GlaxoSmithKline’s darapladib modifies coronary plaque composition and lowers Lp-PLA2 activity, a biomarker predictive of heart attack risk

Results at ESC demonstrated that darapladib:
− Prevented expansion of the necrotic core in human coronary plaques, potentially reducing the risk of plaque rupture and subsequent CV events
− Inhibited activity of plasma Lp-PLA2, an emerging risk factor for CV events

GlaxoSmithKline (GSK) announced today that results of the Integrated Biomarkers and Imaging Study-2 (IBIS-2) showed that use of the selective Lp-PLA2 (lipoprotein-associated phospholipase A2) inhibitor, darapladib, in addition to standard of care treatment, prevented expansion of the necrotic core, a region within coronary plaque associated with a high risk of rupture. Preventing expansion of the necrotic core may reduce the risk of recurrent heart attacks in patients with coronary heart disease (CHD). Although the differences between treatment groups in the primary endpoints of plaque deformability or reduction of the inflammatory biomarker hsCRP were not significant, darapladib significantly reduced activity of the enzyme Lp-PLA2. Numerous studies suggest that high levels of Lp-PLA2 are predictive of coronary heart disease.1

Results of IBIS-2 were presented today at the 2008 Congress of the European Society of Cardiology (ESC) and also were published simultaneously in the American Heart Association’s journal, Circulation.

“Despite many advances in cardiovascular medicine, new approaches are needed to help reduce a patient’s risk of a heart attack, stroke or other cardiovascular event. With darapladib added to current standard therapies, our study suggests that the potential plaque-stabilising effects of darapladib may represent an important approach in treating atherosclerosis and reducing cardiovascular risk,” said Patrick Serruys, MD, PhD, Professor of Medicine, The Erasmus University, Rotterdam, The Netherlands and Chairman of the Steering Committee for IBIS-2.

The year-long Phase II exploratory IBIS-2 trial showed:

− The co-primary endpoints of plaque deformability and plasma levels of hsCRP, showed no significant differences between darapladib and placebo treatment groups, but trended positively.
− Key secondary endpoints showed significant effects of darapladib on plaque composition and plasma levels of Lp-PLA2 activity:
* On average, after 12 months, patients treated with placebo experienced a significant increase in necrotic core volume (p=0.009 vs. baseline) while expansion of the necrotic core was halted in the darapladib-treated group (p=0.71 vs. baseline). This resulted in a significant treatment difference in favour of darapladib (p=0.012 vs. placebo). The effect of darapladib on necrotic core was consistent among several subgroups.
− The activity of circulating Lp-PLA2 was reduced by 59% (p0.001 vs. placebo).

“The effects of darapladib to reduce expansion of the necrotic core of plaques in the study population provide further confidence that Lp-PLA2 inhibition may prove to be an important therapeutic target,” said Patrick Vallance, MD, Senior Vice President, Drug Discovery, GlaxoSmithKline. “We are committed to the development of darapladib and believe it has the potential to become a major treatment option to help reduce the risk of cardiovascular events.”

About IBIS-2
The IBIS-2 study was a one-year international, randomised, placebo-controlled, parallel-group study in 330 patients with angiographically documented CHD. The study was not powered to address the effects of darapladib on cardiovascular outcomes. IBIS-2 used novel intravascular ultrasound (IVUS) methods, a catheter-based system that allows physicians to acquire images of diseased vessels from inside the artery and to acquire data on plaque composition and deformability. Coronary plaque imaging was obtained in precisely matched segments at baseline and follow-up. Approximately 50% of randomised subjects had evidence of acute coronary syndrome. The study compared the effects of darapladib (once-daily, oral Lp-PLA2 inhibitor, 160 mg/day) to placebo on coronary atheroma deformability (IVUS-palpography) and plasma hsCRP. Secondary endpoints included changes in plaque composition (necrotic core size using VH™ IVUS {virtual histology}), plaque size (IVUS-greyscale), and additional blood biomarkers. During the study, patients received recommended standard of care, including antiplatelet agents (99%) and statins (90%).

Overall, darapladib was well tolerated with no major safety concerns observed. The incidence of adverse events leading to withdrawal was similar with 7% (n=11) in placebo and 4% (n=7) in the darapladib group. There were no differences in the composite of CV death, MI, stroke and coronary revascularisation: Placebo 19%, n=29, darapladib 17% (n=29). Within each organ class, the incidence of adverse events leading to withdrawal was 1% in both groups with the exception of 2% (n=4) due to gastrointestinal events in the darapladib group. A higher incidence of malodour (mainly faeces or urine) was reported with darapladib (16%, n=28) compared with placebo (3%, n=5), but was not a common cause of withdrawal from the study (darapladib, 2%, n=3). Routine measurements of systolic blood pressure showed a difference between the groups (darapladib showed mean difference of 3.0 mm Hg, above placebo, p=0.031) that was not previously observed in other clinical trials with darapladib. A post-hoc analysis of intra-arterial blood pressure measured during the IVUS procedure, however, showed no differences in systolic blood pressure between the groups.

About Lp-PLA2
Lp-PLA2 is an enzyme found in blood and atherosclerotic plaque. The underlying process in most heart attacks and strokes is atherosclerosis, which is an inflammatory disease characterised by the build-up of plaque within the walls of arteries. The rupture of unstable atherosclerotic plaque, regardless of the size of the plaque causes most heart attacks and strokes. Enhanced Lp-PLA2 activity has been implicated in the development and progression of atherosclerosis which often leads to heart attacks, strokes and other potentially fatal CV events. Large amounts of Lp-PLA2 are present in the necrotic core of rupture-prone human coronary plaques.

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1 Lipoprotein-Associated Phospholipase A2 and Its Association with Cardiovascular Outcomes in Patients with Acute Coronary Syndromes in the PROVE IT-TIMI 22 Study. Circulation 2006; 113; Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study, Circulation, 2005;111;570-575