心血管疾患予防：高比重リポ蛋白（HDL）治療は治療パラダイムを変えるか

Abstract

Introduction

The notion that raising HDL cholesterol levels can reduce the risk of coronary heart disease is not a new one, yet drug developers have been continually foiled in their attempts to capitalize on this fi nding-as illustrated by Pfi zer' s discontinuation of the once highly promising agent torcetrapib. Several new drugs with novel mechanisms of action are in development, and although they are promising, barriers to entry are high, and they face long-term outcomes trials before being able to secure approval and comfort among physicians.

Get the Answers You Need to Shape Your Strategy

• The notion that raising HDL-C can lower cardiovascular risk has been around for a long time, yet drug developers have had trouble capitalizing on this fact. What are the barriers in this potentially highly lucrative market?
• Pfi zer abruptly halted development of the once-promising CETP inhibitor torcetrapib. What are the implications for Pfi zer as well as for other drug developers of CETP inhibitors?
• The uncertainty around CETP inhibition and HDL-C raising in general has caused some drug developers to create new drugs using decades-old concepts. Which agents and mechanisms of action are being tested and how do they differ from current therapies? What is the commercial potential for these drugs?

Scope

• HDL metabolism and how it relates to atherosclerosis: Overview of HDL metabolism and proposed atheroprotective mechanisms, including reverse cholesterol transport.
• Torcetrapib' s failure and outlook for other CETP inhibitors: A look at what went wrong with Pfi zer' s torcetrapib and what developers can do to avoid a similar fate.
• Implications of the ILLUMINATE trial: Implications for CETP inhibitors and their manufacturers.
• Old concepts get new life: Abbott and Merck are developing new versions of older but safe HDL modulators.

Table of Contents

• Executive Summary
  • Strategic Considerations
  • Stakeholder Implications
• HDL: A Window of Opportunity in the Mature Cardiovascular Market
• Metabolism and Proposed Atheroprotective Mechanisms of HDL
  • Reverse Cholesterol Transport
  • Antioxidant, Anti-Infl ammatory, and Antithrombotic Effects of HDL
• CETP Inhibitors: The Rise and Fall of Torcetrapib
• Implications of the ILLUMINATE Trial Results
• The Resurgence of Old Concepts
  • New Niacin Formulations
  • New Fibrate Formulations
• The Emergence of New Mechanisms of Action
  • Infusions of Reconstituted HDL/Apo A-I
  • Oral Apo A-I Mimetic Peptides
  • Apo-A-I Synthesis Enhancers
  • ABCA1/ABCG1 Gene Expression Enhancers
• Outlook

Tables

• 1. Lipid and Blood Pressure Changes from Baseline in Phase II and Phase III CETP Inhibitor Studies
• 2. A Selection of Confl icting Publications on the Cardiovascular Benefi ts of CETP Inhibition
• 3. Results from the ILLUMINATE Trial
• 4. Key HDL Therapeutics in the Emerging Drug Pipeline

Figures

• 1. Current Targets for Drugs in the Atherosclerosis Pipeline
• 2. The Reverse Cholesterol Transport Pathway
• 3. Proposed Atheroprotective Mechanisms of HDL
• 4. Opportunity for HDL Therapeutics in Anticipated Primary Indications by Region, 2006