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Disappointing Late-Stage Results Reported for Darapladib in Patients With Chronic CHD

Trial fails to meet primary endpoint

Disappointing data from the pivotal phase III STABILITY (STtabilization of Atherosclerotic Plaque By Initiation of DarapLadIb TherapY) trial of darapladib (GlaxoSmithKline) have been presented at the American College of Cardiology’s 63rd Annual Scientific Session in Washington, D.C. The findings were also published in the New England Journal of Medicine.

This global, double-blind, event-driven trial randomly assigned 15,828 patients with chronic coronary heart disease (CHD) to receive darapladib (160 mg) or placebo once daily on a background of standard of care. The study’s primary endpoint was the time to first occurrence of any major adverse cardiovascular event (MACE) (i.e., cardiovascular death, myocardial infarction [MI], and stroke).

Secondary endpoints included major coronary events (MCEs) (i.e., CHD death, MI, or urgent coronary revascularisation for myocardial ischemia); total coronary events (i.e., CHD death, MI, hospitalisation for unstable angina, or any coronary revascularisation procedure); the individual components of MACE; and all-cause mortality.

No difference was seen in the treatment groups in the time to first occurrence of MACE. During a median follow-up period of 3.7 years, the primary endpoint of MACE occurred in 9.7% of patients in the darapladib group and in 10.4% of patients in the placebo group (hazard ratio [HR], 0.94; P = 0.199). HRs for the individual components of MACE were cardiovascular death, 0.96; MI, 0.89; and stroke, 1.01.

Among the secondary endpoints, major coronary events occurred in 9.3% of patients taking darapladib versus 10.3% of the placebo group (HR, 0.90; P = 0.045). Similar effects were observed for the composite of total coronary events, which occurred in 14.9% of patients treated with darapladib compared with 16.1% of patients given placebo (HR, 0.91; P = 0.019). There was no difference in all-cause mortality, which occurred in 7.3% of patients in both groups.

The frequency of serious adverse events was 43% in the darapladib group and 44% in the placebo group. Adverse events leading to treatment discontinuation occurred in 20% of patients in the darapladib group and in 14% of patients in the placebo group.

Darapladib is a selective and orally active inhibitor of Lp-PLA2 (lipoprotein-associated phospholipase A2). The drug is currently being investigated as a potential agent for the reduction of cardiovascular events in patients with CHD. Lp-PLA2 is an enzyme that is found in blood and in atherosclerotic plaques. Elevated Lp-PLA2 activity has been implicated in the development and progression of atherosclerosis.

The STABILITY trial is the first of two phase III studies with darapladib. The second phase III study, SOLID-TIMI 52, will evaluate the effects of darapladib in patients with acute coronary syndrome. This trial has enrolled more than 13,000 patients in 36 countries. SOLID-TIMI 52 is ongoing and remains blinded. The results are expected in the second quarter of 2014.

The study designs of the STABILITY and SOLID-TIMI 52 trials were published in the October 2010 and October 2011 editions of the American Heart Journal, respectively.

Source: GlaxoSmithKline; March 30, 2014.

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