

Metabolic Syndrome

Obesity

Memory Disorders

Inflammation

6.4. Possible Pitfalls

INCB-13739

AMG-221

Preclinical Efforts

6.5. Active Major Companies

Abbott

Amgen

AstraZeneca

Hoffman-La Roche

Janssen

Merck

Pfizer

Takeda

Wyeth

6.6. Other Active Companies

Bionetworks GmbH

Biovitrum AB

Evotec AG

Incyte

Sterix

6.7. Significant Commercial Deals

6.8. Current Outlook

Chapter 7

MELANOCORTIN RECEPTOR MODULATORS

7.1. Melanocortin Receptors

7.2. Drug Targets

7.3. Pathophysiological Role(s)

7.4. Potential Therapeutic Indications

Obesity

Sexual Dysfunction

Depression and Anxiety

7.5. Possible Pitfalls

Bremelanotide

AP-214

Preclinical Efforts

MC4 Agonists

MC4 Antagonists

7.6. Active Major Companies

Eli Lilly

Merck

Novartis

Novo Nordisk

Roche

7.7. Other Active Companies

Action Pharma

Ipsen

Millennium Pharmaceuticals

Neurocrine Biosciences

Palatin Technologies

Procter & Gamble

Santhera

Taisho

7.8. Significant Commercial Deals

7.9. Commercial Outlook

Chapter 8

MELANIN-CONCENTRATING HORMONE RECEPTOR ANTAGONISTS

8.1. Melanin-Concentrating Hormone

8.2. MCH-1 Receptor

8.3. Pathophysiological Role(s)

8.4. Potential Therapeutic Indications

Obesity

Depression and Anxiety

8.5. Possible Pitfalls

8.6. Development Compounds

8.7. Clinical Compounds

AMG-076

856464

NGD-4715

Preclinical Efforts

8.8. Active Major Companies

Abbott Laboratories

Amgen

AstraZeneca

Boehringer Ingelheim

Eli Lilly

GlaxoSmithKline

Merck

sanofi-aventis

Schering-Plough

Takeda

8.9. Other Active Companies

7TM Pharma A/S

Arena Pharmaceuticals

Biovitrum

Lundbeck

Neurocrine Biosciences

Neurogen

Procter & Gamble

Taisho Pharmaceuticals

8.10. Significant Commercial Deals

8.11. Current Outlook

References

Glossary of Selected Terms

Company Index with Web Addresses

FIGURES

Figure 4.1. SWOT Analysis for Chemokine Antagonists

Figure 4.2. Total Literature Activity in the Chemokine Receptor Field, 2000 to 2006

Figure 4.3. Literature Activity by Year in CCR Chemokine Receptor Field, 2000 to 2006

Figure 4.4. Patent Activity by Year in CCR Chemokine Receptor Field, 2000 to 2006

Figure 4.5. Literature Activity by Year in CXCR Chemokine Receptor Field, 2000 to 2006

Figure 4.6. Patent Activity by Year in CXCR Chemokine Receptor Field, 2000 to 2006

Figure 4.7. Patent Activity by Company, for Both CCR and CXCR Antagonists, 2000 to 2006

Figure 5.1. SWOT Analysis for TLR-4 Antagonists

Figure 5.2. SWOT Analysis for TLR-7 Agonists

Figure 5.3. SWOT Analysis for TLR-9 Agonists

Figure 5.4. Increasing Literature Interest in TLRs, 2000 to 2006

Figure 5.5. Patent Activity in TLRs, 2000 to 2006

Figure 5.6. Interest in Patenting TLR Agonists and Antagonists, 2000 to 2006

Figure 6.1. SWOT Analysis for 11¦Â-HSD1

Figure 6.2. Literature and Patent Activity in the 11¦Â-HSD Field, 2000 to 2006

Figure 6.3. Patents Claiming 11¦Â-HSD from Major Companies and Selected Other Companies

Figure 7.1. SWOT Analysis for MC4 Receptor Agonists

Figure 7.2. Increasing Interest in MC Receptors and Their Modulators, 1999 to 2006

Figure 7.3. Patent Activity by Company in Melanocortin Agonists

Figure 8.1. SWOT Analysis for MCH-1 Antagonists

Figure 8.2. Increasing Interest in MCH-1 Receptor and MCH-1 Antagonists, 2000 to 2006

Figure 8.3. Patent Activity from Leading Players in the MCH-1 Antagonist Field

TABLES

Table 1.1. Numbers of Potential Drug Targets of Selected Classes Within the Human Genome

Table 2.1. Development Time Frame of Leading Dipeptidyl Peptidase IV Inhibitors

Table 3.1. Novel Anti-inflammatory Approaches to the Treatment of Arthritis

Table 3.2. Novel Approaches to the Treatment of Diabetes

Table 3.3. Novel Approaches to the Treatment of Obesity

Table 3.4. Novel Approaches to the Treatment of Lipid Disorders

Table 4.1. Chemokine CCR Receptors, Preferred Chemokine Ligand(s), and Main Cellular Expression

Table 4.2. Chemokine CXCR Receptors, Preferred Chemokine Ligand(s), and Main Cellular Expression

Table 4.3. Chemokine Antagonists that Were in Clinical Development for Indications Other than HIV Infection

Table 4.4. Chemokine Antagonists that Are Currently in Clinical Development for Indications Other than HIV Infection

Table 4.5. Chemokine Antagonists Disclosed as Being in Preclinical Development or Discovery for Indications Other than HIV Infection

Table 5.1. Summary of the Human TLRs: Their Natural Ligands and Their Expression Patterns

Table 5.2. Identified TLR Modulators and Their Development Status as of December 2006

Table 6.1. 11¦Â-HSD1 Inhibitors in Clinical or Preclinical Development as of December 2006

Table 7.1. Identified MC Receptor Modulators and Their Development Status as of December 2006

Table 8.1. Identified MCH-1 Antagonists and Their Development Status as of December 2006

Abstract

• Chemokine antagonists
• Toll-like receptors
• Melanin-concentrating hormone antagonists
• Melanocortin MC4 agonists
• 11b-hydroxysteroid dehydrogenase inhibitors

• In January 2007, 11 chemokine antagonists from 9 different companies were in clinical development for the treatment of inflammatory disorders, with 2 of these drugs being the focus of high-value commercial deals. Many more chemokine antagonists are either in preclinical development or lead optimization, and most of the major pharmaceutical companies have current R&D efforts directed at chemokine receptor targets.
• For the 10 identified toll-like receptors (TLRs), current activity centers around development of both TLR agonists and antagonists to treat conditions ranging from sepsis to cancer. Metabolic and Inflammatory Disease R&D: An Assessment of 5 Highly Promising Therapeutic Classes provides a thorough analysis of these TLR potentials, plus succinct charts of Strengths, Weaknesses, Opportunities, and Threats for these and other products in development.

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