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Darapladib: an emerging therapy for atherosclerosis
1Divisions of Cardiology and Cardiovascular Research, University of Washington School of Medicine, Harborview Medical Center, Room 2EH-64, 325 9th Avenue, Seattle, WA 98104, USA. mcorson@u.washington.edu
Therapeutic Advances in Cardiovascular Disease
|July 28, 2010
Summary
Lipoprotein-associated phospholipase-A(2) plays a role in atherosclerosis. Darapladib, an inhibitor, is being tested in large trials to see if it can reduce heart attacks and strokes.
Area of Science:
- Biochemistry
- Cardiovascular Medicine
- Pharmacology
Background:
- Atherosclerotic cardiovascular diseases remain a leading cause of mortality.
- Current lipid-modifying therapies reduce but do not eliminate cardiovascular risk.
- Lipoprotein-associated phospholipase-A(2) (Lp-PLA2) is implicated in atherosclerosis progression and plaque instability.
Purpose of the Study:
- To review preclinical and early clinical data on darapladib, a specific Lp-PLA2 inhibitor.
- To provide context for ongoing Phase III trials evaluating darapladib's efficacy and safety.
- To assess the potential of Lp-PLA2 inhibition as a novel therapeutic strategy for cardiovascular disease.
Main Methods:
- Summary of preclinical studies investigating Lp-PLA2 inhibition.
- Review of early-phase (Phase I/II) clinical trials of darapladib.
- Description of the design and rationale for ongoing Phase III trials.
Main Results:
- Preclinical data suggest Lp-PLA2 contributes to inflammation and plaque vulnerability.
- Early clinical studies demonstrated target engagement and safety of darapladib.
- Phase III trials are designed to assess reduction in major adverse cardiovascular events.
Conclusions:
- Elevated Lp-PLA2 levels are associated with increased risk of myocardial infarction and stroke.
- Darapladib represents a targeted approach to inhibit Lp-PLA2 activity.
- Results from the large Phase III trials are anticipated to clarify the clinical utility of darapladib in reducing cardiovascular events.
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