Evolocumab Scores in Long-Awaited FOURIER Outcomes Trial: Top-line Results

Patrice Wendling

February 03, 2017

THOUSAND OAKS, CA — Additional LDL-cholesterol lowering with the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) significantly reduced the risk of cardiovascular events in patients with atherosclerotic CV disease, according to newly released top-line results[1].

The long-awaited FOURIER Outcomes trial met its primary end point—a composite of CV death, MI, stroke, and hospitalization for unstable angina or coronary revascularization—and a key secondary end point—a composite of CV death, MI, or stroke. And, according to the company, no new safety signals were observed.

The EBBINGHAUS trial also met its primary end point, demonstrating that evolocumab was noninferior to placebo with regard to its effect on cognitive function, the drug maker said in its release. The issue has swirled around this new class of drugs after prior studies found excess neurocognitive events with evolocumab and alirocumab (Praluent, Sanofi/Regeneron), the first PCSK9 inhibitor to enter the US market.

Commenting to heartwire from Medscape in an email, Dr Jeffrey Berger (New York University Langone Medical Center, NY) said, "This is a potentially seismic event for the cardiovascular community, with a possibility for altering the landscape of cardiovascular prevention."

He added, "Nonetheless, prudence is required till we are able to review the primary data of these trials. It is also important to note that we have entered an era of value-based medicine—thus, potential drugs need to prove their value (efficacy combined with cost) for market potential."

The data from both trials are to be presented as late-breaking clinical trials at next month's American College of Cardiology Scientific Sessions in Washington, DC.

The PCSK9 inhibitors have been successful in reducing LDL cholesterol in phase 3 trials, such as the ODYSSEY COMBO II study and GAUSS-2, but without outcomes or long-term safety data, their place in treating and managing patients with elevated cholesterol has been unclear.

Commenting to heartwire via email, Dr Amit Khera (UT Southwestern Medical Center, Dallas) said, "This study is a game changer. Since FDA approval, we have seen in practice the impressive effects of PCSK9 inhibitors for lowering LDL, particularly in the most challenging patients—those with familial hypercholesterolemia and those with CVD but residually higher LDL for various reasons. However, we weren't sure if we were actually lowering events or if there were some untoward side effects that had yet to be uncovered. Assuming the results are as stated when eventually published, this study is really a boon to those patients who previously had few treatment options. I can think of several in my practice, and these results will be very meaningful for them."

He added, "Now the challenge will be determining who would most benefit from these agents, particularly given the cost."

The task could prove quite challenging with an annual cost of about $14,100 for evolocumab and $14,600 for alirocumab, as adjunct to diet and maximally tolerated statin therapy.

The positive FOURIER Outcomes results are based on approximately 27,500 patients who had an MI, ischemic stroke, or symptomatic peripheral artery disease and an LDL cholesterol >70 mg/dL or a non-HDL cholesterol >100 mg/dL despite optimal statin therapy. Patients received 140-mg evolocumab injections every 2 weeks or 420-mg injections monthly or placebo on the same schedule.

The noninferiority EBBINGHAUS trial involves about 1900 patients enrolled in FOURIER Outcomes. The primary outcome was the Spatial Working Memory strategy index of executive function; secondary end points include working memory, memory function, and psychomotor speed as assessed with a tablet-based tool.

Dr Sean E Harper (Amgen, Thousand Oaks, CA) said in the news release, "In the GLAGOV study, we demonstrated that Repatha has an effect on atherosclerosis, the underlying cause of cardiovascular disease. These FOURIER results show unequivocally the connection between lowering LDL cholesterol with Repatha and cardiovascular risk reduction, even in a population already treated with optimized statin therapy."

Berger and Khera reported no relevant financial relationships.

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