Evolocumab, the powerful cholesterol-fighting injection sold as Repatha, offers a 25% reduction in cardiovascular (CV) death, heart attack, or stroke after the first year, giving the PCSK9 inhibitor a clinical advantage over rival alirocumab (Praluent) in addition to the legal edge it currently enjoys in a patent dispute.

Results presented this morning to a capacity crowd at the 66th Scientific Session of the American College of Cardiology (ACC) now raise the question whether FDA will expand the indication for evolocumab, which was approved in August 2015 for a narrower group of patients than seen in Europe.

Both evolocumab and alirocumab, monoclonal antibodies called proprotein convertase subtilisin-kexin 9 (PCSK9) inhibitors, have not met lofty sales expectations; this is partly due to FDA labels, as regulators awaited results of long-term safety trials like the one presented today, known as FOURIER. The other reason is cost: formulary managers and health plans have followed strict protocols for reimbursing PCSK9 inhibitors, as the wholesale prices exceed $14,000 per year.

ACC attendees returned to Washington, DC, where 3 years ago they first heard results about the power of evolocumab to reduce low-density lipoprotein (LDL) cholesterol by up to 60%. Excitement over PCSK9 inhibitors among cardiologists stems from their unique mechanism, which targets a protein that would otherwise make it hard for the liver to get rid of LDL cholesterol. The class offers a therapeutic option for patients with rare genetic conditions of familial hypercholesterolemia but also for those with atherosclerotic cardiovascular disease. In Europe, the PCSK9 inhibitors are approved for those who cannot tolerate statins, but that is not the case in the United States.

In FOURIER, evolocumab cut by 15% the risk of the trial’s primary endpoint—a composite of heart attack, stroke, hospitalization for angina, revascularization, or cardiovascular (CV) death—compared with placebo for a median of 26 months. While the overall finding for the secondary endpoint was 20%—for CV death, heart attack, or stroke—the authors noted in the New England Journal of Medicine, where the study was simultaneously published, that the increase in cholesterol-fighting benefits over time was consistent with findings for other therapies.

“A delay between the onset of LDL cholesterol lowering and the emergence of the full clinical benefit of the intervention in terms of clinical risk reduction has been well documented in trials of statins, ezetimibe, and other LDL cholesterol–lowering therapies,” they wrote. “Likewise, in FOURIER, the magnitude of the risk reduction with regard to the key secondary end point appeared to grow over time, from 16% during the first year to 25% beyond 12 months, which suggests that the translation of reductions in LDL cholesterol levels into cardiovascular clinical benefit requires time.”

“With this trial, we now have definitive data that by adding evolocumab to a background of statin therapy, we can significantly improve cardiovascular outcomes and do so safely,” Marc S. Sabatine, MD, MPH, chair in Cardiovascular Medicine at Brigham and Women’s Hospital in Boston, chair of the Thrombolysis in Myocardial Infarction (TIMI) study group, and the study’s lead author, in a statement. “I think these results are very good news for patients with atherosclerotic disease, who remain at high risk for these events.”

Researchers enrolled 27,564 patients with preexisting CV disease between February 2013 and June 2015 at 1272 sites in 49 countries. Most (81%) had a history of heart attack, while 19% had suffered an ischemic stroke. The average age was 63 years and ranged from 40 to 85 years of age. Of the group, 75% were men. The median baseline LDL cholesterol was 92 mg/dL. To be included, patients had to have an LDL-C ≥70 mg/dL or a non–high density lipoprotein cholesterol ≥100 mg/dL (total cholesterol minus high-density lipoprotein cholesterol to accommodate for other sized cholesterol particles) and be on optimized statin therapy.

The primary endpoint occurred in 11.3% of the placebo group and 9.8% of the evolocumab group.  Overall, 74 patients would need to be treated over a period of 2 years to prevent a cardiovascular death, myocardial infarction, or stroke.

Reductions in the primary and key secondary endpoints were consistent across all key subgroups, including age, sex, and different doses of background statin therapy as well as evolocumab itself. Patients can take injections of 140 mg every 2 weeks or 420 mg once a month.

As he has in the past, Sabatine emphasized the very low LDL cholesterol levels some patients were able to achieve. Those who started at the lowest quartile, 74 mg/dL, reduced their LDL cholesterol to 22 mg/dL, yet there was no difference in the rate of side effects between the 2 study arms.

“We’ve never been able to plumb these depths before. These data strongly suggest that patients benefit from lowering LDL cholesterol well below current targets,” Sabatine said.

Reference
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease [published online March 17, 2017]. N Engl J Med. 2017; DOI: 10.1056/NEJMoa1615664