Highly anticipated results from the FOURIER trial of Amgen’s Repatha (evolocumab) were presented at the American College of Cardiology (ACC) late breaking clinical trial session held in Washington DC. The study demonstrated that long-term use of the drug led to significant and sustained reductions in LDL-C, which translated to reduced risk of CV events, including stroke and MI. Despite this, no effect on CV mortality was observed, which has led some to question the value of this expensive new class of lipid-lowering therapies.
FOURIER enrolled 27,564 patients with established CV disease who were already on an optimized statin regimen. Patients were randomized 1:1 to receive either fortnightly or monthly injections of evolocumab or placebo. The primary endpoint was composite of CV death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization. The median follow up time was 26 weeks.
After just 12 weeks of therapy, a significant decrease in LDL-C was observed and this was sustained throughout the duration of the trial. Median baseline LDL-C levels were 92mg/dL, and this was reduced by 59% (p<0.00001) in the treatment group, to just 30mg/dL. Importantly, these extreme and unprecedented reductions in LDL-C levels translated to reduced risk of experiencing a CV event, providing further support for the LDL hypothesis. A 15% reduction in the broad primary endpoint was observed, and after just one year of therapy, a 25% reduction in CV death, MI or stroke – the study’s key secondary endpoint – was seen. When examined individually, evolocumab use was associated with a 27% risk reduction in MI and 21% risk reduction in stroke. However no significant reduction in CV death was observed with evolocumab compared to placebo.
It was hoped that positive CV outcomes data would help break down the barriers that have been limiting uptake of the drug, namely cost. Despite the impressive reductions in LDL-C, as well as CV events, the lack of mortality benefit will likely allow payers to continue to deny access to Repatha. A clear take home message from the ongoing PCSK9 saga is that drug developers need to start focusing on cost-effectiveness, not just efficacy.