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A boost for GSK's first-in-class heart drug? (antiinflammatory CVD drug)
  News and Analysis
Nature Reviews Drug Discovery 9, 506 (July 2010) | doi:10.1038/nrd3223
A study published in The Lancet ( 375, 1536-1544; 2010) suggests that there is a high degree of association between the risk of coronary heart disease and the activity and mass of the inflammatory enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2), which is the target for GlaxoSmithKline's (GSK's) darapladib, an anti-atherosclerotic drug that is in Phase III trials.
Lp-PLA2 is an enzyme secreted by leukocytes, and various studies have shown that it has a pivotal role in atherosclerotic plaque inflammation. "This inflammation in turn appears to be a driving force in the development of those high-risk lesions that are associated with ischaemic coronary death, myocardial infarction, unstable angina and ischaemic strokes," explains Robert Wilensky, Director of Interventional Cardiology Research, Penn Heart and Vascular Center, and Professor of Medicine at the University of Pennsylvania, Philadelphia, USA.
Darapladib, a first-in-class orally active inhibitor of Lp-PLA2, may therefore provide a new strategy for treating atherosclerosis and could potentially complement the well-established benefits of cholesterol-lowering statins. "If early studies [of darapladib] in both animals and in patients with coronary artery disease are confirmed in ongoing Phase III trials, reducing Lp-PLA2 activity will reduce the untoward effects of high-risk coronary artery disease, independent of an effect on lipid levels," says Wilensky.
The Lancet study, which was partially funded by GSK, was a large meta-analysis involving 79,036 participants from 32 prospective studies, and it examined the association of Lp-PLA2 (its activity or mass concentration) with risk of coronary heart disease, stroke or death. "The results show unequivocally that Lp-PLA2 activity and mass is associated with increased vascular risk and other pro-atherogenic lipids," Wilensky says. "It could also resolve some controversy regarding whether Lp-PLA2 is pro-atherogenic or anti-atherogenic, as the data indicate strongly that increased Lp-PLA2 activity or mass adversely affects vascular health," he adds.
Nevertheless, the study does not provide conclusive evidence that Lp-PLA2 is a valid drug target for coronary heart disease. "Although encouraging, there is no guarantee that a biomarker associated with cardiovascular risk also represents a useful drug target," says Steve Nissen, Chairman of the Department of Cardiovascular Medicine, Cleveland Clinic, Ohio, USA. "The only legitimate approach to validating Lp-PLA2 as a target is a clinical trial showing that a drug that lowers this biomarker reduces adverse cardiovascular outcomes," he adds.
So, the results from the ongoing studies of darapladib are highly anticipated. Darapladib is currently in two Phase III trials - STABILITY, which is studying -15,500 participants with chronic coronary artery disease (estimated completion date October 2010), and SOLID-TIMI 52, which will enrol -11,500 participants with acute coronary syndromes (estimated completion date April 2014).
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