Effects of Varespladib Methyl on Biomarkers and Major Cardiovascular Events in Acute Coronary Syndrome Patients

Abstract

The purpose of this study was to investigate the effects of varespladib on cardiovascular biomarkers in acute coronary syndrome patients. Secretory phospholipase A(2) (sPLA(2)) represents a family of proatherogenic enzymes that hydrolyze lipoprotein phospholipids, increasing their affinity for intimal proteoglycans; contribute to cholesterol loading of macrophages by nonscavenger receptor mediated pathways; and activate inflammatory pathways. In prospective studies, high sPLA(2)-IIA levels predicted major adverse cardiovascular events in acute coronary syndrome (ACS) and stable coronary heart disease patients. This randomized, double-blind, prospective controlled clinical trial (phase 2B) was designed to investigate the effects of sPLA(2) inhibition with varespladib 500 mg daily versus placebo as adjunctive therapy to atorvastatin 80 mg daily on biomarkers (low-density lipoprotein cholesterol [LDL-C], high-sensitivity C-reactive protein [hsCRP], and sPLA(2)-IIA levels), major adverse cardiovascular events (unstable angina, myocardial infarction, death), and safety. In all, 625 ACS subjects were randomized within 96 h of the index event and treated for a minimum of 6 months. After 8 weeks (primary efficacy end point), varespladib/atorvastatin reduced mean LDL-C levels from baseline by 49.6% compared with 43.4% with placebo/atorvastatin (p = 0.002). Respective 8-week median reductions in sPLA(2)-IIA levels were 82.4% and 15.6% (p < 0.0001), and hsCRP levels were lowered by 75.0% and 71.0% (p = 0.097). At 24 weeks, respective reductions with varespladib and placebo were as follows: LDL-C 43.5% versus 37.6% (p < 0.05), hsCRP 79.8% versus 77.0% (p = 0.02), and sPLA(2)-IIA 78.5% versus 6.4% (p < 0.0001). Major adverse cardiovascular events were not different from placebo 6 months post-randomization (7.3% varespladib vs. 7.7% placebo). No treatment differences in elevated liver function studies on >1 occasion were observed. Varespladib therapy effectively reduced LDL-C and inflammatory biomarkers in ACS patients treated with conventional therapy including atorvastatin 80 mg daily. There were no treatment differences in clinical cardiovascular events. (FRANCIS [Fewer Recurrent Acute Coronary Events With Near-Term Cardiovascular Inflammation Suppression]-ACS Trial: A Study of the Safety and Efficacy of A 002 in Subjects With Acute Coronary Syndromes; NCT00743925).